EVIDENCE SUMMARY

A 2017 meta-analysis of 4 RCTs (869 patients) evaluated the effectiveness of prescribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).¹ All 4 trials compared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were systolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor.

Spironolactone markedly lowers systolic and diastolic BP

A statistically significant reduction in SBP occurred in the spironolactone group compared with the placebo group (weighted mean difference [WMD] = −16.7 mm Hg; 95% confidence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg).

Because significant heterogeneity was found in the initial pooled results (I² = 96% for SBP; I² = 85% for DBP), investigators performed an analysis that excluded a single study with a small sample size. The re-analysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I² = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.

Add-on treatment with spironolactone also reduces BP

A 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, including one diuretic.² Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs.

The 24-hour ambulatory BPs were significantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). No significant heterogeneity was noted in these analyses.

Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I² = 94% for SBP and 84.2% for DBP), 2 studies determined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically significant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Heterogeneity also decreased when the 2 studies were excluded (I² = 21% for SBP and I² = 59% for DBP).

How spironolactone compares with alternative drugs

A 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spironolactone (25-50 mg/d) on resistant hypertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (candesartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.³ Follow-up periods ranged from 4 to 16 weeks. Researchers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spironolactone compared with placebo groups, and spironolactone compared with alternative treatment groups.

Continue to: Investigators found a statistically significant...

Investigators found a statistically significant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg).

Spironolactone reduces systolic blood pressure by 11 to 17 mm Hg and diastolic blood pressure by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications.

Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically relevant than decreases in DBP.

RECOMMENDATIONS

The 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hypertension when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihypertensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; reversible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.⁴

The United Kingdom’s National Institute for Health and Care Excellence (NICE) evidence-based guideline recommends considering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potassium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.⁵

Editor’s takeaway

The evidence from multiple RCTs convincingly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pressure goals, and therefore, spironolactone is a good option.

EVIDENCE SUMMARY

A 2017 meta-analysis of 4 RCTs (869 patients) evaluated the effectiveness of prescribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).¹ All 4 trials compared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were systolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor.

Spironolactone markedly lowers systolic and diastolic BP

A statistically significant reduction in SBP occurred in the spironolactone group compared with the placebo group (weighted mean difference [WMD] = −16.7 mm Hg; 95% confidence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg).

Because significant heterogeneity was found in the initial pooled results (I² = 96% for SBP; I² = 85% for DBP), investigators performed an analysis that excluded a single study with a small sample size. The re-analysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I² = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.

Add-on treatment with spironolactone also reduces BP

A 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, including one diuretic.² Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs.

The 24-hour ambulatory BPs were significantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). No significant heterogeneity was noted in these analyses.

Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I² = 94% for SBP and 84.2% for DBP), 2 studies determined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically significant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Heterogeneity also decreased when the 2 studies were excluded (I² = 21% for SBP and I² = 59% for DBP).

How spironolactone compares with alternative drugs

A 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spironolactone (25-50 mg/d) on resistant hypertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (candesartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.³ Follow-up periods ranged from 4 to 16 weeks. Researchers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spironolactone compared with placebo groups, and spironolactone compared with alternative treatment groups.

Continue to: Investigators found a statistically significant...

Investigators found a statistically significant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg).

Spironolactone reduces systolic blood pressure by 11 to 17 mm Hg and diastolic blood pressure by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications.

Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically relevant than decreases in DBP.

RECOMMENDATIONS

The 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hypertension when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihypertensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; reversible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.⁴

The United Kingdom’s National Institute for Health and Care Excellence (NICE) evidence-based guideline recommends considering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potassium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.⁵

Editor’s takeaway

The evidence from multiple RCTs convincingly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pressure goals, and therefore, spironolactone is a good option.

EVIDENCE SUMMARY

A 2017 meta-analysis of 4 RCTs (869 patients) evaluated the effectiveness of prescribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).¹ All 4 trials compared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were systolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor.

Spironolactone markedly lowers systolic and diastolic BP

A statistically significant reduction in SBP occurred in the spironolactone group compared with the placebo group (weighted mean difference [WMD] = −16.7 mm Hg; 95% confidence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg).

Because significant heterogeneity was found in the initial pooled results (I² = 96% for SBP; I² = 85% for DBP), investigators performed an analysis that excluded a single study with a small sample size. The re-analysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I² = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.

Add-on treatment with spironolactone also reduces BP

A 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, including one diuretic.² Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs.

The 24-hour ambulatory BPs were significantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). No significant heterogeneity was noted in these analyses.

Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I² = 94% for SBP and 84.2% for DBP), 2 studies determined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically significant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Heterogeneity also decreased when the 2 studies were excluded (I² = 21% for SBP and I² = 59% for DBP).

How spironolactone compares with alternative drugs

A 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spironolactone (25-50 mg/d) on resistant hypertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (candesartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.³ Follow-up periods ranged from 4 to 16 weeks. Researchers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spironolactone compared with placebo groups, and spironolactone compared with alternative treatment groups.

Continue to: Investigators found a statistically significant...

Investigators found a statistically significant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg).

Spironolactone reduces systolic blood pressure by 11 to 17 mm Hg and diastolic blood pressure by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications.

Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically relevant than decreases in DBP.

RECOMMENDATIONS

The 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hypertension when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihypertensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; reversible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.⁴

The United Kingdom’s National Institute for Health and Care Excellence (NICE) evidence-based guideline recommends considering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potassium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.⁵

Editor’s takeaway

The evidence from multiple RCTs convincingly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pressure goals, and therefore, spironolactone is a good option.

THE CASE

A 4-year-old girl presented to her pediatrician with genital discomfort and dysuria of 6 months’ duration. The patient’s mother said that 3 days earlier, she noticed a tear near the child’s clitoris and a scab on the labia minora that the mother attributed to minor trauma from scratching. The pediatrician was concerned about genital trauma from sexual abuse and referred the patient to the emergency department, where a report with child protective services (CPS) was filed. The mother reported that the patient and her 8-year-old sibling spent 3 to 4 hours a day with a babysitter, who was always supervised, and the parents had no concerns about possible sexual abuse.

Physical examination by our institution’s Child Protection Team revealed clitoral hood swelling with subepithelial hemorrhages, a blood blister on the right labia minora, a fissure and subepithelial hemorrhages on the posterior fourchette, and a thin depigmented figure-of-eight lesion around the vulva and anus.

THE DIAGNOSIS

Since the clinical findings were consistent with prepubertal lichen sclerosus (LS), the CPS case was closed and the patient was referred to Pediatric Gynecology. Treatment with high-potency topical steroids was initiated with clobetasol ointment 0.05% twice daily for 2 weeks, then once daily for 2 weeks. She was then switched to triamcinolone ointment 0.01% twice daily for 2 weeks, then once daily for 2 weeks. These treatments were enough to stop the LS flare and decrease the anogenital itching.

DISCUSSION

Lichen sclerosus is a chronic inflammatory skin disease that primarily presents in the anogenital region; however, extragenital lesions on the upper extremities, thighs, and breasts have been reported in 15% to 20% of patients.¹ Lichen sclerosus most commonly affects females as a result of low estrogen and may occur during puberty or following menopause, but it also is seen in males.^1,2 The estimated prevalence of LS in prepubertal girls is 1 in 900.³ The effects of increased estrogen exposure on LS during puberty are not entirely clear. Lichen sclerosus previously was thought to improve with puberty, since it is not as common in women of reproductive age; however, studies have shown persistent symptoms after menarche in some patients.^4-6

The pathogenesis of LS is multifactorial, likely with an autoimmune component, as it often is associated with other autoimmune findings such as thyroiditis, alopecia, pernicious anemia, and vitiligo.² Diagnosis of prepubertal LS usually is made based on a review of the patient’s history and clinical examination. Presenting symptoms may include pruritus, skin irritation, vulvar pain, dysuria, bleeding from excoriations, fissures, and constipation.^1,3,7

On physical examination, LS can present on the anogenital skin as smooth white spots or wrinkled, blotchy, atrophic patches. The skin around the vaginal opening and anus is thin and often is described as resembling parchment or cigarette paper in a figure-of-eight pattern (FIGURE 1A). Vulvar and anal fissures and subepithelial hemorrhages with the appearance of blood blisters also can be found (FIGURE 1B).⁸ Affected areas are fragile and susceptible to minor trauma, which may result in bruising or bleeding (FIGURE 1C).

Over time, scarring can occur and may result in disruption of the anogenital architecture—specifically loss of the labia minora, narrowing of the introitus, and burying of the clitoris.^1,2 These changes can be similar to the scarring seen in postmenopausal women with LS.

Continue to: The differential diagnosis...

The differential diagnosis for prepubertal LS includes vitiligo, lichen planus, lichen simplex chronicus, psoriasis, eczema, vulvovaginitis, contact dermatitis, and trauma.^2,7 On average, it takes 1 to 2 years after onset of symptoms before a correct diagnosis of prepubertal LS is made, and trauma and/or sexual abuse often are first suspected.^7,9 For clinicians who are unfamiliar with prepubertal LS, the clinical findings of anogenital bruising and bleeding understandably may be suggestive of abuse. It is important to note that diagnosis of LS does not preclude the possibility of sexual abuse; in some cases, LS can be triggered or exacerbated by anogenital trauma, known as the Koebner phenomenon.²

Treatment. After the diagnosis of prepubertal LS is established, the goals of treatment are to provide symptom relief and prevent scarring of the external genitalia. To our knowledge, there have been no randomized controlled trials for treatment of LS in prepubertal girls. In general, acute symptoms are treated with high-potency topical steroids, such as clobetasol propionate or betamethasone valerate, and treatment regimens are variable.⁷

LS has an unpredictable clinical course and there often are recurrences that require repeat courses of topical steroids.⁹ Since concurrent bacterial infection is common,¹⁰ genital cultures should be obtained prior to initiation of topical steroids if an infection is suspected.

Diagnosis of lichen sclerosus should not preclude screening for sexual abuse, as symptoms can be triggered or exacerbated by trauma to the area.

Topical calcineurin inhibitors have been used successfully, but proof of their effectiveness is limited to case reports in the literature.⁷ Surgical treatment of LS typically is reserved for complications associated with symptomatic adhesions that are refractory to medical management.^7,11 Vulvar hygiene is paramount to symptom control, and topical emollients can be used to manage minor irritation.^7,8 In our patient, clobetasol and triamcinolone ointments were enough to stop the LS flare and decrease the anogenital itching.

THE TAKEAWAY

Although LS has very characteristic skin findings, the diagnosis continues to be challenging for physicians who are unfamiliar with this condition. Failure to recognize prepubertal LS not only delays diagnosis and treatment but also may lead to repeated genital examinations and investigation by CPS for suspected sexual abuse. As with any genital complaint in a prepubertal girl, diagnosis of LS should not preclude appropriate screening for sexual abuse. Although providers should be vigilant about potential sexual abuse, familiarity with skin conditions that mimic genital trauma is essential.

CORRESPONDENCE
Monica Rosen, MD, L4000 Women’s Hospital, 1500 E Medical Center Drive, SPC 5276 Ann Arbor, MI 48109; [email protected]

THE CASE

A 4-year-old girl presented to her pediatrician with genital discomfort and dysuria of 6 months’ duration. The patient’s mother said that 3 days earlier, she noticed a tear near the child’s clitoris and a scab on the labia minora that the mother attributed to minor trauma from scratching. The pediatrician was concerned about genital trauma from sexual abuse and referred the patient to the emergency department, where a report with child protective services (CPS) was filed. The mother reported that the patient and her 8-year-old sibling spent 3 to 4 hours a day with a babysitter, who was always supervised, and the parents had no concerns about possible sexual abuse.

Physical examination by our institution’s Child Protection Team revealed clitoral hood swelling with subepithelial hemorrhages, a blood blister on the right labia minora, a fissure and subepithelial hemorrhages on the posterior fourchette, and a thin depigmented figure-of-eight lesion around the vulva and anus.

THE DIAGNOSIS

Since the clinical findings were consistent with prepubertal lichen sclerosus (LS), the CPS case was closed and the patient was referred to Pediatric Gynecology. Treatment with high-potency topical steroids was initiated with clobetasol ointment 0.05% twice daily for 2 weeks, then once daily for 2 weeks. She was then switched to triamcinolone ointment 0.01% twice daily for 2 weeks, then once daily for 2 weeks. These treatments were enough to stop the LS flare and decrease the anogenital itching.

DISCUSSION

Lichen sclerosus is a chronic inflammatory skin disease that primarily presents in the anogenital region; however, extragenital lesions on the upper extremities, thighs, and breasts have been reported in 15% to 20% of patients.¹ Lichen sclerosus most commonly affects females as a result of low estrogen and may occur during puberty or following menopause, but it also is seen in males.^1,2 The estimated prevalence of LS in prepubertal girls is 1 in 900.³ The effects of increased estrogen exposure on LS during puberty are not entirely clear. Lichen sclerosus previously was thought to improve with puberty, since it is not as common in women of reproductive age; however, studies have shown persistent symptoms after menarche in some patients.^4-6

The pathogenesis of LS is multifactorial, likely with an autoimmune component, as it often is associated with other autoimmune findings such as thyroiditis, alopecia, pernicious anemia, and vitiligo.² Diagnosis of prepubertal LS usually is made based on a review of the patient’s history and clinical examination. Presenting symptoms may include pruritus, skin irritation, vulvar pain, dysuria, bleeding from excoriations, fissures, and constipation.^1,3,7

On physical examination, LS can present on the anogenital skin as smooth white spots or wrinkled, blotchy, atrophic patches. The skin around the vaginal opening and anus is thin and often is described as resembling parchment or cigarette paper in a figure-of-eight pattern (FIGURE 1A). Vulvar and anal fissures and subepithelial hemorrhages with the appearance of blood blisters also can be found (FIGURE 1B).⁸ Affected areas are fragile and susceptible to minor trauma, which may result in bruising or bleeding (FIGURE 1C).

Over time, scarring can occur and may result in disruption of the anogenital architecture—specifically loss of the labia minora, narrowing of the introitus, and burying of the clitoris.^1,2 These changes can be similar to the scarring seen in postmenopausal women with LS.

Continue to: The differential diagnosis...

The differential diagnosis for prepubertal LS includes vitiligo, lichen planus, lichen simplex chronicus, psoriasis, eczema, vulvovaginitis, contact dermatitis, and trauma.^2,7 On average, it takes 1 to 2 years after onset of symptoms before a correct diagnosis of prepubertal LS is made, and trauma and/or sexual abuse often are first suspected.^7,9 For clinicians who are unfamiliar with prepubertal LS, the clinical findings of anogenital bruising and bleeding understandably may be suggestive of abuse. It is important to note that diagnosis of LS does not preclude the possibility of sexual abuse; in some cases, LS can be triggered or exacerbated by anogenital trauma, known as the Koebner phenomenon.²

Treatment. After the diagnosis of prepubertal LS is established, the goals of treatment are to provide symptom relief and prevent scarring of the external genitalia. To our knowledge, there have been no randomized controlled trials for treatment of LS in prepubertal girls. In general, acute symptoms are treated with high-potency topical steroids, such as clobetasol propionate or betamethasone valerate, and treatment regimens are variable.⁷

LS has an unpredictable clinical course and there often are recurrences that require repeat courses of topical steroids.⁹ Since concurrent bacterial infection is common,¹⁰ genital cultures should be obtained prior to initiation of topical steroids if an infection is suspected.

Diagnosis of lichen sclerosus should not preclude screening for sexual abuse, as symptoms can be triggered or exacerbated by trauma to the area.

Topical calcineurin inhibitors have been used successfully, but proof of their effectiveness is limited to case reports in the literature.⁷ Surgical treatment of LS typically is reserved for complications associated with symptomatic adhesions that are refractory to medical management.^7,11 Vulvar hygiene is paramount to symptom control, and topical emollients can be used to manage minor irritation.^7,8 In our patient, clobetasol and triamcinolone ointments were enough to stop the LS flare and decrease the anogenital itching.

THE TAKEAWAY

Although LS has very characteristic skin findings, the diagnosis continues to be challenging for physicians who are unfamiliar with this condition. Failure to recognize prepubertal LS not only delays diagnosis and treatment but also may lead to repeated genital examinations and investigation by CPS for suspected sexual abuse. As with any genital complaint in a prepubertal girl, diagnosis of LS should not preclude appropriate screening for sexual abuse. Although providers should be vigilant about potential sexual abuse, familiarity with skin conditions that mimic genital trauma is essential.

CORRESPONDENCE
Monica Rosen, MD, L4000 Women’s Hospital, 1500 E Medical Center Drive, SPC 5276 Ann Arbor, MI 48109; [email protected]

THE CASE

A 4-year-old girl presented to her pediatrician with genital discomfort and dysuria of 6 months’ duration. The patient’s mother said that 3 days earlier, she noticed a tear near the child’s clitoris and a scab on the labia minora that the mother attributed to minor trauma from scratching. The pediatrician was concerned about genital trauma from sexual abuse and referred the patient to the emergency department, where a report with child protective services (CPS) was filed. The mother reported that the patient and her 8-year-old sibling spent 3 to 4 hours a day with a babysitter, who was always supervised, and the parents had no concerns about possible sexual abuse.

Physical examination by our institution’s Child Protection Team revealed clitoral hood swelling with subepithelial hemorrhages, a blood blister on the right labia minora, a fissure and subepithelial hemorrhages on the posterior fourchette, and a thin depigmented figure-of-eight lesion around the vulva and anus.

THE DIAGNOSIS

Since the clinical findings were consistent with prepubertal lichen sclerosus (LS), the CPS case was closed and the patient was referred to Pediatric Gynecology. Treatment with high-potency topical steroids was initiated with clobetasol ointment 0.05% twice daily for 2 weeks, then once daily for 2 weeks. She was then switched to triamcinolone ointment 0.01% twice daily for 2 weeks, then once daily for 2 weeks. These treatments were enough to stop the LS flare and decrease the anogenital itching.

DISCUSSION

Lichen sclerosus is a chronic inflammatory skin disease that primarily presents in the anogenital region; however, extragenital lesions on the upper extremities, thighs, and breasts have been reported in 15% to 20% of patients.¹ Lichen sclerosus most commonly affects females as a result of low estrogen and may occur during puberty or following menopause, but it also is seen in males.^1,2 The estimated prevalence of LS in prepubertal girls is 1 in 900.³ The effects of increased estrogen exposure on LS during puberty are not entirely clear. Lichen sclerosus previously was thought to improve with puberty, since it is not as common in women of reproductive age; however, studies have shown persistent symptoms after menarche in some patients.^4-6

The pathogenesis of LS is multifactorial, likely with an autoimmune component, as it often is associated with other autoimmune findings such as thyroiditis, alopecia, pernicious anemia, and vitiligo.² Diagnosis of prepubertal LS usually is made based on a review of the patient’s history and clinical examination. Presenting symptoms may include pruritus, skin irritation, vulvar pain, dysuria, bleeding from excoriations, fissures, and constipation.^1,3,7

On physical examination, LS can present on the anogenital skin as smooth white spots or wrinkled, blotchy, atrophic patches. The skin around the vaginal opening and anus is thin and often is described as resembling parchment or cigarette paper in a figure-of-eight pattern (FIGURE 1A). Vulvar and anal fissures and subepithelial hemorrhages with the appearance of blood blisters also can be found (FIGURE 1B).⁸ Affected areas are fragile and susceptible to minor trauma, which may result in bruising or bleeding (FIGURE 1C).

Over time, scarring can occur and may result in disruption of the anogenital architecture—specifically loss of the labia minora, narrowing of the introitus, and burying of the clitoris.^1,2 These changes can be similar to the scarring seen in postmenopausal women with LS.

Continue to: The differential diagnosis...

The differential diagnosis for prepubertal LS includes vitiligo, lichen planus, lichen simplex chronicus, psoriasis, eczema, vulvovaginitis, contact dermatitis, and trauma.^2,7 On average, it takes 1 to 2 years after onset of symptoms before a correct diagnosis of prepubertal LS is made, and trauma and/or sexual abuse often are first suspected.^7,9 For clinicians who are unfamiliar with prepubertal LS, the clinical findings of anogenital bruising and bleeding understandably may be suggestive of abuse. It is important to note that diagnosis of LS does not preclude the possibility of sexual abuse; in some cases, LS can be triggered or exacerbated by anogenital trauma, known as the Koebner phenomenon.²

Treatment. After the diagnosis of prepubertal LS is established, the goals of treatment are to provide symptom relief and prevent scarring of the external genitalia. To our knowledge, there have been no randomized controlled trials for treatment of LS in prepubertal girls. In general, acute symptoms are treated with high-potency topical steroids, such as clobetasol propionate or betamethasone valerate, and treatment regimens are variable.⁷

LS has an unpredictable clinical course and there often are recurrences that require repeat courses of topical steroids.⁹ Since concurrent bacterial infection is common,¹⁰ genital cultures should be obtained prior to initiation of topical steroids if an infection is suspected.

Diagnosis of lichen sclerosus should not preclude screening for sexual abuse, as symptoms can be triggered or exacerbated by trauma to the area.

Topical calcineurin inhibitors have been used successfully, but proof of their effectiveness is limited to case reports in the literature.⁷ Surgical treatment of LS typically is reserved for complications associated with symptomatic adhesions that are refractory to medical management.^7,11 Vulvar hygiene is paramount to symptom control, and topical emollients can be used to manage minor irritation.^7,8 In our patient, clobetasol and triamcinolone ointments were enough to stop the LS flare and decrease the anogenital itching.

THE TAKEAWAY

Although LS has very characteristic skin findings, the diagnosis continues to be challenging for physicians who are unfamiliar with this condition. Failure to recognize prepubertal LS not only delays diagnosis and treatment but also may lead to repeated genital examinations and investigation by CPS for suspected sexual abuse. As with any genital complaint in a prepubertal girl, diagnosis of LS should not preclude appropriate screening for sexual abuse. Although providers should be vigilant about potential sexual abuse, familiarity with skin conditions that mimic genital trauma is essential.

CORRESPONDENCE
Monica Rosen, MD, L4000 Women’s Hospital, 1500 E Medical Center Drive, SPC 5276 Ann Arbor, MI 48109; [email protected]

In this issue of JFP, Rajesh and colleagues present a scholarly review that details why it makes sense to integrate behavioral health into primary care. There is strong evidence that the presence of behavioral health care managers in primary care practices improves outcomes for patients with anxiety and depression. The mental health–trained care manager serves as a link between the primary care physician and mental health professional and can provide psychotherapy, as well.

A more integrated model, however, includes a full range of behavioral health services on site. Although not as well studied, co-location is a powerful pairing of physical and mental health treatment. Primary care physicians benefit because referral and feedback are immediate and seamless through warm hand-offs and easy access to medical and mental health notes in a common medical record. Patients benefit because they are more likely to engage with treatment when the physician introduces them to the mental health professional and expresses confidence in his or her abilities.

Patients are more likely to engage with treatment when the physician introduces them to the mental health professional and expresses confidence in his or her abilities.

We know that trust improves treatment outcomes. What better way to encourage trust than with a warm smile and handshake when a patient is most vulnerable? In addition, integrating behavioral health into primary care helps patients avoid the stigma of going to a “mental health clinic.”

Integrating medical and mental health professionals into one practice is hardly a new idea and is spreading quickly in some parts of the country. It is perhaps no coincidence that Rajesh refers to a study of behavioral health integration in Colorado family practice offices. Recently, I (JH) presented a CME program to family physicians in Colorado, and, after reviewing recent studies of anxiety and depression, I asked how many participants had mental health professionals working in their practices. A full third raised their hands.

I (JH) had an excellent psychologist in my practice as far back as 1980, and he was an integral member of the care team. It seems that behavioral health integration has been a long time coming, and as a health care community we would be wise to spread this model of whole-person care to all primary care practices.

In this issue of JFP, Rajesh and colleagues present a scholarly review that details why it makes sense to integrate behavioral health into primary care. There is strong evidence that the presence of behavioral health care managers in primary care practices improves outcomes for patients with anxiety and depression. The mental health–trained care manager serves as a link between the primary care physician and mental health professional and can provide psychotherapy, as well.

A more integrated model, however, includes a full range of behavioral health services on site. Although not as well studied, co-location is a powerful pairing of physical and mental health treatment. Primary care physicians benefit because referral and feedback are immediate and seamless through warm hand-offs and easy access to medical and mental health notes in a common medical record. Patients benefit because they are more likely to engage with treatment when the physician introduces them to the mental health professional and expresses confidence in his or her abilities.

Patients are more likely to engage with treatment when the physician introduces them to the mental health professional and expresses confidence in his or her abilities.

We know that trust improves treatment outcomes. What better way to encourage trust than with a warm smile and handshake when a patient is most vulnerable? In addition, integrating behavioral health into primary care helps patients avoid the stigma of going to a “mental health clinic.”

Integrating medical and mental health professionals into one practice is hardly a new idea and is spreading quickly in some parts of the country. It is perhaps no coincidence that Rajesh refers to a study of behavioral health integration in Colorado family practice offices. Recently, I (JH) presented a CME program to family physicians in Colorado, and, after reviewing recent studies of anxiety and depression, I asked how many participants had mental health professionals working in their practices. A full third raised their hands.

I (JH) had an excellent psychologist in my practice as far back as 1980, and he was an integral member of the care team. It seems that behavioral health integration has been a long time coming, and as a health care community we would be wise to spread this model of whole-person care to all primary care practices.

In this issue of JFP, Rajesh and colleagues present a scholarly review that details why it makes sense to integrate behavioral health into primary care. There is strong evidence that the presence of behavioral health care managers in primary care practices improves outcomes for patients with anxiety and depression. The mental health–trained care manager serves as a link between the primary care physician and mental health professional and can provide psychotherapy, as well.

A more integrated model, however, includes a full range of behavioral health services on site. Although not as well studied, co-location is a powerful pairing of physical and mental health treatment. Primary care physicians benefit because referral and feedback are immediate and seamless through warm hand-offs and easy access to medical and mental health notes in a common medical record. Patients benefit because they are more likely to engage with treatment when the physician introduces them to the mental health professional and expresses confidence in his or her abilities.

Patients are more likely to engage with treatment when the physician introduces them to the mental health professional and expresses confidence in his or her abilities.

We know that trust improves treatment outcomes. What better way to encourage trust than with a warm smile and handshake when a patient is most vulnerable? In addition, integrating behavioral health into primary care helps patients avoid the stigma of going to a “mental health clinic.”

Integrating medical and mental health professionals into one practice is hardly a new idea and is spreading quickly in some parts of the country. It is perhaps no coincidence that Rajesh refers to a study of behavioral health integration in Colorado family practice offices. Recently, I (JH) presented a CME program to family physicians in Colorado, and, after reviewing recent studies of anxiety and depression, I asked how many participants had mental health professionals working in their practices. A full third raised their hands.

I (JH) had an excellent psychologist in my practice as far back as 1980, and he was an integral member of the care team. It seems that behavioral health integration has been a long time coming, and as a health care community we would be wise to spread this model of whole-person care to all primary care practices.

A 97-year-old woman with a history of atrial fibrillation and nonmelanoma skin cancer presented to our clinic from an assisted living facility with a several-month history of rapidly growing forehead lesions. She denied symptoms, other than some bleeding and crusting, but was concerned about their appearance. She reported a notable history of sun exposure.

The patient had 3 confluent, but distinct, lesions on her forehead: an erythematous crateriform nodule with overlying hyperkeratotic scale (FIGURE, Lesion A); a nodular hyperpigmented plaque with irregular color and borders (Lesion B); and a pearly well-vascularized erythematous nodule with surrounding hemorrhagic crust (Lesion C).

She also had scattered, thin, gritty pink papules and plaques on the face that were thought to be actinic keratosis and nonmelanoma skin cancers based on clinical morphology; however, the patient deferred workup and treatment of these lesions to focus on the forehead lesions. The decision was made to biopsy all 3 clinical morphologies seen. The risks and benefits of biopsy were reviewed with the patient and her daughter, and they opted to proceed. The areas were anesthetized with an injection of 1% lidocaine and epinephrine 1:100,000; 3 shave biopsies were performed. Hemostasis was obtained with electrodesiccation.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A histopathology report revealed that Lesion A was squamous cell carcinoma (SCC), Lesion B was a melanoma with a Breslow depth of at least 1.2 mm, and Lesion C was basal cell carcinoma (BCC). It is unusual to have a patient present with BCC, SCC, and melanoma concurrently in the same anatomic region.

Two of the lesions were nonmelanoma skin cancers (NMSC). BCC is the most common NMSC in the United States, affecting more than 3.3 million people per year.¹ Although there are several subtypes of BCC with varying clinical presentations, the most classic appearance is a pearly papule with or without surface telangiectasias.²

The findings in this case serve as an important reminder to biopsy lesions with varying morphologies even when they are in close proximity to one another.

SCC has an incidence of 200,000 to 400,000 cases per year in the United States and the lifetime risk is 9% to 14% in men and 4% to 9% in women.³ SCC most commonly presents as a hyperkeratotic papule or plaque.² Lesions suspicious for SCC and BCC should be biopsied and the diagnosis confirmed by histopathologic analysis. These NMSCs are locally destructive, but rarely metastatic with a generally good prognosis. The standard treatment for both is surgical excision with consideration for other treatment modalities, such as topical therapies, chemotherapy, and radiation, depending on tumor characteristics as well as whether the patient is a good surgical candidate.^1,3

Melanoma is rising in incidence each year, with nearly 100,000 new cases expected in the United States this year.⁴ It is the leading cause of skin cancer related mortality.⁵ The most common suspicious lesions are variably pigmented macules with irregular borders. Biopsy and subsequent histopathologic analysis will confirm the diagnosis.

When a lesion is clinically suspicious for melanoma, it is particularly important to consider an excisional biopsy to allow for proper staging.⁵ Examples of appropriate excisional biopsies include elliptical excisions, punch biopsies, and deep shave biopsies.⁵ Definitive treatment involves a wider and deeper excision with histologically confirmed clear margins.⁵

Continue to: This case required a multidisciplinary team

This case required a multidisciplinary team

The patient underwent magnetic resonance imaging and positron emission tomography/computed tomography; the scans revealed no metastatic disease. She was evaluated by a multidisciplinary head and neck cancer team, and various treatment options were explored. Resection typically is the definitive treatment for localized cutaneous melanoma; however, given the configuration of the lesions, it was deemed impractical to resect this patient’s melanoma and not the other lesions. Radiotherapy can be effective for BCC and SCC, but it is traditionally not as effective for melanoma.⁶ The options presented to the patient were radiotherapy or surgical resection to all 3 lesions, and she decided to pursue resection.

The patient was cleared for surgery; however, after the patient held her warfarin in preparation for the resection, she suffered a left frontal operculum infarction. At this point, she was re-evaluated by her head and neck physician, cardiologist, and anesthesiologist. Consensus was reached that the patient was at high perioperative risk for morbidity and mortality, and surgical intervention was no longer considered a viable option.

The patient then opted for palliative radiation therapy to all 3 lesions, with the understanding that the local control offered by radiotherapy would be inferior to what resection would provide for the melanoma lesion. Although not curative, radiotherapy was expected to provide local symptom relief for the melanoma, consistent with the patient’s palliative goals of care. In the past, melanoma was thought to be resistant to radiation, but recent evidence suggests that it may be at least partially susceptible to hypofractionated courses of radiation.⁶

Radiation oncology recommended a 6 to 15 fraction regimen and she had a good clinical response with > 50% decrease in the size of all 3 lesions along with cessation of bleeding.

The take-home lesson. The findings in this case serve as an important reminder to biopsy lesions with varying morphologies—even when they are in close proximity to one another. Foregoing any of the biopsies in this case would have led to a missed diagnosis, which has implications for optimal management and treatment.

CORRESPONDENCE
Jennifer L. Hsiao, MD, 2020 Santa Monica Boulevard, Suite 510, Santa Monica, CA 90404; [email protected]

A 97-year-old woman with a history of atrial fibrillation and nonmelanoma skin cancer presented to our clinic from an assisted living facility with a several-month history of rapidly growing forehead lesions. She denied symptoms, other than some bleeding and crusting, but was concerned about their appearance. She reported a notable history of sun exposure.

The patient had 3 confluent, but distinct, lesions on her forehead: an erythematous crateriform nodule with overlying hyperkeratotic scale (FIGURE, Lesion A); a nodular hyperpigmented plaque with irregular color and borders (Lesion B); and a pearly well-vascularized erythematous nodule with surrounding hemorrhagic crust (Lesion C).

She also had scattered, thin, gritty pink papules and plaques on the face that were thought to be actinic keratosis and nonmelanoma skin cancers based on clinical morphology; however, the patient deferred workup and treatment of these lesions to focus on the forehead lesions. The decision was made to biopsy all 3 clinical morphologies seen. The risks and benefits of biopsy were reviewed with the patient and her daughter, and they opted to proceed. The areas were anesthetized with an injection of 1% lidocaine and epinephrine 1:100,000; 3 shave biopsies were performed. Hemostasis was obtained with electrodesiccation.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A histopathology report revealed that Lesion A was squamous cell carcinoma (SCC), Lesion B was a melanoma with a Breslow depth of at least 1.2 mm, and Lesion C was basal cell carcinoma (BCC). It is unusual to have a patient present with BCC, SCC, and melanoma concurrently in the same anatomic region.

Two of the lesions were nonmelanoma skin cancers (NMSC). BCC is the most common NMSC in the United States, affecting more than 3.3 million people per year.¹ Although there are several subtypes of BCC with varying clinical presentations, the most classic appearance is a pearly papule with or without surface telangiectasias.²

The findings in this case serve as an important reminder to biopsy lesions with varying morphologies even when they are in close proximity to one another.

SCC has an incidence of 200,000 to 400,000 cases per year in the United States and the lifetime risk is 9% to 14% in men and 4% to 9% in women.³ SCC most commonly presents as a hyperkeratotic papule or plaque.² Lesions suspicious for SCC and BCC should be biopsied and the diagnosis confirmed by histopathologic analysis. These NMSCs are locally destructive, but rarely metastatic with a generally good prognosis. The standard treatment for both is surgical excision with consideration for other treatment modalities, such as topical therapies, chemotherapy, and radiation, depending on tumor characteristics as well as whether the patient is a good surgical candidate.^1,3

Melanoma is rising in incidence each year, with nearly 100,000 new cases expected in the United States this year.⁴ It is the leading cause of skin cancer related mortality.⁵ The most common suspicious lesions are variably pigmented macules with irregular borders. Biopsy and subsequent histopathologic analysis will confirm the diagnosis.

When a lesion is clinically suspicious for melanoma, it is particularly important to consider an excisional biopsy to allow for proper staging.⁵ Examples of appropriate excisional biopsies include elliptical excisions, punch biopsies, and deep shave biopsies.⁵ Definitive treatment involves a wider and deeper excision with histologically confirmed clear margins.⁵

Continue to: This case required a multidisciplinary team

This case required a multidisciplinary team

The patient underwent magnetic resonance imaging and positron emission tomography/computed tomography; the scans revealed no metastatic disease. She was evaluated by a multidisciplinary head and neck cancer team, and various treatment options were explored. Resection typically is the definitive treatment for localized cutaneous melanoma; however, given the configuration of the lesions, it was deemed impractical to resect this patient’s melanoma and not the other lesions. Radiotherapy can be effective for BCC and SCC, but it is traditionally not as effective for melanoma.⁶ The options presented to the patient were radiotherapy or surgical resection to all 3 lesions, and she decided to pursue resection.

The patient was cleared for surgery; however, after the patient held her warfarin in preparation for the resection, she suffered a left frontal operculum infarction. At this point, she was re-evaluated by her head and neck physician, cardiologist, and anesthesiologist. Consensus was reached that the patient was at high perioperative risk for morbidity and mortality, and surgical intervention was no longer considered a viable option.

The patient then opted for palliative radiation therapy to all 3 lesions, with the understanding that the local control offered by radiotherapy would be inferior to what resection would provide for the melanoma lesion. Although not curative, radiotherapy was expected to provide local symptom relief for the melanoma, consistent with the patient’s palliative goals of care. In the past, melanoma was thought to be resistant to radiation, but recent evidence suggests that it may be at least partially susceptible to hypofractionated courses of radiation.⁶

Radiation oncology recommended a 6 to 15 fraction regimen and she had a good clinical response with > 50% decrease in the size of all 3 lesions along with cessation of bleeding.

The take-home lesson. The findings in this case serve as an important reminder to biopsy lesions with varying morphologies—even when they are in close proximity to one another. Foregoing any of the biopsies in this case would have led to a missed diagnosis, which has implications for optimal management and treatment.

CORRESPONDENCE
Jennifer L. Hsiao, MD, 2020 Santa Monica Boulevard, Suite 510, Santa Monica, CA 90404; [email protected]

A 97-year-old woman with a history of atrial fibrillation and nonmelanoma skin cancer presented to our clinic from an assisted living facility with a several-month history of rapidly growing forehead lesions. She denied symptoms, other than some bleeding and crusting, but was concerned about their appearance. She reported a notable history of sun exposure.

The patient had 3 confluent, but distinct, lesions on her forehead: an erythematous crateriform nodule with overlying hyperkeratotic scale (FIGURE, Lesion A); a nodular hyperpigmented plaque with irregular color and borders (Lesion B); and a pearly well-vascularized erythematous nodule with surrounding hemorrhagic crust (Lesion C).

She also had scattered, thin, gritty pink papules and plaques on the face that were thought to be actinic keratosis and nonmelanoma skin cancers based on clinical morphology; however, the patient deferred workup and treatment of these lesions to focus on the forehead lesions. The decision was made to biopsy all 3 clinical morphologies seen. The risks and benefits of biopsy were reviewed with the patient and her daughter, and they opted to proceed. The areas were anesthetized with an injection of 1% lidocaine and epinephrine 1:100,000; 3 shave biopsies were performed. Hemostasis was obtained with electrodesiccation.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

A histopathology report revealed that Lesion A was squamous cell carcinoma (SCC), Lesion B was a melanoma with a Breslow depth of at least 1.2 mm, and Lesion C was basal cell carcinoma (BCC). It is unusual to have a patient present with BCC, SCC, and melanoma concurrently in the same anatomic region.

Two of the lesions were nonmelanoma skin cancers (NMSC). BCC is the most common NMSC in the United States, affecting more than 3.3 million people per year.¹ Although there are several subtypes of BCC with varying clinical presentations, the most classic appearance is a pearly papule with or without surface telangiectasias.²

The findings in this case serve as an important reminder to biopsy lesions with varying morphologies even when they are in close proximity to one another.

SCC has an incidence of 200,000 to 400,000 cases per year in the United States and the lifetime risk is 9% to 14% in men and 4% to 9% in women.³ SCC most commonly presents as a hyperkeratotic papule or plaque.² Lesions suspicious for SCC and BCC should be biopsied and the diagnosis confirmed by histopathologic analysis. These NMSCs are locally destructive, but rarely metastatic with a generally good prognosis. The standard treatment for both is surgical excision with consideration for other treatment modalities, such as topical therapies, chemotherapy, and radiation, depending on tumor characteristics as well as whether the patient is a good surgical candidate.^1,3

Melanoma is rising in incidence each year, with nearly 100,000 new cases expected in the United States this year.⁴ It is the leading cause of skin cancer related mortality.⁵ The most common suspicious lesions are variably pigmented macules with irregular borders. Biopsy and subsequent histopathologic analysis will confirm the diagnosis.

When a lesion is clinically suspicious for melanoma, it is particularly important to consider an excisional biopsy to allow for proper staging.⁵ Examples of appropriate excisional biopsies include elliptical excisions, punch biopsies, and deep shave biopsies.⁵ Definitive treatment involves a wider and deeper excision with histologically confirmed clear margins.⁵

Continue to: This case required a multidisciplinary team

This case required a multidisciplinary team

The patient underwent magnetic resonance imaging and positron emission tomography/computed tomography; the scans revealed no metastatic disease. She was evaluated by a multidisciplinary head and neck cancer team, and various treatment options were explored. Resection typically is the definitive treatment for localized cutaneous melanoma; however, given the configuration of the lesions, it was deemed impractical to resect this patient’s melanoma and not the other lesions. Radiotherapy can be effective for BCC and SCC, but it is traditionally not as effective for melanoma.⁶ The options presented to the patient were radiotherapy or surgical resection to all 3 lesions, and she decided to pursue resection.

The patient was cleared for surgery; however, after the patient held her warfarin in preparation for the resection, she suffered a left frontal operculum infarction. At this point, she was re-evaluated by her head and neck physician, cardiologist, and anesthesiologist. Consensus was reached that the patient was at high perioperative risk for morbidity and mortality, and surgical intervention was no longer considered a viable option.

The patient then opted for palliative radiation therapy to all 3 lesions, with the understanding that the local control offered by radiotherapy would be inferior to what resection would provide for the melanoma lesion. Although not curative, radiotherapy was expected to provide local symptom relief for the melanoma, consistent with the patient’s palliative goals of care. In the past, melanoma was thought to be resistant to radiation, but recent evidence suggests that it may be at least partially susceptible to hypofractionated courses of radiation.⁶

Radiation oncology recommended a 6 to 15 fraction regimen and she had a good clinical response with > 50% decrease in the size of all 3 lesions along with cessation of bleeding.

The take-home lesson. The findings in this case serve as an important reminder to biopsy lesions with varying morphologies—even when they are in close proximity to one another. Foregoing any of the biopsies in this case would have led to a missed diagnosis, which has implications for optimal management and treatment.

CORRESPONDENCE
Jennifer L. Hsiao, MD, 2020 Santa Monica Boulevard, Suite 510, Santa Monica, CA 90404; [email protected]

CASE 1

Two days after reviving her boyfriend with naloxone, a woman and her 30-year-old boyfriend presented to our family medicine clinic. They explained that he had injected heroin and shortly thereafter he stopped breathing and his lips turned blue. The patient’s girlfriend did not call emergency medical services (EMS) at the time because she was afraid of getting arrested due to past incarceration for possession of illegal drugs. Instead, she revived him with naloxone that she found in his bag.

Both the patient and his girlfriend were scared and surprised by his “terrible reaction,” as he had previously purchased heroin from the same dealer and used the same dose without similar effects. However, the patient did note that the drug he purchased this time had a bright white tinge, when normally the drug was light yellow.

On physical examination, the patient’s heart rate and blood pressure were normal. There were needle track marks on both forearms, elbows, and upper arms. A laboratory workup obtained during this visit revealed anemia and a normal basic metabolic panel. A hepatitis C virus antibody test was positive, and a hepatic function panel revealed elevated transaminase levels. Urine toxicology was positive for opioids and negative for other substances.

CASE 2

A 58-year-old man with a history of chronic hepatitis C, polysubstance abuse, and schizophrenia was transported to the emergency department by EMS after his family found him unresponsive in his bedroom. The patient had agonal breathing when EMS arrived, so they administered naloxone (4 mg intranasal and 4 mg intravenous). His breathing improved, but his mental status did not. He was still obtunded upon arrival in the emergency department and vomited 4 tan-colored patches. The patient was tachycardic (heart rate, 108 beats/min), hypertensive (blood pressure, 189/95 mm Hg), and had rapid shallow breathing (respiratory rate, 38 breaths/min). He was intubated for airway protection, at which time 2 more tan-colored patches were removed from his pharynx.

Laboratory evaluation revealed an acute kidney injury with a high anion metabolic acidosis. A hepatic function panel showed elevated transaminase levels. Plasma acetaminophen and salicylate levels were normal. A computed tomography head scan was normal. Urine toxicology was negative for opioids but was positive for cocaine and benzodiazepines.

THE DIAGNOSIS

Opioid overdose caused the acute respiratory depression in both cases. In Case 1, the patient unknowingly overdosed on heroin laced with fentanyl, known as China White, which likely caused the drug’s bright white tinge. In Case 2, the patient’s overdose was the result of oral ingestion of fentanyl patches. (Limited urine toxicology was negative for opiates because fentanyl is a fully synthetic opioid that shows up only with a specific or extended assay. More on this in a bit.)

DISCUSSION

The fatal drug overdose epidemic in the United States is growing. From 2000 to 2014, the mortality rate from drug overdose increased by 137%, including a 200% increase in the rate of overdose deaths related to opioids (ie, pain medications, heroin).¹ Between 2013 and 2014, the age-adjusted mortality rate related to methadone, a synthetic opioid, remained unchanged; however, age-adjusted mortality rates related to natural and semisynthetic opioid pain medications, heroin, and synthetic opioids other than methadone (eg, fentanyl) increased by 9%, 26%, and 80%, respectively. In 2014, a sharp increase in overdose deaths related to synthetic opioids other than methadone coincided with law enforcement reports of increased availability of illegal fentanyl; however, the toxicology panel used by coroners and medical examiners at that time could not distinguish between illegal and prescription fentanyl.¹

Continue to: Among 70,237 drug overdose deaths...

Among 70,237 drug overdose deaths in the United States in 2017, 47,600 (67.8%) involved an opioid. From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and the District of Columbia, and significant increases in death rates involving synthetic opioids occurred in 15 out of 20 states, likely driven by illicitly manufactured fentanyl.²

Fentanyl-laced heroin: More common, but not new

In October 1991, 3-methylfentanyl was identified in 16 fatal drug overdoses in Allegheny County, Pennsylvania, contributing to a 4-fold increase in overdose deaths compared to the previous year. Fentanyl mixed with heroin and other drugs is commonly found in the Midwest, Northeast, and Southern regions of the United States; in 2014, more than 80% of fentanyl confiscations occurred in 10 states within these regions, with the highest incidence occurring in Ohio.³

When combined with fentanyl, heroin becomes 50 to 100 times more potent, resulting in a subjective high with exaggerated central nervous system depression manifesting as lethargy, miosis, and respiratory depression.⁴ Most drug users are unaware and unable to identify when heroin is laced with fentanyl, which may contribute to the rise in deaths from unintentional drug overdose.^1,5,6

Oral abuse of fentanyl patches can be fatal

Heroin is 50 to 100 times more potent when combined with fentanyl.

Outcomes from oral abuse of fentanyl patches have ranged from transient overdose symptoms, such as lethargy and respiratory depression, to death.^7-9 When administered in a medical setting, transbuccal fentanyl has a bioavailability of 50% to 65% across the buccal membrane. Nearly 20% of the drug escapes hepatic first pass metabolism when fentanyl patches are ingested orally and enters the systemic circulation, resulting in severe overdose and potentially death. Prolonged chewing and sucking on fentanyl patches increases the contact time with the buccal membrane, resulting in increased systemic absorption compared to oral ingestion without chewing/sucking.^7-9

Urine toxicology screening detects compounds based on a chemical assay for drugs—generally codeine, morphine, and their metabolites. Because fentanyl is a fully synthetic opioid, its structure is not like morphine or codeine. Therefore, fentanyl could not be detected on traditional urine toxicology screens for opiates. To detect the fentanyl, a urine drug screen would need an assay exclusively for fentanyl or its metabolite, norfentanyl.¹⁰ The fentanyl specific assay is increasingly available as part of commercially available, extended-panel urine toxicology testing.¹¹

Continue to: Survival of fentanyl overdose depends on naloxone availability

Naloxone is a safe and effective antidote to an opioid overdose. It comes in 3 preparations, including intramuscular and subcutaneous injections and an intranasal spray.¹² Concerns that naloxone will harm patients with opioid dependence are unfounded. Naloxone can induce symptoms of opioid withdrawal, such as yawning, lacrimation, piloerection, diaphoresis, myalgia, vomiting, and diarrhea. While these withdrawal symptoms are unpleasant, they are not life threatening.¹² Due to its high potency, large doses of naloxone (ie, 4–16 mg) are required to reverse the effects of a fentanyl overdose.¹³ Intranasal naloxone hydrochloride 4 mg delivered in a single spray is preferred due to the ease of administration. Repeat doses may be necessary if respiratory depression continues or recurs prior to the arrival of emergency medical services. Increasing the availability of naloxone to first responders has the potential to save many lives.⁶

THE TAKEAWAY

Fentanyl is a major contributor to the growing drug overdose crisis in the United States. When laced with heroin or consumed orally in the form of transdermal patches, fentanyl becomes more potent and is increasingly fatal. It’s crucial that primary care physicians be able to identify and educate at-risk patients about the fatal consequences of fentanyl overdose and coordinate care to help get them into an appropriate rehabilitation program.

In order to quickly recognize the signs of fentanyl-related overdose, it’s important to be alert for this possibility. At the bedside, the most easily recognized abnormality associated with fentanyl or other opioid overdose is a decline in respiratory rate culminating in apnea.¹⁰ A respiratory rate of 12 breaths/min or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Other signs include bradycardia, hypotension, and seizures from anoxia.¹⁰

Naloxone is a safe and effective antidote that is critical to the prevention of fatal opioid overdoses.

Apart from the severity of symptoms, it is hard to clinically distinguish fentanyl overdose from other opiate overdose incidents. Given the degree to which illegal opiates are contaminated with fentanyl in the United States,³ it is appropriate to screen for fentanyl with extended panel urine toxicology testing in patients with suspected opioid overdose.

CORRESPONDENCE
Jaividhya Dasarathy, MD, 2500 MetroHealth Medical Center, Cleveland, OH 44109; [email protected]

CASE 1

Two days after reviving her boyfriend with naloxone, a woman and her 30-year-old boyfriend presented to our family medicine clinic. They explained that he had injected heroin and shortly thereafter he stopped breathing and his lips turned blue. The patient’s girlfriend did not call emergency medical services (EMS) at the time because she was afraid of getting arrested due to past incarceration for possession of illegal drugs. Instead, she revived him with naloxone that she found in his bag.

Both the patient and his girlfriend were scared and surprised by his “terrible reaction,” as he had previously purchased heroin from the same dealer and used the same dose without similar effects. However, the patient did note that the drug he purchased this time had a bright white tinge, when normally the drug was light yellow.

On physical examination, the patient’s heart rate and blood pressure were normal. There were needle track marks on both forearms, elbows, and upper arms. A laboratory workup obtained during this visit revealed anemia and a normal basic metabolic panel. A hepatitis C virus antibody test was positive, and a hepatic function panel revealed elevated transaminase levels. Urine toxicology was positive for opioids and negative for other substances.

CASE 2

A 58-year-old man with a history of chronic hepatitis C, polysubstance abuse, and schizophrenia was transported to the emergency department by EMS after his family found him unresponsive in his bedroom. The patient had agonal breathing when EMS arrived, so they administered naloxone (4 mg intranasal and 4 mg intravenous). His breathing improved, but his mental status did not. He was still obtunded upon arrival in the emergency department and vomited 4 tan-colored patches. The patient was tachycardic (heart rate, 108 beats/min), hypertensive (blood pressure, 189/95 mm Hg), and had rapid shallow breathing (respiratory rate, 38 breaths/min). He was intubated for airway protection, at which time 2 more tan-colored patches were removed from his pharynx.

Laboratory evaluation revealed an acute kidney injury with a high anion metabolic acidosis. A hepatic function panel showed elevated transaminase levels. Plasma acetaminophen and salicylate levels were normal. A computed tomography head scan was normal. Urine toxicology was negative for opioids but was positive for cocaine and benzodiazepines.

THE DIAGNOSIS

Opioid overdose caused the acute respiratory depression in both cases. In Case 1, the patient unknowingly overdosed on heroin laced with fentanyl, known as China White, which likely caused the drug’s bright white tinge. In Case 2, the patient’s overdose was the result of oral ingestion of fentanyl patches. (Limited urine toxicology was negative for opiates because fentanyl is a fully synthetic opioid that shows up only with a specific or extended assay. More on this in a bit.)

DISCUSSION

The fatal drug overdose epidemic in the United States is growing. From 2000 to 2014, the mortality rate from drug overdose increased by 137%, including a 200% increase in the rate of overdose deaths related to opioids (ie, pain medications, heroin).¹ Between 2013 and 2014, the age-adjusted mortality rate related to methadone, a synthetic opioid, remained unchanged; however, age-adjusted mortality rates related to natural and semisynthetic opioid pain medications, heroin, and synthetic opioids other than methadone (eg, fentanyl) increased by 9%, 26%, and 80%, respectively. In 2014, a sharp increase in overdose deaths related to synthetic opioids other than methadone coincided with law enforcement reports of increased availability of illegal fentanyl; however, the toxicology panel used by coroners and medical examiners at that time could not distinguish between illegal and prescription fentanyl.¹

Continue to: Among 70,237 drug overdose deaths...

Among 70,237 drug overdose deaths in the United States in 2017, 47,600 (67.8%) involved an opioid. From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and the District of Columbia, and significant increases in death rates involving synthetic opioids occurred in 15 out of 20 states, likely driven by illicitly manufactured fentanyl.²

Fentanyl-laced heroin: More common, but not new

In October 1991, 3-methylfentanyl was identified in 16 fatal drug overdoses in Allegheny County, Pennsylvania, contributing to a 4-fold increase in overdose deaths compared to the previous year. Fentanyl mixed with heroin and other drugs is commonly found in the Midwest, Northeast, and Southern regions of the United States; in 2014, more than 80% of fentanyl confiscations occurred in 10 states within these regions, with the highest incidence occurring in Ohio.³

When combined with fentanyl, heroin becomes 50 to 100 times more potent, resulting in a subjective high with exaggerated central nervous system depression manifesting as lethargy, miosis, and respiratory depression.⁴ Most drug users are unaware and unable to identify when heroin is laced with fentanyl, which may contribute to the rise in deaths from unintentional drug overdose.^1,5,6

Oral abuse of fentanyl patches can be fatal

Heroin is 50 to 100 times more potent when combined with fentanyl.

Outcomes from oral abuse of fentanyl patches have ranged from transient overdose symptoms, such as lethargy and respiratory depression, to death.^7-9 When administered in a medical setting, transbuccal fentanyl has a bioavailability of 50% to 65% across the buccal membrane. Nearly 20% of the drug escapes hepatic first pass metabolism when fentanyl patches are ingested orally and enters the systemic circulation, resulting in severe overdose and potentially death. Prolonged chewing and sucking on fentanyl patches increases the contact time with the buccal membrane, resulting in increased systemic absorption compared to oral ingestion without chewing/sucking.^7-9

Urine toxicology screening detects compounds based on a chemical assay for drugs—generally codeine, morphine, and their metabolites. Because fentanyl is a fully synthetic opioid, its structure is not like morphine or codeine. Therefore, fentanyl could not be detected on traditional urine toxicology screens for opiates. To detect the fentanyl, a urine drug screen would need an assay exclusively for fentanyl or its metabolite, norfentanyl.¹⁰ The fentanyl specific assay is increasingly available as part of commercially available, extended-panel urine toxicology testing.¹¹

Continue to: Survival of fentanyl overdose depends on naloxone availability

Naloxone is a safe and effective antidote to an opioid overdose. It comes in 3 preparations, including intramuscular and subcutaneous injections and an intranasal spray.¹² Concerns that naloxone will harm patients with opioid dependence are unfounded. Naloxone can induce symptoms of opioid withdrawal, such as yawning, lacrimation, piloerection, diaphoresis, myalgia, vomiting, and diarrhea. While these withdrawal symptoms are unpleasant, they are not life threatening.¹² Due to its high potency, large doses of naloxone (ie, 4–16 mg) are required to reverse the effects of a fentanyl overdose.¹³ Intranasal naloxone hydrochloride 4 mg delivered in a single spray is preferred due to the ease of administration. Repeat doses may be necessary if respiratory depression continues or recurs prior to the arrival of emergency medical services. Increasing the availability of naloxone to first responders has the potential to save many lives.⁶

THE TAKEAWAY

Fentanyl is a major contributor to the growing drug overdose crisis in the United States. When laced with heroin or consumed orally in the form of transdermal patches, fentanyl becomes more potent and is increasingly fatal. It’s crucial that primary care physicians be able to identify and educate at-risk patients about the fatal consequences of fentanyl overdose and coordinate care to help get them into an appropriate rehabilitation program.

In order to quickly recognize the signs of fentanyl-related overdose, it’s important to be alert for this possibility. At the bedside, the most easily recognized abnormality associated with fentanyl or other opioid overdose is a decline in respiratory rate culminating in apnea.¹⁰ A respiratory rate of 12 breaths/min or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Other signs include bradycardia, hypotension, and seizures from anoxia.¹⁰

Naloxone is a safe and effective antidote that is critical to the prevention of fatal opioid overdoses.

Apart from the severity of symptoms, it is hard to clinically distinguish fentanyl overdose from other opiate overdose incidents. Given the degree to which illegal opiates are contaminated with fentanyl in the United States,³ it is appropriate to screen for fentanyl with extended panel urine toxicology testing in patients with suspected opioid overdose.

CORRESPONDENCE
Jaividhya Dasarathy, MD, 2500 MetroHealth Medical Center, Cleveland, OH 44109; [email protected]

CASE 1

Two days after reviving her boyfriend with naloxone, a woman and her 30-year-old boyfriend presented to our family medicine clinic. They explained that he had injected heroin and shortly thereafter he stopped breathing and his lips turned blue. The patient’s girlfriend did not call emergency medical services (EMS) at the time because she was afraid of getting arrested due to past incarceration for possession of illegal drugs. Instead, she revived him with naloxone that she found in his bag.

Both the patient and his girlfriend were scared and surprised by his “terrible reaction,” as he had previously purchased heroin from the same dealer and used the same dose without similar effects. However, the patient did note that the drug he purchased this time had a bright white tinge, when normally the drug was light yellow.

On physical examination, the patient’s heart rate and blood pressure were normal. There were needle track marks on both forearms, elbows, and upper arms. A laboratory workup obtained during this visit revealed anemia and a normal basic metabolic panel. A hepatitis C virus antibody test was positive, and a hepatic function panel revealed elevated transaminase levels. Urine toxicology was positive for opioids and negative for other substances.

CASE 2

A 58-year-old man with a history of chronic hepatitis C, polysubstance abuse, and schizophrenia was transported to the emergency department by EMS after his family found him unresponsive in his bedroom. The patient had agonal breathing when EMS arrived, so they administered naloxone (4 mg intranasal and 4 mg intravenous). His breathing improved, but his mental status did not. He was still obtunded upon arrival in the emergency department and vomited 4 tan-colored patches. The patient was tachycardic (heart rate, 108 beats/min), hypertensive (blood pressure, 189/95 mm Hg), and had rapid shallow breathing (respiratory rate, 38 breaths/min). He was intubated for airway protection, at which time 2 more tan-colored patches were removed from his pharynx.

Laboratory evaluation revealed an acute kidney injury with a high anion metabolic acidosis. A hepatic function panel showed elevated transaminase levels. Plasma acetaminophen and salicylate levels were normal. A computed tomography head scan was normal. Urine toxicology was negative for opioids but was positive for cocaine and benzodiazepines.

THE DIAGNOSIS

Opioid overdose caused the acute respiratory depression in both cases. In Case 1, the patient unknowingly overdosed on heroin laced with fentanyl, known as China White, which likely caused the drug’s bright white tinge. In Case 2, the patient’s overdose was the result of oral ingestion of fentanyl patches. (Limited urine toxicology was negative for opiates because fentanyl is a fully synthetic opioid that shows up only with a specific or extended assay. More on this in a bit.)

DISCUSSION

The fatal drug overdose epidemic in the United States is growing. From 2000 to 2014, the mortality rate from drug overdose increased by 137%, including a 200% increase in the rate of overdose deaths related to opioids (ie, pain medications, heroin).¹ Between 2013 and 2014, the age-adjusted mortality rate related to methadone, a synthetic opioid, remained unchanged; however, age-adjusted mortality rates related to natural and semisynthetic opioid pain medications, heroin, and synthetic opioids other than methadone (eg, fentanyl) increased by 9%, 26%, and 80%, respectively. In 2014, a sharp increase in overdose deaths related to synthetic opioids other than methadone coincided with law enforcement reports of increased availability of illegal fentanyl; however, the toxicology panel used by coroners and medical examiners at that time could not distinguish between illegal and prescription fentanyl.¹

Continue to: Among 70,237 drug overdose deaths...

Among 70,237 drug overdose deaths in the United States in 2017, 47,600 (67.8%) involved an opioid. From 2013 to 2017, drug overdose death rates increased in 35 of 50 states and the District of Columbia, and significant increases in death rates involving synthetic opioids occurred in 15 out of 20 states, likely driven by illicitly manufactured fentanyl.²

Fentanyl-laced heroin: More common, but not new

In October 1991, 3-methylfentanyl was identified in 16 fatal drug overdoses in Allegheny County, Pennsylvania, contributing to a 4-fold increase in overdose deaths compared to the previous year. Fentanyl mixed with heroin and other drugs is commonly found in the Midwest, Northeast, and Southern regions of the United States; in 2014, more than 80% of fentanyl confiscations occurred in 10 states within these regions, with the highest incidence occurring in Ohio.³

When combined with fentanyl, heroin becomes 50 to 100 times more potent, resulting in a subjective high with exaggerated central nervous system depression manifesting as lethargy, miosis, and respiratory depression.⁴ Most drug users are unaware and unable to identify when heroin is laced with fentanyl, which may contribute to the rise in deaths from unintentional drug overdose.^1,5,6

Oral abuse of fentanyl patches can be fatal

Heroin is 50 to 100 times more potent when combined with fentanyl.

Outcomes from oral abuse of fentanyl patches have ranged from transient overdose symptoms, such as lethargy and respiratory depression, to death.^7-9 When administered in a medical setting, transbuccal fentanyl has a bioavailability of 50% to 65% across the buccal membrane. Nearly 20% of the drug escapes hepatic first pass metabolism when fentanyl patches are ingested orally and enters the systemic circulation, resulting in severe overdose and potentially death. Prolonged chewing and sucking on fentanyl patches increases the contact time with the buccal membrane, resulting in increased systemic absorption compared to oral ingestion without chewing/sucking.^7-9

Urine toxicology screening detects compounds based on a chemical assay for drugs—generally codeine, morphine, and their metabolites. Because fentanyl is a fully synthetic opioid, its structure is not like morphine or codeine. Therefore, fentanyl could not be detected on traditional urine toxicology screens for opiates. To detect the fentanyl, a urine drug screen would need an assay exclusively for fentanyl or its metabolite, norfentanyl.¹⁰ The fentanyl specific assay is increasingly available as part of commercially available, extended-panel urine toxicology testing.¹¹

Continue to: Survival of fentanyl overdose depends on naloxone availability

Naloxone is a safe and effective antidote to an opioid overdose. It comes in 3 preparations, including intramuscular and subcutaneous injections and an intranasal spray.¹² Concerns that naloxone will harm patients with opioid dependence are unfounded. Naloxone can induce symptoms of opioid withdrawal, such as yawning, lacrimation, piloerection, diaphoresis, myalgia, vomiting, and diarrhea. While these withdrawal symptoms are unpleasant, they are not life threatening.¹² Due to its high potency, large doses of naloxone (ie, 4–16 mg) are required to reverse the effects of a fentanyl overdose.¹³ Intranasal naloxone hydrochloride 4 mg delivered in a single spray is preferred due to the ease of administration. Repeat doses may be necessary if respiratory depression continues or recurs prior to the arrival of emergency medical services. Increasing the availability of naloxone to first responders has the potential to save many lives.⁶

THE TAKEAWAY

Fentanyl is a major contributor to the growing drug overdose crisis in the United States. When laced with heroin or consumed orally in the form of transdermal patches, fentanyl becomes more potent and is increasingly fatal. It’s crucial that primary care physicians be able to identify and educate at-risk patients about the fatal consequences of fentanyl overdose and coordinate care to help get them into an appropriate rehabilitation program.

In order to quickly recognize the signs of fentanyl-related overdose, it’s important to be alert for this possibility. At the bedside, the most easily recognized abnormality associated with fentanyl or other opioid overdose is a decline in respiratory rate culminating in apnea.¹⁰ A respiratory rate of 12 breaths/min or less in a patient who is not in physiologic sleep strongly suggests acute opioid intoxication, particularly when accompanied by miosis or stupor. Other signs include bradycardia, hypotension, and seizures from anoxia.¹⁰

Naloxone is a safe and effective antidote that is critical to the prevention of fatal opioid overdoses.

Apart from the severity of symptoms, it is hard to clinically distinguish fentanyl overdose from other opiate overdose incidents. Given the degree to which illegal opiates are contaminated with fentanyl in the United States,³ it is appropriate to screen for fentanyl with extended panel urine toxicology testing in patients with suspected opioid overdose.

CORRESPONDENCE
Jaividhya Dasarathy, MD, 2500 MetroHealth Medical Center, Cleveland, OH 44109; [email protected]

ILLUSTRATIVE CASE

Penny E is a 48-year-old woman with a history of asthma who presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. Pulmonary embolism (PE) is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration and it returns at 700 ng/mL. Should you order computed tomography pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2 people/1000 population and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

The use of a diagnostic algorithm that includes the Wells’ criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insufficient time in busy emergency departments, adherence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used despite an absolute reduction of 11.6% (95% confidence interval [CI], 10.5-12.9) in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients > 50 years).⁷

Three items of the original Wells’ criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPAs. Decreasing CTPAs would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ After excluding 151 patients who met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA), investigators managed 3465 study patients according to the YEARS algorithm. This algorithm called for obtaining a D-dimer concentration in all patients and assessment using the YEARS clinical decision rule, consisting of 3 items assessed by an attending physician: clinical signs of deep vein thrombosis, hemoptysis, and whether PE was the most likely diagnosis. PE was considered excluded if a patient had no positive YEARS items and a D-dimer concentration < 1000 ng/mL or if the patient had one or more YEARS items and a D-dimer concentration < 500 ng/mL. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells’ diagnostic algorithm had been implemented.

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000 ng/mL threshold. Fifty-five of the 423 who had a D-dimer ≥ 1000 ng/mL had confirmed PE by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of those 1391 had PE confirmed by CTPA.

Continue to: Eighteen of the 2964 patients...

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%; 95% CI, 0.36-0.96), with 6 patients (0.20%; 95% CI, 0.07-0.44) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43% (95% CI, 0.17-0.88), which is similar to the 0.34% (0.036-0.96) reported in a previous meta-analysis of the Wells’ rule algorithm.¹³ Overall, fatal PE occurred in 0.3% (95% CI, 0.12-0.78) of patients in the YEARS cohort vs 0.6% (0.4-1.1) in a meta-analysis of studies using standard algorithms.¹⁴

The new diagnostic algorithm reduced the use of CT pulmonary angiography by 14% and produced a cost savings of $309,096.

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells’ algorithm, for an absolute difference of 13% (95% CI, 10-15) and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% (95% CI, 12-16) and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference; 95% CI, 12-16) when compared with using the Wells’ rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria does not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% (95% CI, 6.4-11) in CTPAs.⁷

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Penny E is a 48-year-old woman with a history of asthma who presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. Pulmonary embolism (PE) is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration and it returns at 700 ng/mL. Should you order computed tomography pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2 people/1000 population and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

The use of a diagnostic algorithm that includes the Wells’ criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insufficient time in busy emergency departments, adherence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used despite an absolute reduction of 11.6% (95% confidence interval [CI], 10.5-12.9) in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients > 50 years).⁷

Three items of the original Wells’ criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPAs. Decreasing CTPAs would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ After excluding 151 patients who met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA), investigators managed 3465 study patients according to the YEARS algorithm. This algorithm called for obtaining a D-dimer concentration in all patients and assessment using the YEARS clinical decision rule, consisting of 3 items assessed by an attending physician: clinical signs of deep vein thrombosis, hemoptysis, and whether PE was the most likely diagnosis. PE was considered excluded if a patient had no positive YEARS items and a D-dimer concentration < 1000 ng/mL or if the patient had one or more YEARS items and a D-dimer concentration < 500 ng/mL. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells’ diagnostic algorithm had been implemented.

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000 ng/mL threshold. Fifty-five of the 423 who had a D-dimer ≥ 1000 ng/mL had confirmed PE by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of those 1391 had PE confirmed by CTPA.

Continue to: Eighteen of the 2964 patients...

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%; 95% CI, 0.36-0.96), with 6 patients (0.20%; 95% CI, 0.07-0.44) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43% (95% CI, 0.17-0.88), which is similar to the 0.34% (0.036-0.96) reported in a previous meta-analysis of the Wells’ rule algorithm.¹³ Overall, fatal PE occurred in 0.3% (95% CI, 0.12-0.78) of patients in the YEARS cohort vs 0.6% (0.4-1.1) in a meta-analysis of studies using standard algorithms.¹⁴

The new diagnostic algorithm reduced the use of CT pulmonary angiography by 14% and produced a cost savings of $309,096.

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells’ algorithm, for an absolute difference of 13% (95% CI, 10-15) and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% (95% CI, 12-16) and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference; 95% CI, 12-16) when compared with using the Wells’ rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria does not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% (95% CI, 6.4-11) in CTPAs.⁷

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

Penny E is a 48-year-old woman with a history of asthma who presents with wheezing and respiratory distress. There are no clinical signs of deep vein thrombosis or hemoptysis. Pulmonary embolism (PE) is not your most likely diagnosis, but it is included in the differential, so you order a D-dimer concentration and it returns at 700 ng/mL. Should you order computed tomography pulmonary angiography (CTPA) to evaluate for PE?

PE is the third most common type of cardiovascular disease after coronary artery disease and stroke, with an estimated incidence in the United States of 1-2 people/1000 population and a 30-day mortality rate between 10% and 30%.² Improved adherence to a clinical decision support system has been shown to significantly decrease the number of diagnostic tests performed and the number of diagnostic failures.³

The use of a diagnostic algorithm that includes the Wells’ criteria and a D-dimer concentration can exclude PE without CTPA in 20% to 30% of patients.⁴ However, due to the complexity of the algorithm and insufficient time in busy emergency departments, adherence to recommended diagnostic strategies is variable.⁵

Further, it is common for a D-dimer test to be obtained before clinical assessment by a provider.⁶ A fixed cutoff D-dimer concentration of 500 ng/mL is commonly used despite an absolute reduction of 11.6% (95% confidence interval [CI], 10.5-12.9) in the need for CTPA using an age-adjusted D-dimer concentration threshold (age × 10 ng/mL for patients > 50 years).⁷

Three items of the original Wells’ criteria—clinical signs of deep vein thrombosis, hemoptysis, and whether PE is the most likely diagnosis—are the most predictive for PE.⁸ The development of a more efficient algorithm based on these 3 items that uses differential D-dimer concentration thresholds could retain sensitivity and decrease unnecessary CTPAs. Decreasing CTPAs would avoid contrast-induced nephropathy and decrease cancers associated with radiation exposure.^9-11 Significant cost savings could also be achieved, as the estimated cost of one CTPA is $648, while a D-dimer concentration is estimated to cost $14.¹²

STUDY SUMMARY

Simplified algorithm diagnoses PE with fewer CTPAs

The YEARS study was a prospective cohort study conducted in 12 hospitals in the Netherlands that included 3616 patients with clinically suspected PE.¹ After excluding 151 patients who met exclusion criteria (life expectancy < 3 months, ongoing anticoagulation treatment, pregnancy, and contraindication to CTPA), investigators managed 3465 study patients according to the YEARS algorithm. This algorithm called for obtaining a D-dimer concentration in all patients and assessment using the YEARS clinical decision rule, consisting of 3 items assessed by an attending physician: clinical signs of deep vein thrombosis, hemoptysis, and whether PE was the most likely diagnosis. PE was considered excluded if a patient had no positive YEARS items and a D-dimer concentration < 1000 ng/mL or if the patient had one or more YEARS items and a D-dimer concentration < 500 ng/mL. The primary outcome was venous thromboembolism (VTE) events at 3 months’ follow-up once PE was excluded. The secondary outcome was the number of required CTPAs using the YEARS decision rule compared with the number that would have been required if the Wells’ diagnostic algorithm had been implemented.

Of the 1743 patients who had none of the 3 YEARS items, 1320 had a D-dimer concentration below the 1000 ng/mL threshold. Fifty-five of the 423 who had a D-dimer ≥ 1000 ng/mL had confirmed PE by CTPA. In the 1722 patients who had at least 1 YEARS item, 1391 had a D-dimer concentration ≥ 500 ng/mL threshold; 401 of those 1391 had PE confirmed by CTPA.

Continue to: Eighteen of the 2964 patients...

Eighteen of the 2964 patients who had PE ruled out by the YEARS algorithm at baseline were found to have symptomatic VTE during the follow-up period (0.61%; 95% CI, 0.36-0.96), with 6 patients (0.20%; 95% CI, 0.07-0.44) sustaining a fatal PE. The 3-month incidence of VTE in patients who did not have CTPA was 0.43% (95% CI, 0.17-0.88), which is similar to the 0.34% (0.036-0.96) reported in a previous meta-analysis of the Wells’ rule algorithm.¹³ Overall, fatal PE occurred in 0.3% (95% CI, 0.12-0.78) of patients in the YEARS cohort vs 0.6% (0.4-1.1) in a meta-analysis of studies using standard algorithms.¹⁴

The new diagnostic algorithm reduced the use of CT pulmonary angiography by 14% and produced a cost savings of $309,096.

Using an intention-to-diagnose analysis, 1611 (46%) patients did not have a CTPA indicated by the YEARS algorithm compared with 1174 (34%) using the Wells’ algorithm, for an absolute difference of 13% (95% CI, 10-15) and estimated cost savings of $283,176 in this sample. The per-protocol analysis also had a decrease of CTPA examinations in favor of the YEARS algorithm, ruling out 1651 (48%) patients—a decrease of 14% (95% CI, 12-16) and an estimated savings of $309,096.

WHAT’S NEW

High-level evidence says 14% fewer CTPAs

The YEARS study provides a high level of evidence that a new, simple diagnostic algorithm can reliably and efficiently exclude PE and decrease the need for CTPA by 14% (absolute difference; 95% CI, 12-16) when compared with using the Wells’ rule and fixed D-dimer threshold of < 500 ng/mL.

CAVEATS

No adjusting D-dimer for age

The YEARS criteria does not consider an age-adjusted D-dimer threshold, which has been shown to further decrease CTPA use.⁶ This does not preclude the use of YEARS criteria; applying age-adjusted D-dimer thresholds would have led to an absolute reduction of 8.7% (95% CI, 6.4-11) in CTPAs.⁷

CHALLENGES TO IMPLEMENTATION

None to speak of

We see no challenges to the implementation of this recommendation.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

In a typical primary care practice, detecting and managing mental health problems competes with other priorities such as treating acute physical illness, monitoring chronic disease, providing preventive health services, and assessing compliance with standards of care.¹ These competing demands for a primary care provider’s time, paired with limited mental health resources in the community, may result in suboptimal behavioral health care.^1-3 Even when referrals are made to mental health care providers, depression is adequately treated only 20% of the time.^2,3 Additionally, individuals with serious mental illness and substance use disorders often do not receive adequate general medical care.^4,5

Approximately 30% of adults with physical disorders also have one or more behavioral health conditions, such as anxiety, panic, mood, or substance use disorders.⁶ Although physical and behavioral health conditions are inextricably linked, their assessment and treatment get separated into different silos.⁷ Given that fewer than 20% of depressed patients are seen by a psychiatrist or psychologist,⁸ the responsibility of providing mental health care often falls on the primary care physician.^8,9

Efforts to improve the treatment of common mental disorders in primary care have traditionally focused on screening for these disorders, educating primary care providers, developing treatment guidelines, and referring patients to mental health specialty care.¹⁰ However, behavioral health integration offers another way forward.

WHAT IS BEHAVIORAL HEALTH INTEGRATION?

Behavioral health integration (BHI) in primary care refers to primary care physicians and behavioral health clinicians working in concert with patients to address their primary care and behavioral health needs.¹¹

Numerous overlapping terms have been used to describe BHI, and this has caused some confusion. In 2013, the Agency for Healthcare Research and Quality (AHRQ) issued a lexicon standardizing the terminology used in BHI.¹¹ The commonly used terms are coordinated care, co-located care, and integrated care (TABLE 1),^11,12 and they may be best understood as part of a BHI continuum. A combined expert panel of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Health Resources and Services Administration (HRSA) has developed a conceptual framework defining 6 levels of integrated care spanning the 3 practice structures of coordinated care, co-located care, and integrated care (FIGURE 1).^12,13Reverse co-location is another frequently used term; it refers to primary care providers who work in settings devoted to mental health or chemical dependency treatment.¹¹

COORDINATED CARE AND THE COLLABORATIVE CARE MODEL

BHI at the level of coordinated care has almost exclusively been studied and practiced along the lines of the collaborative care model (CCM).^14-16 This model represents an advanced level of coordinated care in the BHI continuum. The most substantial evidence for CCM lies in the management of depression and anxiety.^14-16

Usual care involves the primary care physician and the patient. CCM adds 2 vital roles—a behavioral health care manager and a psychiatric consultant. A behavioral health care manager is typically a counselor, clinical social worker, psychologist, or psychiatric nurse who performs all care-management tasks including offering psychotherapy when that is part of the treatment plan.

Continue to: The care manager's functions include...

The care manager’s functions include systematic follow-up with structured monitoring of symptoms and treatment adherence, coordination and communication among care providers, patient education, and self-management support, including the use of motivational interviewing. The behavioral health care manager performs this systematic follow up by maintaining a patient “registry”—case-management software used in conjunction with, or embedded in, the practice electronic health record to track patients’ data and clinical outcomes, as well as to facilitate decision-making.

The care manager communicates with the psychiatrist, who offers suggestions for drug therapy, which is prescribed by the primary care physician. The care manager also regularly evaluates the patient’s status using a standardized scale, communicates these scores to the psychiatrist, and transmits any recommendations to the primary care physician (FIGURE 2).¹⁷

EVIDENCE FOR CCM

Collaborative and routine care were compared in a 2012 Cochrane review that included 79 randomized controlled trials (RCTs) involving 24,308 patients worldwide.¹⁶ Seventy-two of the 79 RCTs focused on patients with depression or depression with anxiety, while 6 studies included participants with only anxiety disorders.¹⁶ One additional study focused on mental health quality of life. (To learn about CCM and severe mental illness and substance use disorder, see “Less well studied: CCM and severe mental illness, alcohol dependence.”^18-20)

For adults with depression treated with the CCM, significantly greater improvement in depression outcome measures was seen in the short-term (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI], -0.41 to -0.27; risk ratio [RR] = 1.32; 95% CI, 1.22-1.43), in the medium term (SMD = -0.28; 95% CI, -0.41 to -0.15; RR = 1.31; 95% CI, 1.17–1.48), and in the long term (SMD = -0.35; 95% CI, -0.46 to -0.24; RR = 1.29; 95% CI, 1.18–1.41).¹⁶

Comparisons of mental health quality of life over the short term (0-6 months), medium term (7-12 months), and long term (13-24 months) did not show any significant difference between CCM and routine care.¹⁶ Comparisons of physical health quality of life over the short term and medium term did not show any significant difference between CCM and routine care.¹⁶

Continue to: Significantly greater improvement...

Significantly greater improvement in anxiety outcomes was seen for adults treated with CCM in the short term (SMD = -0.30; 95% CI, -0.44 to -0.17; RR = 1.50; 95% CI, 1.21–1.87), in the medium term (SMD = -0.33; 95% CI, -0.47 to -0.19; RR = 1.41; 95% CI, 1.18-1.69), and in the long term (SMD = -0.20; 95% CI, -0.34 to -0.06; RR = 1.26; 95% CI, 1.11–1.42).¹⁶

A 2016 systematic review of 94 RCTs involving more than 25,000 patients also provided high-quality evidence that collaborative care yields small-to-moderate improvements in symptoms from mood disorders and mental health-related quality of life.¹⁵ A 2006 meta-analysis of 37 RCTs comprising 12,355 patients showed that collaborative care involving a case manager is more effective than standard care in improving depression outcomes at 6 months (SMD = 0.25; 95% CI, 0.18-0.32) and up to 5 years (SMD = 0.15; 95% CI, 0.001-0.31).²¹

Better care of mental health disorders also improves medical outcomes

Several trials have focused on jointly managing depression and a chronic physical condition such as chronic pain, diabetes, and coronary heart disease,²² demonstrating improved outcomes for both depression and the comanaged conditions.

• Chronic pain. When compared with usual care, collaborative care resulted in moderate reductions in both pain severity and associated disability (41.5% vs 17.3%; RR = 2.4; 95% CI, 1.6-3.2).²³
• Diabetes. Patients managed collaboratively were more likely to have a decrease of ≥ 1% in the glycated hemoglobin level from baseline (36% vs 19%; P = .006).²⁴
• Cardiovascular disease. Significant real-world risk reduction was achieved by improving blood pressure control (58% achieved blood pressure control compared with a projected target of 20%).²²

IS THERE A COMMON THREAD AMONG SUCCESSFUL CCMs?

Attempts to identify commonalities between the many iterations of successful CCMs have produced varying results due to differing selections of relevant RCTs.^25-29 However, a few common features have been identified:

• care managers assess symptoms at baseline and at follow-up using a standardized measure such as the Patient Health Questionnaire (PHQ-9);
• care managers monitor treatment adherence;
• follow-up is active for at least 16 weeks;
• primary care and mental health providers actively engage in patient management; and
• mental health specialists regularly supervise care managers.

The one feature that is consistent with improved outcomes is the presence of the care manager.^25-29

Continue to: The improvement associated...

The improvement associated with collaborative care is clinically meaningful to patients and physicians. In one RCT, collaborative care doubled response rates of depression treatment compared with usual care.³ Quality improvement data from real-world implementation of collaborative care programs suggests that similar outcomes can be achieved in a variety of settings.³⁰

COST BENEFITS OF CCM

Collaborative care for depression is associated with lower health care costs.^29,31

Patients with diabetes managed collaboratively have shown HbA_1c decreases of ≥ 1% from baseline more frequently than usual-care patients.

A meta-analysis of 57 RCTs in 2012 showed that CCM improves depression outcomes across populations, settings, and outcome domains, and that these results are achieved at little to no increase in treatment costs compared with usual care (Cohen’s d = 0.05; 95% CI, –0.02–0.12).²⁶

When collaborative care was compared with routine care in an RCT involving 1801 primary care patients ≥ 60 years who were suffering from depression, a cost saving of $3363 per patient over 4 years was demonstrated in the intervention arm.³¹

A technical analysis of 94 RCTs in 2015 concluded that CCM is cost effective compared with usual care, with a range of $15,000 to $80,000 per quality-adjusted life year gained. These studies also indicated that organizations’ costs to implement CCM increase in the short term. Based on this analysis, organizations would need to invest between $3 to $22 per patient per month to implement and sustain CCMs, depending on the prevalence of depression in the population.²⁹

Continue to: OTHER MODELS OF BHI

Higher levels of BHI such as co-location and integration do not have the same quality of evidence as CCM.

A 2009 Cochrane review of 42 studies involving 3880 patients found that mental health workers delivering psychological therapy and psychosocial interventions in primary care settings brought about significant reductions in primary care physician consultations (SMD = ‐0.17; 95% CI, ‐0.30 to ‐0.05); a relative risk reduction of 23% in psychotropic prescribing (RR = 0.67; 95% CI, 0.56–0.79); a decrease in prescribing costs (SMD = ‐0.22; 95% CI, ‐0.38 to ‐0.07); and a relative risk reduction in mental health referral of 87% (RR = 0.13; 95% CI, 0.09–0.20) for the patients they were seeing.³² The authors concluded the changes were modest in magnitude and inconsistent across different studies.³²

Collaborative care has improved depression outcomes at little to no increase in treatment costs compared with usual care.

Embedding medical providers in behavior health centers—ie, the reverse co-location model—also has very limited evidence. An RCT involving 120 veterans found that patients enrolled in a reverse co-location clinic did significantly better than controls seen in a general care clinic in terms of continuity of care and preventive care such as screening for hypertension (84.7% vs 65.6%; X ² = 5.9, P = .01), diabetes (71.2% vs 45.9%; X ² = 7.9, P < .005), hepatitis (39% vs 14.8%; X ² = 9, P = .003), and cholesterol (79.7% vs 57.4%; X ² = 6.9, P = .009).³³

HOW TO IMPLEMENT A SUCCESSFUL BHI PROGRAM

A demonstration and evaluation project involving 11 diverse practices in Colorado explored ways to integrate behavioral health in primary care. Five main themes emerged^34,35:

• Frame integrated care as a necessary paradigm shift to patient-centered, whole-person health care.
• Define relationships and protocols up front, understanding that they will evolve.
• Build inclusive, empowered teams to provide the foundation for integration.
• Develop a change management strategy of continuous evaluation and course correction.
• Use targeted data collection pertinent to integrated care to drive improvement and impart accountability.

The one feature that is consistent with improved outcomes is the presence of a care manager.

The Institute for Clinical and Economic Review has organized an extensive list of resources³⁶ for implementing BHI models, a sampling of which is shown in TABLE 2.

Continue to: TAKE-AWAY POINTS

There is high quality evidence that collaborative care works for the management of depression and anxiety disorder in primary care, and this is associated with significant cost savings. The one feature consistent in most successful BHI models is the care manager. More research is needed to identify which model of BHI works best for patients with SMI and substance use disorders. BHI cannot be accomplished by a few small changes to traditional care but requires a fundamental rethinking of care practices.

CORRESPONDENCE
Rajesh (FNU) Rajesh, MD, Main Campus Family Medicine Clinic, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected]

In a typical primary care practice, detecting and managing mental health problems competes with other priorities such as treating acute physical illness, monitoring chronic disease, providing preventive health services, and assessing compliance with standards of care.¹ These competing demands for a primary care provider’s time, paired with limited mental health resources in the community, may result in suboptimal behavioral health care.^1-3 Even when referrals are made to mental health care providers, depression is adequately treated only 20% of the time.^2,3 Additionally, individuals with serious mental illness and substance use disorders often do not receive adequate general medical care.^4,5

Approximately 30% of adults with physical disorders also have one or more behavioral health conditions, such as anxiety, panic, mood, or substance use disorders.⁶ Although physical and behavioral health conditions are inextricably linked, their assessment and treatment get separated into different silos.⁷ Given that fewer than 20% of depressed patients are seen by a psychiatrist or psychologist,⁸ the responsibility of providing mental health care often falls on the primary care physician.^8,9

Efforts to improve the treatment of common mental disorders in primary care have traditionally focused on screening for these disorders, educating primary care providers, developing treatment guidelines, and referring patients to mental health specialty care.¹⁰ However, behavioral health integration offers another way forward.

WHAT IS BEHAVIORAL HEALTH INTEGRATION?

Behavioral health integration (BHI) in primary care refers to primary care physicians and behavioral health clinicians working in concert with patients to address their primary care and behavioral health needs.¹¹

Numerous overlapping terms have been used to describe BHI, and this has caused some confusion. In 2013, the Agency for Healthcare Research and Quality (AHRQ) issued a lexicon standardizing the terminology used in BHI.¹¹ The commonly used terms are coordinated care, co-located care, and integrated care (TABLE 1),^11,12 and they may be best understood as part of a BHI continuum. A combined expert panel of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Health Resources and Services Administration (HRSA) has developed a conceptual framework defining 6 levels of integrated care spanning the 3 practice structures of coordinated care, co-located care, and integrated care (FIGURE 1).^12,13Reverse co-location is another frequently used term; it refers to primary care providers who work in settings devoted to mental health or chemical dependency treatment.¹¹

COORDINATED CARE AND THE COLLABORATIVE CARE MODEL

BHI at the level of coordinated care has almost exclusively been studied and practiced along the lines of the collaborative care model (CCM).^14-16 This model represents an advanced level of coordinated care in the BHI continuum. The most substantial evidence for CCM lies in the management of depression and anxiety.^14-16

Usual care involves the primary care physician and the patient. CCM adds 2 vital roles—a behavioral health care manager and a psychiatric consultant. A behavioral health care manager is typically a counselor, clinical social worker, psychologist, or psychiatric nurse who performs all care-management tasks including offering psychotherapy when that is part of the treatment plan.

Continue to: The care manager's functions include...

The care manager’s functions include systematic follow-up with structured monitoring of symptoms and treatment adherence, coordination and communication among care providers, patient education, and self-management support, including the use of motivational interviewing. The behavioral health care manager performs this systematic follow up by maintaining a patient “registry”—case-management software used in conjunction with, or embedded in, the practice electronic health record to track patients’ data and clinical outcomes, as well as to facilitate decision-making.

The care manager communicates with the psychiatrist, who offers suggestions for drug therapy, which is prescribed by the primary care physician. The care manager also regularly evaluates the patient’s status using a standardized scale, communicates these scores to the psychiatrist, and transmits any recommendations to the primary care physician (FIGURE 2).¹⁷

EVIDENCE FOR CCM

Collaborative and routine care were compared in a 2012 Cochrane review that included 79 randomized controlled trials (RCTs) involving 24,308 patients worldwide.¹⁶ Seventy-two of the 79 RCTs focused on patients with depression or depression with anxiety, while 6 studies included participants with only anxiety disorders.¹⁶ One additional study focused on mental health quality of life. (To learn about CCM and severe mental illness and substance use disorder, see “Less well studied: CCM and severe mental illness, alcohol dependence.”^18-20)

For adults with depression treated with the CCM, significantly greater improvement in depression outcome measures was seen in the short-term (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI], -0.41 to -0.27; risk ratio [RR] = 1.32; 95% CI, 1.22-1.43), in the medium term (SMD = -0.28; 95% CI, -0.41 to -0.15; RR = 1.31; 95% CI, 1.17–1.48), and in the long term (SMD = -0.35; 95% CI, -0.46 to -0.24; RR = 1.29; 95% CI, 1.18–1.41).¹⁶

Comparisons of mental health quality of life over the short term (0-6 months), medium term (7-12 months), and long term (13-24 months) did not show any significant difference between CCM and routine care.¹⁶ Comparisons of physical health quality of life over the short term and medium term did not show any significant difference between CCM and routine care.¹⁶

Continue to: Significantly greater improvement...

Significantly greater improvement in anxiety outcomes was seen for adults treated with CCM in the short term (SMD = -0.30; 95% CI, -0.44 to -0.17; RR = 1.50; 95% CI, 1.21–1.87), in the medium term (SMD = -0.33; 95% CI, -0.47 to -0.19; RR = 1.41; 95% CI, 1.18-1.69), and in the long term (SMD = -0.20; 95% CI, -0.34 to -0.06; RR = 1.26; 95% CI, 1.11–1.42).¹⁶

A 2016 systematic review of 94 RCTs involving more than 25,000 patients also provided high-quality evidence that collaborative care yields small-to-moderate improvements in symptoms from mood disorders and mental health-related quality of life.¹⁵ A 2006 meta-analysis of 37 RCTs comprising 12,355 patients showed that collaborative care involving a case manager is more effective than standard care in improving depression outcomes at 6 months (SMD = 0.25; 95% CI, 0.18-0.32) and up to 5 years (SMD = 0.15; 95% CI, 0.001-0.31).²¹

Better care of mental health disorders also improves medical outcomes

Several trials have focused on jointly managing depression and a chronic physical condition such as chronic pain, diabetes, and coronary heart disease,²² demonstrating improved outcomes for both depression and the comanaged conditions.

• Chronic pain. When compared with usual care, collaborative care resulted in moderate reductions in both pain severity and associated disability (41.5% vs 17.3%; RR = 2.4; 95% CI, 1.6-3.2).²³
• Diabetes. Patients managed collaboratively were more likely to have a decrease of ≥ 1% in the glycated hemoglobin level from baseline (36% vs 19%; P = .006).²⁴
• Cardiovascular disease. Significant real-world risk reduction was achieved by improving blood pressure control (58% achieved blood pressure control compared with a projected target of 20%).²²

IS THERE A COMMON THREAD AMONG SUCCESSFUL CCMs?

Attempts to identify commonalities between the many iterations of successful CCMs have produced varying results due to differing selections of relevant RCTs.^25-29 However, a few common features have been identified:

• care managers assess symptoms at baseline and at follow-up using a standardized measure such as the Patient Health Questionnaire (PHQ-9);
• care managers monitor treatment adherence;
• follow-up is active for at least 16 weeks;
• primary care and mental health providers actively engage in patient management; and
• mental health specialists regularly supervise care managers.

The one feature that is consistent with improved outcomes is the presence of the care manager.^25-29

Continue to: The improvement associated...

The improvement associated with collaborative care is clinically meaningful to patients and physicians. In one RCT, collaborative care doubled response rates of depression treatment compared with usual care.³ Quality improvement data from real-world implementation of collaborative care programs suggests that similar outcomes can be achieved in a variety of settings.³⁰

COST BENEFITS OF CCM

Collaborative care for depression is associated with lower health care costs.^29,31

Patients with diabetes managed collaboratively have shown HbA_1c decreases of ≥ 1% from baseline more frequently than usual-care patients.

A meta-analysis of 57 RCTs in 2012 showed that CCM improves depression outcomes across populations, settings, and outcome domains, and that these results are achieved at little to no increase in treatment costs compared with usual care (Cohen’s d = 0.05; 95% CI, –0.02–0.12).²⁶

When collaborative care was compared with routine care in an RCT involving 1801 primary care patients ≥ 60 years who were suffering from depression, a cost saving of $3363 per patient over 4 years was demonstrated in the intervention arm.³¹

A technical analysis of 94 RCTs in 2015 concluded that CCM is cost effective compared with usual care, with a range of $15,000 to $80,000 per quality-adjusted life year gained. These studies also indicated that organizations’ costs to implement CCM increase in the short term. Based on this analysis, organizations would need to invest between $3 to $22 per patient per month to implement and sustain CCMs, depending on the prevalence of depression in the population.²⁹

Continue to: OTHER MODELS OF BHI

Higher levels of BHI such as co-location and integration do not have the same quality of evidence as CCM.

A 2009 Cochrane review of 42 studies involving 3880 patients found that mental health workers delivering psychological therapy and psychosocial interventions in primary care settings brought about significant reductions in primary care physician consultations (SMD = ‐0.17; 95% CI, ‐0.30 to ‐0.05); a relative risk reduction of 23% in psychotropic prescribing (RR = 0.67; 95% CI, 0.56–0.79); a decrease in prescribing costs (SMD = ‐0.22; 95% CI, ‐0.38 to ‐0.07); and a relative risk reduction in mental health referral of 87% (RR = 0.13; 95% CI, 0.09–0.20) for the patients they were seeing.³² The authors concluded the changes were modest in magnitude and inconsistent across different studies.³²

Collaborative care has improved depression outcomes at little to no increase in treatment costs compared with usual care.

Embedding medical providers in behavior health centers—ie, the reverse co-location model—also has very limited evidence. An RCT involving 120 veterans found that patients enrolled in a reverse co-location clinic did significantly better than controls seen in a general care clinic in terms of continuity of care and preventive care such as screening for hypertension (84.7% vs 65.6%; X ² = 5.9, P = .01), diabetes (71.2% vs 45.9%; X ² = 7.9, P < .005), hepatitis (39% vs 14.8%; X ² = 9, P = .003), and cholesterol (79.7% vs 57.4%; X ² = 6.9, P = .009).³³

HOW TO IMPLEMENT A SUCCESSFUL BHI PROGRAM

A demonstration and evaluation project involving 11 diverse practices in Colorado explored ways to integrate behavioral health in primary care. Five main themes emerged^34,35:

• Frame integrated care as a necessary paradigm shift to patient-centered, whole-person health care.
• Define relationships and protocols up front, understanding that they will evolve.
• Build inclusive, empowered teams to provide the foundation for integration.
• Develop a change management strategy of continuous evaluation and course correction.
• Use targeted data collection pertinent to integrated care to drive improvement and impart accountability.

The one feature that is consistent with improved outcomes is the presence of a care manager.

The Institute for Clinical and Economic Review has organized an extensive list of resources³⁶ for implementing BHI models, a sampling of which is shown in TABLE 2.

Continue to: TAKE-AWAY POINTS

There is high quality evidence that collaborative care works for the management of depression and anxiety disorder in primary care, and this is associated with significant cost savings. The one feature consistent in most successful BHI models is the care manager. More research is needed to identify which model of BHI works best for patients with SMI and substance use disorders. BHI cannot be accomplished by a few small changes to traditional care but requires a fundamental rethinking of care practices.

CORRESPONDENCE
Rajesh (FNU) Rajesh, MD, Main Campus Family Medicine Clinic, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected]

In a typical primary care practice, detecting and managing mental health problems competes with other priorities such as treating acute physical illness, monitoring chronic disease, providing preventive health services, and assessing compliance with standards of care.¹ These competing demands for a primary care provider’s time, paired with limited mental health resources in the community, may result in suboptimal behavioral health care.^1-3 Even when referrals are made to mental health care providers, depression is adequately treated only 20% of the time.^2,3 Additionally, individuals with serious mental illness and substance use disorders often do not receive adequate general medical care.^4,5

Approximately 30% of adults with physical disorders also have one or more behavioral health conditions, such as anxiety, panic, mood, or substance use disorders.⁶ Although physical and behavioral health conditions are inextricably linked, their assessment and treatment get separated into different silos.⁷ Given that fewer than 20% of depressed patients are seen by a psychiatrist or psychologist,⁸ the responsibility of providing mental health care often falls on the primary care physician.^8,9

Efforts to improve the treatment of common mental disorders in primary care have traditionally focused on screening for these disorders, educating primary care providers, developing treatment guidelines, and referring patients to mental health specialty care.¹⁰ However, behavioral health integration offers another way forward.

WHAT IS BEHAVIORAL HEALTH INTEGRATION?

Behavioral health integration (BHI) in primary care refers to primary care physicians and behavioral health clinicians working in concert with patients to address their primary care and behavioral health needs.¹¹

Numerous overlapping terms have been used to describe BHI, and this has caused some confusion. In 2013, the Agency for Healthcare Research and Quality (AHRQ) issued a lexicon standardizing the terminology used in BHI.¹¹ The commonly used terms are coordinated care, co-located care, and integrated care (TABLE 1),^11,12 and they may be best understood as part of a BHI continuum. A combined expert panel of the Substance Abuse and Mental Health Services Administration (SAMHSA) and the Health Resources and Services Administration (HRSA) has developed a conceptual framework defining 6 levels of integrated care spanning the 3 practice structures of coordinated care, co-located care, and integrated care (FIGURE 1).^12,13Reverse co-location is another frequently used term; it refers to primary care providers who work in settings devoted to mental health or chemical dependency treatment.¹¹

COORDINATED CARE AND THE COLLABORATIVE CARE MODEL

BHI at the level of coordinated care has almost exclusively been studied and practiced along the lines of the collaborative care model (CCM).^14-16 This model represents an advanced level of coordinated care in the BHI continuum. The most substantial evidence for CCM lies in the management of depression and anxiety.^14-16

Usual care involves the primary care physician and the patient. CCM adds 2 vital roles—a behavioral health care manager and a psychiatric consultant. A behavioral health care manager is typically a counselor, clinical social worker, psychologist, or psychiatric nurse who performs all care-management tasks including offering psychotherapy when that is part of the treatment plan.

Continue to: The care manager's functions include...

The care manager’s functions include systematic follow-up with structured monitoring of symptoms and treatment adherence, coordination and communication among care providers, patient education, and self-management support, including the use of motivational interviewing. The behavioral health care manager performs this systematic follow up by maintaining a patient “registry”—case-management software used in conjunction with, or embedded in, the practice electronic health record to track patients’ data and clinical outcomes, as well as to facilitate decision-making.

The care manager communicates with the psychiatrist, who offers suggestions for drug therapy, which is prescribed by the primary care physician. The care manager also regularly evaluates the patient’s status using a standardized scale, communicates these scores to the psychiatrist, and transmits any recommendations to the primary care physician (FIGURE 2).¹⁷

EVIDENCE FOR CCM

Collaborative and routine care were compared in a 2012 Cochrane review that included 79 randomized controlled trials (RCTs) involving 24,308 patients worldwide.¹⁶ Seventy-two of the 79 RCTs focused on patients with depression or depression with anxiety, while 6 studies included participants with only anxiety disorders.¹⁶ One additional study focused on mental health quality of life. (To learn about CCM and severe mental illness and substance use disorder, see “Less well studied: CCM and severe mental illness, alcohol dependence.”^18-20)

For adults with depression treated with the CCM, significantly greater improvement in depression outcome measures was seen in the short-term (standardized mean difference [SMD] = -0.34; 95% confidence interval [CI], -0.41 to -0.27; risk ratio [RR] = 1.32; 95% CI, 1.22-1.43), in the medium term (SMD = -0.28; 95% CI, -0.41 to -0.15; RR = 1.31; 95% CI, 1.17–1.48), and in the long term (SMD = -0.35; 95% CI, -0.46 to -0.24; RR = 1.29; 95% CI, 1.18–1.41).¹⁶

Comparisons of mental health quality of life over the short term (0-6 months), medium term (7-12 months), and long term (13-24 months) did not show any significant difference between CCM and routine care.¹⁶ Comparisons of physical health quality of life over the short term and medium term did not show any significant difference between CCM and routine care.¹⁶

Continue to: Significantly greater improvement...

Significantly greater improvement in anxiety outcomes was seen for adults treated with CCM in the short term (SMD = -0.30; 95% CI, -0.44 to -0.17; RR = 1.50; 95% CI, 1.21–1.87), in the medium term (SMD = -0.33; 95% CI, -0.47 to -0.19; RR = 1.41; 95% CI, 1.18-1.69), and in the long term (SMD = -0.20; 95% CI, -0.34 to -0.06; RR = 1.26; 95% CI, 1.11–1.42).¹⁶

A 2016 systematic review of 94 RCTs involving more than 25,000 patients also provided high-quality evidence that collaborative care yields small-to-moderate improvements in symptoms from mood disorders and mental health-related quality of life.¹⁵ A 2006 meta-analysis of 37 RCTs comprising 12,355 patients showed that collaborative care involving a case manager is more effective than standard care in improving depression outcomes at 6 months (SMD = 0.25; 95% CI, 0.18-0.32) and up to 5 years (SMD = 0.15; 95% CI, 0.001-0.31).²¹

Better care of mental health disorders also improves medical outcomes

Several trials have focused on jointly managing depression and a chronic physical condition such as chronic pain, diabetes, and coronary heart disease,²² demonstrating improved outcomes for both depression and the comanaged conditions.

• Chronic pain. When compared with usual care, collaborative care resulted in moderate reductions in both pain severity and associated disability (41.5% vs 17.3%; RR = 2.4; 95% CI, 1.6-3.2).²³
• Diabetes. Patients managed collaboratively were more likely to have a decrease of ≥ 1% in the glycated hemoglobin level from baseline (36% vs 19%; P = .006).²⁴
• Cardiovascular disease. Significant real-world risk reduction was achieved by improving blood pressure control (58% achieved blood pressure control compared with a projected target of 20%).²²

IS THERE A COMMON THREAD AMONG SUCCESSFUL CCMs?

Attempts to identify commonalities between the many iterations of successful CCMs have produced varying results due to differing selections of relevant RCTs.^25-29 However, a few common features have been identified:

• care managers assess symptoms at baseline and at follow-up using a standardized measure such as the Patient Health Questionnaire (PHQ-9);
• care managers monitor treatment adherence;
• follow-up is active for at least 16 weeks;
• primary care and mental health providers actively engage in patient management; and
• mental health specialists regularly supervise care managers.

The one feature that is consistent with improved outcomes is the presence of the care manager.^25-29

Continue to: The improvement associated...

The improvement associated with collaborative care is clinically meaningful to patients and physicians. In one RCT, collaborative care doubled response rates of depression treatment compared with usual care.³ Quality improvement data from real-world implementation of collaborative care programs suggests that similar outcomes can be achieved in a variety of settings.³⁰

COST BENEFITS OF CCM

Collaborative care for depression is associated with lower health care costs.^29,31

Patients with diabetes managed collaboratively have shown HbA_1c decreases of ≥ 1% from baseline more frequently than usual-care patients.

A meta-analysis of 57 RCTs in 2012 showed that CCM improves depression outcomes across populations, settings, and outcome domains, and that these results are achieved at little to no increase in treatment costs compared with usual care (Cohen’s d = 0.05; 95% CI, –0.02–0.12).²⁶

When collaborative care was compared with routine care in an RCT involving 1801 primary care patients ≥ 60 years who were suffering from depression, a cost saving of $3363 per patient over 4 years was demonstrated in the intervention arm.³¹

A technical analysis of 94 RCTs in 2015 concluded that CCM is cost effective compared with usual care, with a range of $15,000 to $80,000 per quality-adjusted life year gained. These studies also indicated that organizations’ costs to implement CCM increase in the short term. Based on this analysis, organizations would need to invest between $3 to $22 per patient per month to implement and sustain CCMs, depending on the prevalence of depression in the population.²⁹

Continue to: OTHER MODELS OF BHI

Higher levels of BHI such as co-location and integration do not have the same quality of evidence as CCM.

A 2009 Cochrane review of 42 studies involving 3880 patients found that mental health workers delivering psychological therapy and psychosocial interventions in primary care settings brought about significant reductions in primary care physician consultations (SMD = ‐0.17; 95% CI, ‐0.30 to ‐0.05); a relative risk reduction of 23% in psychotropic prescribing (RR = 0.67; 95% CI, 0.56–0.79); a decrease in prescribing costs (SMD = ‐0.22; 95% CI, ‐0.38 to ‐0.07); and a relative risk reduction in mental health referral of 87% (RR = 0.13; 95% CI, 0.09–0.20) for the patients they were seeing.³² The authors concluded the changes were modest in magnitude and inconsistent across different studies.³²

Collaborative care has improved depression outcomes at little to no increase in treatment costs compared with usual care.

Embedding medical providers in behavior health centers—ie, the reverse co-location model—also has very limited evidence. An RCT involving 120 veterans found that patients enrolled in a reverse co-location clinic did significantly better than controls seen in a general care clinic in terms of continuity of care and preventive care such as screening for hypertension (84.7% vs 65.6%; X ² = 5.9, P = .01), diabetes (71.2% vs 45.9%; X ² = 7.9, P < .005), hepatitis (39% vs 14.8%; X ² = 9, P = .003), and cholesterol (79.7% vs 57.4%; X ² = 6.9, P = .009).³³

HOW TO IMPLEMENT A SUCCESSFUL BHI PROGRAM

A demonstration and evaluation project involving 11 diverse practices in Colorado explored ways to integrate behavioral health in primary care. Five main themes emerged^34,35:

• Frame integrated care as a necessary paradigm shift to patient-centered, whole-person health care.
• Define relationships and protocols up front, understanding that they will evolve.
• Build inclusive, empowered teams to provide the foundation for integration.
• Develop a change management strategy of continuous evaluation and course correction.
• Use targeted data collection pertinent to integrated care to drive improvement and impart accountability.

The one feature that is consistent with improved outcomes is the presence of a care manager.

The Institute for Clinical and Economic Review has organized an extensive list of resources³⁶ for implementing BHI models, a sampling of which is shown in TABLE 2.

Continue to: TAKE-AWAY POINTS

There is high quality evidence that collaborative care works for the management of depression and anxiety disorder in primary care, and this is associated with significant cost savings. The one feature consistent in most successful BHI models is the care manager. More research is needed to identify which model of BHI works best for patients with SMI and substance use disorders. BHI cannot be accomplished by a few small changes to traditional care but requires a fundamental rethinking of care practices.

CORRESPONDENCE
Rajesh (FNU) Rajesh, MD, Main Campus Family Medicine Clinic, MetroHealth, 2500 MetroHealth Drive, Cleveland, OH 44109; [email protected]

ABSTRACT

Purpose To avoid disruption of administrative and clinical workflow in an increasingly complex system of health information technology, health care systems and providers have started using medical scribes. The purpose of this study was to investigate the impact of medical scribes on patient satisfaction, physician satisfaction, and quality measure documentation in a family medicine office.

Methods We reviewed 1000 electronic health records for documentation of specified quality measures in the family medicine setting, before and after the use of medical scribes. We surveyed 150 patients on attitude, comfort, and acceptance of medical scribes during their visit. Five physicians shared their perceptions related to productivity, efficiency, and overall job satisfaction on working with medical scribes.

Results Documentation of 4 quality measures improved with the use of scribes, demonstrating statistical significance: fall risk assessment (odds ratio [OR] = 5.5; P = .02), follow-up tobacco screen (OR = 6.4; P = .01), follow-up body mass index plan (OR = 6.2; P < .01), and follow-up blood pressure plan (OR = 39.6; P < .01). Patients reported comfort with scribes in the examination room (96%, n = 144), a more focused health care provider (76%, n = 113), increased efficiency (74%, n = 109), and a higher degree of satisfaction with the office visit (61%, n = 90). Physicians believed they were providing better care and developing better relationships with patients while spending less time documenting and experiencing less stress.

Conclusions Use of medical scribes in a primary care setting was associated with higher patient and physician satisfaction. Patients felt comfortable with a medical scribe in the room, attested to their professionalism, and understood their purpose during the visit. The use of medical scribes in this primary care setting improved documentation of 4 quality measures.

[polldaddy:10339849]

The widespread implementation and adoption of electronic health records (EHRs) continues to increase, primarily motivated by federal incentives through the Centers for Medicare and Medicaid Services to positively impact patient care. Physician use of the EHR in the exam room has the potential to affect the patient-physician relationship, patient satisfaction, physician satisfaction, physician productivity, and physician reimbursement. In the United States, the Health Information Technology for Economic and Clinical Health Act of 2009 established incentive programs to promote meaningful use of EHRs in primary care.¹ Integrating EHRs into physician practice, adoption of meaningful use, and the increasing challenge of pay-for-performance quality measures have generated additional hours of administrative work for health care providers. These intrusions on routine clinical care, while hypothesized to improve care, have diminished physician satisfaction, increased stress, and contributed to physician burnout.²

The expanded role of clinicians incentivized to capture metrics for value-based care introduces an unprecedented level of multitasking required at the point of care. In a clinical setting, multitasking undermines the core clinical activities of observation, communication, problem solving, and, ultimately, the development of trusting relationships.^3,4 EHR documentation creates a barrier to patient engagement and may contribute to patients feeling isolated when unable to view data being entered.^5,6

Potential benefits of scribes. One means of increasing physician satisfaction and productivity may be the integration of medical scribes into health care systems. Medical scribes do not operate independently but are able to document activities or receive dictation critical for patient management—eg, recording patient histories, documenting physical examination findings and procedures, and following up on lab reports.⁷

Continue to: In a 2015 systematic review...

In a 2015 systematic review, Shultz and Holmstrom found that medical scribes in specialty settings may improve clinician satisfaction, productivity, time-related efficiency, revenue, and patient-clinician interactions.⁸ The use of scribes in one study increased the number of patients seen and time saved by emergency physicians, thereby increasing physician productivity.⁹ Studies have also shown that physicians were more satisfied during scribe engagement, related to increased time spent with patients, decreased work-related stress, and increased overall workplace satisfaction.^10-12

Sixty-one percent of patients were more satisfied with their office visit with a scribe present.

Studies on the use of medical scribes have mainly focused on physician satisfaction and productivity; however, the data on patient satisfaction are limited. Data about the use of the medical scribe in the primary care setting are also limited. The aim of our research was threefold. We wanted to evaluate the effects of using a medical scribe on: (1) patient satisfaction, (2) documentation of primary care pay-for-performance quality measures, and (3) physicians’ perceptions of the use of scribes in the primary care setting.

METHODS

Data collection

This study was conducted at Family Practice Group in Arlington, Massachusetts, where 5 part-time physicians and 3 full-time physician assistants see approximately 400 patients each week. The representative patient population is approximately 80% privately insured, 10% Medicaid, and 10% Medicare. The EHR system is eClinicalWorks.

The scribes were undergraduate college students who were interested in careers as health care professionals. They had no scribe training or experience working in a medical office. These scribes underwent 4 hours of training in EHR functionality, pay-for-performance quality measures, and risk coding (using appropriate medical codes that capture the patient’s level of medical complexity). The Independent Physician Association affiliated with Family Practice Group provided this training at no cost to the practice. The 3 scribes worked full-time with the 5 part-time physicians in the study. Scribes were not required to have had a medical background prior to entering the program.

After the aforementioned training, scribes began working full-time with physicians during patient visits and continued learning on the job through feedback from supervising physicians. Scribes documented the patient encounters, recording medical and social histories and physical exam findings, and transcribing discussions of treatment plans and physicians’ instructions to patients.

Continue to: We reviewed patient EHRs...

We reviewed patient EHRs of 5 family physicians over 2 time periods: the 3 months prior to having a medical scribe and the 3 months after beginning to work with a medical scribe. Chart data extraction occurred from 4/11/13 to 8/28/14. We reviewed 1000 patient EHRs—100 EHRs each for the 5 participating physicians before and after scribe use. Selected EHRs ran chronologically from the start of each 3-month period. Reviewing EHRs at 3 months after the onset of the medical scribe program allowed time for the scribes to be fully integrated into the practice and confident in their job responsibilities. Chart review was performed by an office administrator who was blinded as to whether documentation had been done with or without a scribe present during the visit.

Eight quality measures were evaluated in chart review. These measures were drawn from the Healthcare Effectiveness Data and Information Set (HEDIS), a tool used to measure performance in medical care and service.

We surveyed 30 patients of each of the 5 providers, yielding a total of 150 survey responses. A medical assistant gave surveys to patients in the exam room following each office visit, to be completed anonymously and privately. Patients were told that surveys would take less than 2 minutes to complete. Office visits included episodic visits, physical exams, and chronic disease management.

Physicians believed they were saving, on average, 1.5 hours each day with the use of a scribe.

After the trial period, we surveyed participating physicians regarding medical scribe assistance with documentation. We also asked the physicians 3 open-ended questions regarding their experiences with their medical scribe.

This study was reviewed and approved (IRB Approval #11424) by the Tufts Health Science Campus Institutional Review Board.

Continue to: Data analysis

During chart review, we assessed the rate at which documentation was completed for 8 quality outcome measures commonly used in the primary care setting (TABLE 1), before and after the introduction of medical scribes. These quality measures and pertinent descriptors are listed in TABLE 2.¹³ Presence or absence of documentation on all quality measures was noted for all applicable patients.

One hundred fifty patients were surveyed immediately after their office visit on their perceptions of medical scribes, including their attitude toward, comfort with, and acceptance of medical scribes (TABLE 3). Five participating physicians were surveyed to assess their perceptions related to productivity and job satisfaction with the use of medical scribes (TABLE 4), and regarding time saved and additional patients seen. Those who collected and analyzed the data from the surveys were blinded to patient and physician identifiers.

Statistical analysis

Using chi-squared tests, we compared the number of positive documentations for the 8 outcome measures before and after the use of medical scribes. Two-sided P values < .05 were considered statistically significant. All statistical analyses were performed with the use of STATA version 9 (StataCorp LP. College Station, Tex).

Physician survey data were calculated on a Likert scale, with a score of 1 corresponding to “strongly disagree,” 2 “disagree,” 3 “neither agree nor disagree,” 4 “agree,” and 5 “strongly agree.” Using the 5 answers generated from the 5 physicians, we calculated the mean for each question.

RESULTS

The use of scribes demonstrated a statistically significant improvement in the documentation of 4 (out of 8) pay-for-performance measures (TABLE 1): fall risk assessment (odds ratio [OR] = 5.5, P = .02), follow-up tobacco screen (OR = 6.4; P = .01), follow-up body mass index (BMI) plan (OR = 6.2; P < .01), and follow-up blood pressure plan (OR = 39.6; P < .01). Sample sizes of each quality measure vary as there were differing numbers of applicable patients for each quality measure within the overall 1000 charts.

Continue to: We established at the beginning...

We established at the beginning of the study a target of obtaining surveys from 30 patients of each of the 5 physicians (total of 150). Response rates for surveys were 100% for both the 150 patients and the 5 physicians. No patients declined to complete the survey, although some did not answer every question.

Patients generally had positive experiences with medical scribes (TABLE 3). The majority of patients (96%, n = 144) felt comfortable with the scribe in the room during the visit with their provider. Patients felt that the provider focused on them “a little to a lot more” (75.8%, n = 113) and thought their visit was more efficient (73.6%, n = 109) as a result of the scribe being present vs not being present. Most patients were more satisfied with their office visit with the scribe being present (60.8%, n = 90).

Physicians felt that working with a medical scribe helped them connect with their patients, made patients feel that their physician was more attentive to them, contributed to better patient care, decreased the time they spent documenting in EHR, and contributed to faster work flow (TABLE 4). The physicians also believed they had saved a mean of 1.5 hours each day with the use of a medical scribe, and that they did not have to change their schedule in any way to accommodate additional patients as a result of having a scribe.

DISCUSSION

Documentation of fall risk assessment, follow-up tobacco screening, follow-up BMI plan, and follow-up blood pressure plan all demonstrated statistically significant increases with the use of medical scribes compared with practice before scribes. Follow-up depression screen and transition of care management had relatively high ORs (3.2 and 8, respectively), but did not yield statistically significant values, in part due to small sample sizes as the number of patients who were hospitalized and the number of patients who screened positive for depression were relatively small out of the total group of 1000 patients. The use of scribes had little effect on depression screen and tobacco screen. This is likely due to the fact that there were already effective office systems in place at the practice that alerted medical assistants to complete these screens for each appropriate patient.

We found that the use of medical scribes in a primary care setting was associated with both higher patient and physician satisfaction. Although the 5 physicians in this study chose not to see additional patients when using a medical scribe, they believed they were saving, on average, 1.5 hours of time each day with the use of a scribe. All 5 physicians reported that medical scribes enabled them to provide better patient care and to help patients feel as though they had more of the physician’s attention. Patient respondents attested to their provider focusing on them more during the visit. According to patient surveys, 40.4% of respondents felt that physicians addressed their concerns more thoroughly during the visit, while the remainder of patients did not.

Continue to: Some concerns...

Some concerns of introducing medical scribes into a health care system include possible patient discomfort with a third party being present during the visit and the cost of employing medical scribes. In this study, the vast majority of patients (96%) felt comfortable with a scribe in the room. Future research could compare patient discomfort due to the presence of a medical scribe with patient discomfort due to a physician using a computer during the visit.

Limitations of this study include the small sample size of both physicians and patients; a lack of validated measures for calculating productivity, time/efficiency, and overall satisfaction; and short time periods leading up to and following the introduction of medical scribes. In addition, EHRs of patients were chosen sequentially and not randomly, which could be a confounder. Participating physicians were aware of being studied; therefore, documentation could have been affected by the Hawthorne effect. The study also was limited to one family medicine site. Although improved documentation of primary care pay-for-performance quality measures was reported, wide confidence intervals and small patient numbers hindered generalizability of findings.

Documentation of 4 out of 8 pay-forperformance measures showed statistically significant improvement with the use of scribes.

Additional studies are needed with a robust analytic plan sufficient to demonstrate baseline provider familiarity with EHRs, accuracy of medical scribe documentation, and improved documentation of pay-for-performance quality measures. Additional investigation regarding the variable competency of different medical scribes could be useful in measuring the effects of the scribe on a variety of outcomes related to both the physician and patient.

It is possible that the improved documentation yielded by the use of medical scribes could generate billing codes that reimburse physicians at a higher level (eg, a higher ratio of 99214 to 99213), leading to increased pay. Future research could aim to quantify this source of increased revenue. Furthermore, investigations could aim to quantify the revenue that medical scribes generate via improved quality measure pay-for-performance documentation.

CORRESPONDENCE
Jessica Platt, MD, 195 Canal Street, Malden, MA 02148; [email protected].

ABSTRACT

Purpose To avoid disruption of administrative and clinical workflow in an increasingly complex system of health information technology, health care systems and providers have started using medical scribes. The purpose of this study was to investigate the impact of medical scribes on patient satisfaction, physician satisfaction, and quality measure documentation in a family medicine office.

Methods We reviewed 1000 electronic health records for documentation of specified quality measures in the family medicine setting, before and after the use of medical scribes. We surveyed 150 patients on attitude, comfort, and acceptance of medical scribes during their visit. Five physicians shared their perceptions related to productivity, efficiency, and overall job satisfaction on working with medical scribes.

Results Documentation of 4 quality measures improved with the use of scribes, demonstrating statistical significance: fall risk assessment (odds ratio [OR] = 5.5; P = .02), follow-up tobacco screen (OR = 6.4; P = .01), follow-up body mass index plan (OR = 6.2; P < .01), and follow-up blood pressure plan (OR = 39.6; P < .01). Patients reported comfort with scribes in the examination room (96%, n = 144), a more focused health care provider (76%, n = 113), increased efficiency (74%, n = 109), and a higher degree of satisfaction with the office visit (61%, n = 90). Physicians believed they were providing better care and developing better relationships with patients while spending less time documenting and experiencing less stress.

Conclusions Use of medical scribes in a primary care setting was associated with higher patient and physician satisfaction. Patients felt comfortable with a medical scribe in the room, attested to their professionalism, and understood their purpose during the visit. The use of medical scribes in this primary care setting improved documentation of 4 quality measures.

[polldaddy:10339849]

The widespread implementation and adoption of electronic health records (EHRs) continues to increase, primarily motivated by federal incentives through the Centers for Medicare and Medicaid Services to positively impact patient care. Physician use of the EHR in the exam room has the potential to affect the patient-physician relationship, patient satisfaction, physician satisfaction, physician productivity, and physician reimbursement. In the United States, the Health Information Technology for Economic and Clinical Health Act of 2009 established incentive programs to promote meaningful use of EHRs in primary care.¹ Integrating EHRs into physician practice, adoption of meaningful use, and the increasing challenge of pay-for-performance quality measures have generated additional hours of administrative work for health care providers. These intrusions on routine clinical care, while hypothesized to improve care, have diminished physician satisfaction, increased stress, and contributed to physician burnout.²

The expanded role of clinicians incentivized to capture metrics for value-based care introduces an unprecedented level of multitasking required at the point of care. In a clinical setting, multitasking undermines the core clinical activities of observation, communication, problem solving, and, ultimately, the development of trusting relationships.^3,4 EHR documentation creates a barrier to patient engagement and may contribute to patients feeling isolated when unable to view data being entered.^5,6

Potential benefits of scribes. One means of increasing physician satisfaction and productivity may be the integration of medical scribes into health care systems. Medical scribes do not operate independently but are able to document activities or receive dictation critical for patient management—eg, recording patient histories, documenting physical examination findings and procedures, and following up on lab reports.⁷

Continue to: In a 2015 systematic review...

In a 2015 systematic review, Shultz and Holmstrom found that medical scribes in specialty settings may improve clinician satisfaction, productivity, time-related efficiency, revenue, and patient-clinician interactions.⁸ The use of scribes in one study increased the number of patients seen and time saved by emergency physicians, thereby increasing physician productivity.⁹ Studies have also shown that physicians were more satisfied during scribe engagement, related to increased time spent with patients, decreased work-related stress, and increased overall workplace satisfaction.^10-12

Sixty-one percent of patients were more satisfied with their office visit with a scribe present.

Studies on the use of medical scribes have mainly focused on physician satisfaction and productivity; however, the data on patient satisfaction are limited. Data about the use of the medical scribe in the primary care setting are also limited. The aim of our research was threefold. We wanted to evaluate the effects of using a medical scribe on: (1) patient satisfaction, (2) documentation of primary care pay-for-performance quality measures, and (3) physicians’ perceptions of the use of scribes in the primary care setting.

METHODS

Data collection

This study was conducted at Family Practice Group in Arlington, Massachusetts, where 5 part-time physicians and 3 full-time physician assistants see approximately 400 patients each week. The representative patient population is approximately 80% privately insured, 10% Medicaid, and 10% Medicare. The EHR system is eClinicalWorks.

The scribes were undergraduate college students who were interested in careers as health care professionals. They had no scribe training or experience working in a medical office. These scribes underwent 4 hours of training in EHR functionality, pay-for-performance quality measures, and risk coding (using appropriate medical codes that capture the patient’s level of medical complexity). The Independent Physician Association affiliated with Family Practice Group provided this training at no cost to the practice. The 3 scribes worked full-time with the 5 part-time physicians in the study. Scribes were not required to have had a medical background prior to entering the program.

After the aforementioned training, scribes began working full-time with physicians during patient visits and continued learning on the job through feedback from supervising physicians. Scribes documented the patient encounters, recording medical and social histories and physical exam findings, and transcribing discussions of treatment plans and physicians’ instructions to patients.

Continue to: We reviewed patient EHRs...

We reviewed patient EHRs of 5 family physicians over 2 time periods: the 3 months prior to having a medical scribe and the 3 months after beginning to work with a medical scribe. Chart data extraction occurred from 4/11/13 to 8/28/14. We reviewed 1000 patient EHRs—100 EHRs each for the 5 participating physicians before and after scribe use. Selected EHRs ran chronologically from the start of each 3-month period. Reviewing EHRs at 3 months after the onset of the medical scribe program allowed time for the scribes to be fully integrated into the practice and confident in their job responsibilities. Chart review was performed by an office administrator who was blinded as to whether documentation had been done with or without a scribe present during the visit.

Eight quality measures were evaluated in chart review. These measures were drawn from the Healthcare Effectiveness Data and Information Set (HEDIS), a tool used to measure performance in medical care and service.

We surveyed 30 patients of each of the 5 providers, yielding a total of 150 survey responses. A medical assistant gave surveys to patients in the exam room following each office visit, to be completed anonymously and privately. Patients were told that surveys would take less than 2 minutes to complete. Office visits included episodic visits, physical exams, and chronic disease management.

Physicians believed they were saving, on average, 1.5 hours each day with the use of a scribe.

After the trial period, we surveyed participating physicians regarding medical scribe assistance with documentation. We also asked the physicians 3 open-ended questions regarding their experiences with their medical scribe.

This study was reviewed and approved (IRB Approval #11424) by the Tufts Health Science Campus Institutional Review Board.

Continue to: Data analysis

During chart review, we assessed the rate at which documentation was completed for 8 quality outcome measures commonly used in the primary care setting (TABLE 1), before and after the introduction of medical scribes. These quality measures and pertinent descriptors are listed in TABLE 2.¹³ Presence or absence of documentation on all quality measures was noted for all applicable patients.

One hundred fifty patients were surveyed immediately after their office visit on their perceptions of medical scribes, including their attitude toward, comfort with, and acceptance of medical scribes (TABLE 3). Five participating physicians were surveyed to assess their perceptions related to productivity and job satisfaction with the use of medical scribes (TABLE 4), and regarding time saved and additional patients seen. Those who collected and analyzed the data from the surveys were blinded to patient and physician identifiers.

Statistical analysis

Using chi-squared tests, we compared the number of positive documentations for the 8 outcome measures before and after the use of medical scribes. Two-sided P values < .05 were considered statistically significant. All statistical analyses were performed with the use of STATA version 9 (StataCorp LP. College Station, Tex).

Physician survey data were calculated on a Likert scale, with a score of 1 corresponding to “strongly disagree,” 2 “disagree,” 3 “neither agree nor disagree,” 4 “agree,” and 5 “strongly agree.” Using the 5 answers generated from the 5 physicians, we calculated the mean for each question.

RESULTS

The use of scribes demonstrated a statistically significant improvement in the documentation of 4 (out of 8) pay-for-performance measures (TABLE 1): fall risk assessment (odds ratio [OR] = 5.5, P = .02), follow-up tobacco screen (OR = 6.4; P = .01), follow-up body mass index (BMI) plan (OR = 6.2; P < .01), and follow-up blood pressure plan (OR = 39.6; P < .01). Sample sizes of each quality measure vary as there were differing numbers of applicable patients for each quality measure within the overall 1000 charts.

Continue to: We established at the beginning...

We established at the beginning of the study a target of obtaining surveys from 30 patients of each of the 5 physicians (total of 150). Response rates for surveys were 100% for both the 150 patients and the 5 physicians. No patients declined to complete the survey, although some did not answer every question.

Patients generally had positive experiences with medical scribes (TABLE 3). The majority of patients (96%, n = 144) felt comfortable with the scribe in the room during the visit with their provider. Patients felt that the provider focused on them “a little to a lot more” (75.8%, n = 113) and thought their visit was more efficient (73.6%, n = 109) as a result of the scribe being present vs not being present. Most patients were more satisfied with their office visit with the scribe being present (60.8%, n = 90).

Physicians felt that working with a medical scribe helped them connect with their patients, made patients feel that their physician was more attentive to them, contributed to better patient care, decreased the time they spent documenting in EHR, and contributed to faster work flow (TABLE 4). The physicians also believed they had saved a mean of 1.5 hours each day with the use of a medical scribe, and that they did not have to change their schedule in any way to accommodate additional patients as a result of having a scribe.

DISCUSSION

Documentation of fall risk assessment, follow-up tobacco screening, follow-up BMI plan, and follow-up blood pressure plan all demonstrated statistically significant increases with the use of medical scribes compared with practice before scribes. Follow-up depression screen and transition of care management had relatively high ORs (3.2 and 8, respectively), but did not yield statistically significant values, in part due to small sample sizes as the number of patients who were hospitalized and the number of patients who screened positive for depression were relatively small out of the total group of 1000 patients. The use of scribes had little effect on depression screen and tobacco screen. This is likely due to the fact that there were already effective office systems in place at the practice that alerted medical assistants to complete these screens for each appropriate patient.

We found that the use of medical scribes in a primary care setting was associated with both higher patient and physician satisfaction. Although the 5 physicians in this study chose not to see additional patients when using a medical scribe, they believed they were saving, on average, 1.5 hours of time each day with the use of a scribe. All 5 physicians reported that medical scribes enabled them to provide better patient care and to help patients feel as though they had more of the physician’s attention. Patient respondents attested to their provider focusing on them more during the visit. According to patient surveys, 40.4% of respondents felt that physicians addressed their concerns more thoroughly during the visit, while the remainder of patients did not.

Continue to: Some concerns...

Some concerns of introducing medical scribes into a health care system include possible patient discomfort with a third party being present during the visit and the cost of employing medical scribes. In this study, the vast majority of patients (96%) felt comfortable with a scribe in the room. Future research could compare patient discomfort due to the presence of a medical scribe with patient discomfort due to a physician using a computer during the visit.

Limitations of this study include the small sample size of both physicians and patients; a lack of validated measures for calculating productivity, time/efficiency, and overall satisfaction; and short time periods leading up to and following the introduction of medical scribes. In addition, EHRs of patients were chosen sequentially and not randomly, which could be a confounder. Participating physicians were aware of being studied; therefore, documentation could have been affected by the Hawthorne effect. The study also was limited to one family medicine site. Although improved documentation of primary care pay-for-performance quality measures was reported, wide confidence intervals and small patient numbers hindered generalizability of findings.

Documentation of 4 out of 8 pay-forperformance measures showed statistically significant improvement with the use of scribes.

Additional studies are needed with a robust analytic plan sufficient to demonstrate baseline provider familiarity with EHRs, accuracy of medical scribe documentation, and improved documentation of pay-for-performance quality measures. Additional investigation regarding the variable competency of different medical scribes could be useful in measuring the effects of the scribe on a variety of outcomes related to both the physician and patient.

It is possible that the improved documentation yielded by the use of medical scribes could generate billing codes that reimburse physicians at a higher level (eg, a higher ratio of 99214 to 99213), leading to increased pay. Future research could aim to quantify this source of increased revenue. Furthermore, investigations could aim to quantify the revenue that medical scribes generate via improved quality measure pay-for-performance documentation.

CORRESPONDENCE
Jessica Platt, MD, 195 Canal Street, Malden, MA 02148; [email protected].

ABSTRACT

Purpose To avoid disruption of administrative and clinical workflow in an increasingly complex system of health information technology, health care systems and providers have started using medical scribes. The purpose of this study was to investigate the impact of medical scribes on patient satisfaction, physician satisfaction, and quality measure documentation in a family medicine office.

Methods We reviewed 1000 electronic health records for documentation of specified quality measures in the family medicine setting, before and after the use of medical scribes. We surveyed 150 patients on attitude, comfort, and acceptance of medical scribes during their visit. Five physicians shared their perceptions related to productivity, efficiency, and overall job satisfaction on working with medical scribes.

Results Documentation of 4 quality measures improved with the use of scribes, demonstrating statistical significance: fall risk assessment (odds ratio [OR] = 5.5; P = .02), follow-up tobacco screen (OR = 6.4; P = .01), follow-up body mass index plan (OR = 6.2; P < .01), and follow-up blood pressure plan (OR = 39.6; P < .01). Patients reported comfort with scribes in the examination room (96%, n = 144), a more focused health care provider (76%, n = 113), increased efficiency (74%, n = 109), and a higher degree of satisfaction with the office visit (61%, n = 90). Physicians believed they were providing better care and developing better relationships with patients while spending less time documenting and experiencing less stress.

Conclusions Use of medical scribes in a primary care setting was associated with higher patient and physician satisfaction. Patients felt comfortable with a medical scribe in the room, attested to their professionalism, and understood their purpose during the visit. The use of medical scribes in this primary care setting improved documentation of 4 quality measures.

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The widespread implementation and adoption of electronic health records (EHRs) continues to increase, primarily motivated by federal incentives through the Centers for Medicare and Medicaid Services to positively impact patient care. Physician use of the EHR in the exam room has the potential to affect the patient-physician relationship, patient satisfaction, physician satisfaction, physician productivity, and physician reimbursement. In the United States, the Health Information Technology for Economic and Clinical Health Act of 2009 established incentive programs to promote meaningful use of EHRs in primary care.¹ Integrating EHRs into physician practice, adoption of meaningful use, and the increasing challenge of pay-for-performance quality measures have generated additional hours of administrative work for health care providers. These intrusions on routine clinical care, while hypothesized to improve care, have diminished physician satisfaction, increased stress, and contributed to physician burnout.²

The expanded role of clinicians incentivized to capture metrics for value-based care introduces an unprecedented level of multitasking required at the point of care. In a clinical setting, multitasking undermines the core clinical activities of observation, communication, problem solving, and, ultimately, the development of trusting relationships.^3,4 EHR documentation creates a barrier to patient engagement and may contribute to patients feeling isolated when unable to view data being entered.^5,6

Potential benefits of scribes. One means of increasing physician satisfaction and productivity may be the integration of medical scribes into health care systems. Medical scribes do not operate independently but are able to document activities or receive dictation critical for patient management—eg, recording patient histories, documenting physical examination findings and procedures, and following up on lab reports.⁷

Continue to: In a 2015 systematic review...

In a 2015 systematic review, Shultz and Holmstrom found that medical scribes in specialty settings may improve clinician satisfaction, productivity, time-related efficiency, revenue, and patient-clinician interactions.⁸ The use of scribes in one study increased the number of patients seen and time saved by emergency physicians, thereby increasing physician productivity.⁹ Studies have also shown that physicians were more satisfied during scribe engagement, related to increased time spent with patients, decreased work-related stress, and increased overall workplace satisfaction.^10-12

Sixty-one percent of patients were more satisfied with their office visit with a scribe present.

Studies on the use of medical scribes have mainly focused on physician satisfaction and productivity; however, the data on patient satisfaction are limited. Data about the use of the medical scribe in the primary care setting are also limited. The aim of our research was threefold. We wanted to evaluate the effects of using a medical scribe on: (1) patient satisfaction, (2) documentation of primary care pay-for-performance quality measures, and (3) physicians’ perceptions of the use of scribes in the primary care setting.

METHODS

Data collection

This study was conducted at Family Practice Group in Arlington, Massachusetts, where 5 part-time physicians and 3 full-time physician assistants see approximately 400 patients each week. The representative patient population is approximately 80% privately insured, 10% Medicaid, and 10% Medicare. The EHR system is eClinicalWorks.

The scribes were undergraduate college students who were interested in careers as health care professionals. They had no scribe training or experience working in a medical office. These scribes underwent 4 hours of training in EHR functionality, pay-for-performance quality measures, and risk coding (using appropriate medical codes that capture the patient’s level of medical complexity). The Independent Physician Association affiliated with Family Practice Group provided this training at no cost to the practice. The 3 scribes worked full-time with the 5 part-time physicians in the study. Scribes were not required to have had a medical background prior to entering the program.

After the aforementioned training, scribes began working full-time with physicians during patient visits and continued learning on the job through feedback from supervising physicians. Scribes documented the patient encounters, recording medical and social histories and physical exam findings, and transcribing discussions of treatment plans and physicians’ instructions to patients.

Continue to: We reviewed patient EHRs...

We reviewed patient EHRs of 5 family physicians over 2 time periods: the 3 months prior to having a medical scribe and the 3 months after beginning to work with a medical scribe. Chart data extraction occurred from 4/11/13 to 8/28/14. We reviewed 1000 patient EHRs—100 EHRs each for the 5 participating physicians before and after scribe use. Selected EHRs ran chronologically from the start of each 3-month period. Reviewing EHRs at 3 months after the onset of the medical scribe program allowed time for the scribes to be fully integrated into the practice and confident in their job responsibilities. Chart review was performed by an office administrator who was blinded as to whether documentation had been done with or without a scribe present during the visit.

Eight quality measures were evaluated in chart review. These measures were drawn from the Healthcare Effectiveness Data and Information Set (HEDIS), a tool used to measure performance in medical care and service.

We surveyed 30 patients of each of the 5 providers, yielding a total of 150 survey responses. A medical assistant gave surveys to patients in the exam room following each office visit, to be completed anonymously and privately. Patients were told that surveys would take less than 2 minutes to complete. Office visits included episodic visits, physical exams, and chronic disease management.

Physicians believed they were saving, on average, 1.5 hours each day with the use of a scribe.

After the trial period, we surveyed participating physicians regarding medical scribe assistance with documentation. We also asked the physicians 3 open-ended questions regarding their experiences with their medical scribe.

This study was reviewed and approved (IRB Approval #11424) by the Tufts Health Science Campus Institutional Review Board.

Continue to: Data analysis

During chart review, we assessed the rate at which documentation was completed for 8 quality outcome measures commonly used in the primary care setting (TABLE 1), before and after the introduction of medical scribes. These quality measures and pertinent descriptors are listed in TABLE 2.¹³ Presence or absence of documentation on all quality measures was noted for all applicable patients.

One hundred fifty patients were surveyed immediately after their office visit on their perceptions of medical scribes, including their attitude toward, comfort with, and acceptance of medical scribes (TABLE 3). Five participating physicians were surveyed to assess their perceptions related to productivity and job satisfaction with the use of medical scribes (TABLE 4), and regarding time saved and additional patients seen. Those who collected and analyzed the data from the surveys were blinded to patient and physician identifiers.

Statistical analysis

Using chi-squared tests, we compared the number of positive documentations for the 8 outcome measures before and after the use of medical scribes. Two-sided P values < .05 were considered statistically significant. All statistical analyses were performed with the use of STATA version 9 (StataCorp LP. College Station, Tex).

Physician survey data were calculated on a Likert scale, with a score of 1 corresponding to “strongly disagree,” 2 “disagree,” 3 “neither agree nor disagree,” 4 “agree,” and 5 “strongly agree.” Using the 5 answers generated from the 5 physicians, we calculated the mean for each question.

RESULTS

The use of scribes demonstrated a statistically significant improvement in the documentation of 4 (out of 8) pay-for-performance measures (TABLE 1): fall risk assessment (odds ratio [OR] = 5.5, P = .02), follow-up tobacco screen (OR = 6.4; P = .01), follow-up body mass index (BMI) plan (OR = 6.2; P < .01), and follow-up blood pressure plan (OR = 39.6; P < .01). Sample sizes of each quality measure vary as there were differing numbers of applicable patients for each quality measure within the overall 1000 charts.

Continue to: We established at the beginning...

We established at the beginning of the study a target of obtaining surveys from 30 patients of each of the 5 physicians (total of 150). Response rates for surveys were 100% for both the 150 patients and the 5 physicians. No patients declined to complete the survey, although some did not answer every question.

Patients generally had positive experiences with medical scribes (TABLE 3). The majority of patients (96%, n = 144) felt comfortable with the scribe in the room during the visit with their provider. Patients felt that the provider focused on them “a little to a lot more” (75.8%, n = 113) and thought their visit was more efficient (73.6%, n = 109) as a result of the scribe being present vs not being present. Most patients were more satisfied with their office visit with the scribe being present (60.8%, n = 90).

Physicians felt that working with a medical scribe helped them connect with their patients, made patients feel that their physician was more attentive to them, contributed to better patient care, decreased the time they spent documenting in EHR, and contributed to faster work flow (TABLE 4). The physicians also believed they had saved a mean of 1.5 hours each day with the use of a medical scribe, and that they did not have to change their schedule in any way to accommodate additional patients as a result of having a scribe.

DISCUSSION

Documentation of fall risk assessment, follow-up tobacco screening, follow-up BMI plan, and follow-up blood pressure plan all demonstrated statistically significant increases with the use of medical scribes compared with practice before scribes. Follow-up depression screen and transition of care management had relatively high ORs (3.2 and 8, respectively), but did not yield statistically significant values, in part due to small sample sizes as the number of patients who were hospitalized and the number of patients who screened positive for depression were relatively small out of the total group of 1000 patients. The use of scribes had little effect on depression screen and tobacco screen. This is likely due to the fact that there were already effective office systems in place at the practice that alerted medical assistants to complete these screens for each appropriate patient.

We found that the use of medical scribes in a primary care setting was associated with both higher patient and physician satisfaction. Although the 5 physicians in this study chose not to see additional patients when using a medical scribe, they believed they were saving, on average, 1.5 hours of time each day with the use of a scribe. All 5 physicians reported that medical scribes enabled them to provide better patient care and to help patients feel as though they had more of the physician’s attention. Patient respondents attested to their provider focusing on them more during the visit. According to patient surveys, 40.4% of respondents felt that physicians addressed their concerns more thoroughly during the visit, while the remainder of patients did not.

Continue to: Some concerns...

Some concerns of introducing medical scribes into a health care system include possible patient discomfort with a third party being present during the visit and the cost of employing medical scribes. In this study, the vast majority of patients (96%) felt comfortable with a scribe in the room. Future research could compare patient discomfort due to the presence of a medical scribe with patient discomfort due to a physician using a computer during the visit.

Limitations of this study include the small sample size of both physicians and patients; a lack of validated measures for calculating productivity, time/efficiency, and overall satisfaction; and short time periods leading up to and following the introduction of medical scribes. In addition, EHRs of patients were chosen sequentially and not randomly, which could be a confounder. Participating physicians were aware of being studied; therefore, documentation could have been affected by the Hawthorne effect. The study also was limited to one family medicine site. Although improved documentation of primary care pay-for-performance quality measures was reported, wide confidence intervals and small patient numbers hindered generalizability of findings.

Documentation of 4 out of 8 pay-forperformance measures showed statistically significant improvement with the use of scribes.

Additional studies are needed with a robust analytic plan sufficient to demonstrate baseline provider familiarity with EHRs, accuracy of medical scribe documentation, and improved documentation of pay-for-performance quality measures. Additional investigation regarding the variable competency of different medical scribes could be useful in measuring the effects of the scribe on a variety of outcomes related to both the physician and patient.

It is possible that the improved documentation yielded by the use of medical scribes could generate billing codes that reimburse physicians at a higher level (eg, a higher ratio of 99214 to 99213), leading to increased pay. Future research could aim to quantify this source of increased revenue. Furthermore, investigations could aim to quantify the revenue that medical scribes generate via improved quality measure pay-for-performance documentation.

CORRESPONDENCE
Jessica Platt, MD, 195 Canal Street, Malden, MA 02148; [email protected].

The 2012 US Food and Drug Administration (FDA) approval of daily emtricitabine plus tenofovir disoproxil fumarate as HIV pre-exposure prophylaxis (PrEP) re-energized the field of human immunodeficiency virus (HIV) prevention. In subsequent years, PrEP uptake has increased, particularly in people at high risk of HIV infection.

However, since 2012, progress in controlling the HIV epidemic has been uneven across communities and populations. For instance, in 2014, the southern United States accounted for an estimated 50% of infections, but PrEP uptake has remained low there, with only 1% of the estimated number of eligible people taking PrEP.^1,2 Among African American men who have sex with men (MSM), it is predicted that 1 of every 2 will become infected in his lifetime; among Latino MSM, the prediction is 1 of every 5.³ The expanding opioid epidemic is further jeopardizing the progress made in reducing HIV infection among people who inject drugs.

A “test and treat” strategy is insufficient. Mathematical modeling suggests that “test and treat” without a higher level of coverage is insufficient to control the HIV epidemic.⁴ In the absence of an HIV vaccine, these models find that widespread uptake of PrEP among people at risk of HIV acquisition is needed—in combination with HIV treatment as prevention, condom promotion, and needle exchange—to realize the potential to end the HIV epidemic.⁴

A recent proposal by the US Department of Health and Human Services would establish an initiative to address the continuing HIV public health crisis, with a goal of reducing the numbers of incident HIV infections in the United States by 75% in 5 years and then by 90% in 10 years. That strategic initiative includes 4 “pillars” for preventing HIV acquisition—one of which is the use of PrEP by at-risk people.⁵

Although PrEP is often prescribed by HIV specialists and in sexually transmitted infection (STI) clinics, many patients seek PrEP from family physicians (and other primary care clinicians), who are now also being called on to identify patients in their practice at risk of HIV infection⁶ and to offer them PrEP. In this article, we provide an overview of PrEP and discuss how best to integrate PrEP into a family medicine practice.

Understanding PrEP and how it is used

PrEP is one of 2 related biomedical interventions to prevent HIV acquisition. Many clinicians are familiar with postexposure prophylaxis, a regimen of 3 anti-HIV medications given for 1 month to patients who are within 72 hours of a possible exposure. In contrast, PrEP is a once-daily, fixed-dose combination of 2 medications commonly used in the treatment of HIV infection: emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg. This combination is the only FDA-approved regimen for daily use as PrEP in the United States.

At-risk patients should take PrEP daily—regardless of how often they engage in risky behaviors.

PrEP is indicated for people whose ongoing sexual or drug injection behaviors put them at substantial risk of HIV infection, and should be taken daily regardless of the frequency of risk-taking behavior. Since 2010, several randomized placebo-controlled trials (RCTs) have reported that, when medication adherence is high (measured by drug levels in blood), PrEP can reduce new HIV infections by more than 90% in high-risk populations.⁷ In clinical practice, HIV infection is uncommon because of the effectiveness of daily PrEP; when infections have occurred, almost all have been in patients not taking the medications as prescribed.⁸

Continue to: Infection with HIV...

Infection with HIV in which viral mutations are associated with emtricitabine or tenofovir resistance is rare among the few people infected with HIV after starting PrEP.⁹ In RCTs, most drug resistance occurred among people who started PrEP when they were already HIV-positive (because they were screened with antibody-only HIV tests that did not detect recent infection).¹⁰

Other medications, routes of administration, and dosing schedules are being studied for safety and efficacy as PrEP for HIV infection.^11,12

For whom should PrEP be prescribed? There are 2 ways to identify candidates for PrEP:

• Passive prescribing relies on patients self-identifying as being at risk of HIV infection and asking about PrEP. Many at-risk patients do not recognize their need for PrEP, however.¹³
• Active screening requires that physicians, or their staff, take a sexual history from all patients. However, reviewing detailed sexual histories with every patient in a busy practice can be overwhelming. One way to begin identifying patients for whom PrEP is appropriate is to commit to talking to subsets of potentially high-risk patients, such as MSM or transgender patients.⁶ Sexual orientation and gender identity are not direct risk factors; a nuanced sexual history is often needed to understand potential exposures. A diagnosis of syphilis or other bacterial STI is a marker of high risk of HIV acquisition.¹⁴

To help identify which of your patients might benefit from PrEP, the PrEP guidelines from the Centers for Disease Control and Prevention (CDC)¹⁵ and tools developed by other sources^16,17 recommend several key screening questions about sexual behavior and substance abuse (TABLE 1^15-17).

Familiarity with PrEP and comfort taking a sexual history to screen for risk of HIV acquisition are essential first steps in prescribing PrEP under CDC guidelines.^6,18 In primary care, female patients are routinely questioned to assess their need for contraception; similarly, screening questions to assess PrEP eligibility can be easily incorporated into practice.

Continue to: What are the indications for PrEP?

Patients in whom PrEP is indicated include sexually active adults and adolescents (> 35 kg)¹⁹ whose use of a condom is inconsistent or who have had multiple recent sex partners; those with a recent bacterial STI; and men or women with a sexual or injection partner known to be HIV-infected (TABLE 2).¹⁵

What steps should be taken before and after initiating PrEP?

Providing PrEP is a harm-reduction strategy similar to prescribing other common preventive medications, such as statins to reduce hyperlipidemia and prevent myocardial infarction; oral contraceptives to prevent unwanted pregnancy; and metformin to prevent complications of diabetes. There are a few screening criteria prior to initiating PrEP (TABLE 3)¹⁰:

• A patient starting PrEP should be (1) HIV-negative, ideally screened by a laboratory-based antigen–antibody (ie, fourth-generation) HIV test or HIV RNA test, and (2) without symptoms of acute HIV infection.²⁰ (Note: Do not hold off PrEP and HIV testing until the patient has achieved a period of sexual abstinence.)
• A patient starting PrEP should have normal renal function and should not be taking contraindicated medications, such as long-term high-dose nonsteroidal anti-inflammatory agents.
• Hepatitis B virus (HBV) surface antigen, surface antibody, and core antibody should be tested because both emtricitabine and tenofovir are active against HBV. For a patient who has active HBV infection, particularly with cirrhosis, there is a theoretical concern that starting and stopping PrEP can lead to flares of HBV infection. Patients who are not HBV-immune should be vaccinated.
• Baseline hepatitis C virus testing is recommended for patients who inject drugs, MSM, or those who were born between 1945 and 1965; annual hepatitis C virus testing is recommended for patients who inject drugs.¹⁵

When it has been determined that a patient is eligible for PrEP, a prescription is written for no longer than 90 days to ensure regular monitoring for HIV infection, STIs, and renal function.

Adherence counseling is a key component of PrEP delivery—as it is with oral contraception, antihypertensive medical therapy, and other medications. As noted, HIV acquisition in PrEP users is most often reported in patients with poor adherence,⁸ especially among adolescents.²¹ PrEP is part of comprehensive sexual health care, and safer sex behaviors, such as condom use, should be encouraged to reduce the risk of acquiring other STIs. Condom use should not, however, be a requirement for continuing to receive PrEP.

Is PrEP safe?

Although PrEP might be new to many family physicians and their patients, trials and observational studies have repeatedly shown that for people without HIV infection, taking daily emtricitabine and tenofovir for prevention of HIV infection is safe. No clinically significant renal, bone, or other toxicity has been reported, although there is concern about potential toxicity after decades of use.^22,23 A recent narrative review from the David Geffen School of Medicine at the University of California Los Angeles compared safety findings from 5 major studies on PrEP with 2 major studies on aspirin safety and found that PrEP is as safe as aspirin, although the authors cautioned that more study on long-term use is needed.²⁴

Continue to: What to tell patients

What to tell patients. Tell patients that within the first weeks of starting PrEP, they might experience a start-up syndrome that typically manifests as gastrointestinal symptoms, headache, and fatigue. These symptoms usually resolve without the need to discontinue the medications.²⁵

Any other concerns about PrEP?

When PrEP was first approved by the FDA, many physicians raised concern about the possibility that PrEP use would lead to increased community-level HIV drug resistance and that behavioral disinhibition might diminish the benefit of PrEP and lead to rampant STIs.²⁶ To date, these fears have not been borne out.

When medication adherence is high, PrEP can reduce new HIV infections by more than 90% in high-risk populations.

Acquired drug resistance, which happens after a person becomes HIV-positive, is a real concern, particularly among people who are screened with antibody-only HIV tests that cannot detect HIV in the so-called window period and who then start PrEP during acute HIV infection. If a person is truly HIV-negative when he (she) starts PrEP, the risk of either acquired or transmitted HIV drug resistance is low and is far outweighed by the preventive benefit of PrEP.²⁷

Similarly, there is a suggestion that syphilis infection is increasing among HIV-negative MSM due to decreased HIV-related stigma and increased mixing between HIV-negative and HIV-positive people. The evidence that PrEP has led to an increase in STI rates²⁸ is mixed, however, and is confounded by temporal increases in STI rates and increased detection of asymptomatic STIs among people on PrEP as a result of regular screening.²⁹

Who pays for PrEP?

The cost of PrEP medications and associated clinical care is covered by nearly all private, employer, and public health insurance. Prior authorization might be required to ensure that testing has excluded HIV infection before prescribing and then refilling prescriptions.

Continue to: For patients who have health insurance...

For patients who have health insurance, assistance with copays or coinsurance is available through the producer of PrEP (Gilead Sciences, Inc.) and other national foundations. Many people who seek PrEP might be eligible for Medicaid if they are otherwise uninsured. Other low-income and uninsured people, including those who are not legal residents or US citizens, usually qualify for the PrEP medication assistance program; the application for this benefit must be completed by the physician.

One way to identify patients for whom PrEP might be appropriate is to talk to subsets of potentially high-risk patients, such as men who have sex with men and transgender patients.

A billing guide on PrEP for physicians is available to assist with International Classification of Disease (ICD)-10 coding.^30,31 If a patient has difficulty with laboratory copays, free HIV and STI testing might be available at local STI clinics and acquired immunodeficiency syndrome (AIDS) service organizations.

Providing PrEP within a primary care setting

The unmet need for PrEP highlights how important it is for family medicine and other primary care practices to incorporate HIV prevention into their suite of services.³²

Patients are most likely to experience adverse effects during the first month of taking PrEP—the same period in which they are establishing their pattern of adherence. It might be helpful to check in with patients at the end of the first month to assess their symptoms and adherence. After this phase, quarterly follow-up is simple, with routine lab monitoring and check-in about continued risk of HIV and adherence challenges (TABLE 3¹⁰).

At our local Ryan White HIV/AIDS Program-funded HIV clinic, which also provides PrEP, computer-ordering checklists (so-called smartsets) for the PrEP initial visit and follow-up visits are programmed into the records system (TABLE 4¹⁵). Other clinics also have developed templates for PrEP visit notes. Adherence monitoring, behavioral counseling, and other preventive services can be integrated into the regular paper- or computer-based intake survey, so that conversations are focused on areas of need.⁶ Family physicians in large practices can develop in-office protocols, based on CDC PrEP guidelines, to assign roles (eg, paperwork assistant, behavioral counselor, prescriber) to staff members.

Continue to: Partnering with HIV specialists, organizations, and pharmacists

Family physicians who are unsure about initiating PrEP might consider referring complex patients, such as those with unclear eligibility or active HBV infection, to an infectious disease or HIV specialist or clinic for the initial evaluation. Once a patient has been started on PrEP, quarterly monitoring is simple and can be easily completed in a family medicine practice.

Depending on location and available services, pharmacists and local HIV and AIDS organizations might provide behavioral and adherence counseling and repeat testing during follow-up appointments. In our experience, working with a primary pharmacy that is familiar with patient assistance programs and prior authorization requirements facilitates smoother prescribing. The result? Lower cost to patients because of knowledge of copays and other assistance programs and willingness to use these secondary payers.

Bringing PrEP into the practice is workable

Providing PrEP is well within your scope of practice as a family physician. To assist you in making PrEP an effective component of your practice, we provide a list of sources of PrEP support in TABLE 5.

Because some physicians might still be reluctant to prescribe PrEP for patients who maintain their risk of HIV acquisition, we recommend that you think of PrEP as you do about statins. Discussing diet and exercise as a means of reducing cardiovascular events for every patient with hyperlipidemia is often insufficient; most physicians therefore also prescribe medication for patients who cannot change behaviors sufficiently to modify their cardiovascular risk factors. Similarly, you now have a preventive for HIV—a costly, lifelong infection—that is as cost-effective as statins are.^26,33

CORRESPONDENCE
Joanne D. Stekler, MD, MPH, Box 359931, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104; [email protected].

The 2012 US Food and Drug Administration (FDA) approval of daily emtricitabine plus tenofovir disoproxil fumarate as HIV pre-exposure prophylaxis (PrEP) re-energized the field of human immunodeficiency virus (HIV) prevention. In subsequent years, PrEP uptake has increased, particularly in people at high risk of HIV infection.

However, since 2012, progress in controlling the HIV epidemic has been uneven across communities and populations. For instance, in 2014, the southern United States accounted for an estimated 50% of infections, but PrEP uptake has remained low there, with only 1% of the estimated number of eligible people taking PrEP.^1,2 Among African American men who have sex with men (MSM), it is predicted that 1 of every 2 will become infected in his lifetime; among Latino MSM, the prediction is 1 of every 5.³ The expanding opioid epidemic is further jeopardizing the progress made in reducing HIV infection among people who inject drugs.

A “test and treat” strategy is insufficient. Mathematical modeling suggests that “test and treat” without a higher level of coverage is insufficient to control the HIV epidemic.⁴ In the absence of an HIV vaccine, these models find that widespread uptake of PrEP among people at risk of HIV acquisition is needed—in combination with HIV treatment as prevention, condom promotion, and needle exchange—to realize the potential to end the HIV epidemic.⁴

A recent proposal by the US Department of Health and Human Services would establish an initiative to address the continuing HIV public health crisis, with a goal of reducing the numbers of incident HIV infections in the United States by 75% in 5 years and then by 90% in 10 years. That strategic initiative includes 4 “pillars” for preventing HIV acquisition—one of which is the use of PrEP by at-risk people.⁵

Although PrEP is often prescribed by HIV specialists and in sexually transmitted infection (STI) clinics, many patients seek PrEP from family physicians (and other primary care clinicians), who are now also being called on to identify patients in their practice at risk of HIV infection⁶ and to offer them PrEP. In this article, we provide an overview of PrEP and discuss how best to integrate PrEP into a family medicine practice.

Understanding PrEP and how it is used

PrEP is one of 2 related biomedical interventions to prevent HIV acquisition. Many clinicians are familiar with postexposure prophylaxis, a regimen of 3 anti-HIV medications given for 1 month to patients who are within 72 hours of a possible exposure. In contrast, PrEP is a once-daily, fixed-dose combination of 2 medications commonly used in the treatment of HIV infection: emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg. This combination is the only FDA-approved regimen for daily use as PrEP in the United States.

At-risk patients should take PrEP daily—regardless of how often they engage in risky behaviors.

PrEP is indicated for people whose ongoing sexual or drug injection behaviors put them at substantial risk of HIV infection, and should be taken daily regardless of the frequency of risk-taking behavior. Since 2010, several randomized placebo-controlled trials (RCTs) have reported that, when medication adherence is high (measured by drug levels in blood), PrEP can reduce new HIV infections by more than 90% in high-risk populations.⁷ In clinical practice, HIV infection is uncommon because of the effectiveness of daily PrEP; when infections have occurred, almost all have been in patients not taking the medications as prescribed.⁸

Continue to: Infection with HIV...

Infection with HIV in which viral mutations are associated with emtricitabine or tenofovir resistance is rare among the few people infected with HIV after starting PrEP.⁹ In RCTs, most drug resistance occurred among people who started PrEP when they were already HIV-positive (because they were screened with antibody-only HIV tests that did not detect recent infection).¹⁰

Other medications, routes of administration, and dosing schedules are being studied for safety and efficacy as PrEP for HIV infection.^11,12

For whom should PrEP be prescribed? There are 2 ways to identify candidates for PrEP:

• Passive prescribing relies on patients self-identifying as being at risk of HIV infection and asking about PrEP. Many at-risk patients do not recognize their need for PrEP, however.¹³
• Active screening requires that physicians, or their staff, take a sexual history from all patients. However, reviewing detailed sexual histories with every patient in a busy practice can be overwhelming. One way to begin identifying patients for whom PrEP is appropriate is to commit to talking to subsets of potentially high-risk patients, such as MSM or transgender patients.⁶ Sexual orientation and gender identity are not direct risk factors; a nuanced sexual history is often needed to understand potential exposures. A diagnosis of syphilis or other bacterial STI is a marker of high risk of HIV acquisition.¹⁴

To help identify which of your patients might benefit from PrEP, the PrEP guidelines from the Centers for Disease Control and Prevention (CDC)¹⁵ and tools developed by other sources^16,17 recommend several key screening questions about sexual behavior and substance abuse (TABLE 1^15-17).

Familiarity with PrEP and comfort taking a sexual history to screen for risk of HIV acquisition are essential first steps in prescribing PrEP under CDC guidelines.^6,18 In primary care, female patients are routinely questioned to assess their need for contraception; similarly, screening questions to assess PrEP eligibility can be easily incorporated into practice.

Continue to: What are the indications for PrEP?

Patients in whom PrEP is indicated include sexually active adults and adolescents (> 35 kg)¹⁹ whose use of a condom is inconsistent or who have had multiple recent sex partners; those with a recent bacterial STI; and men or women with a sexual or injection partner known to be HIV-infected (TABLE 2).¹⁵

What steps should be taken before and after initiating PrEP?

Providing PrEP is a harm-reduction strategy similar to prescribing other common preventive medications, such as statins to reduce hyperlipidemia and prevent myocardial infarction; oral contraceptives to prevent unwanted pregnancy; and metformin to prevent complications of diabetes. There are a few screening criteria prior to initiating PrEP (TABLE 3)¹⁰:

• A patient starting PrEP should be (1) HIV-negative, ideally screened by a laboratory-based antigen–antibody (ie, fourth-generation) HIV test or HIV RNA test, and (2) without symptoms of acute HIV infection.²⁰ (Note: Do not hold off PrEP and HIV testing until the patient has achieved a period of sexual abstinence.)
• A patient starting PrEP should have normal renal function and should not be taking contraindicated medications, such as long-term high-dose nonsteroidal anti-inflammatory agents.
• Hepatitis B virus (HBV) surface antigen, surface antibody, and core antibody should be tested because both emtricitabine and tenofovir are active against HBV. For a patient who has active HBV infection, particularly with cirrhosis, there is a theoretical concern that starting and stopping PrEP can lead to flares of HBV infection. Patients who are not HBV-immune should be vaccinated.
• Baseline hepatitis C virus testing is recommended for patients who inject drugs, MSM, or those who were born between 1945 and 1965; annual hepatitis C virus testing is recommended for patients who inject drugs.¹⁵

When it has been determined that a patient is eligible for PrEP, a prescription is written for no longer than 90 days to ensure regular monitoring for HIV infection, STIs, and renal function.

Adherence counseling is a key component of PrEP delivery—as it is with oral contraception, antihypertensive medical therapy, and other medications. As noted, HIV acquisition in PrEP users is most often reported in patients with poor adherence,⁸ especially among adolescents.²¹ PrEP is part of comprehensive sexual health care, and safer sex behaviors, such as condom use, should be encouraged to reduce the risk of acquiring other STIs. Condom use should not, however, be a requirement for continuing to receive PrEP.

Is PrEP safe?

Although PrEP might be new to many family physicians and their patients, trials and observational studies have repeatedly shown that for people without HIV infection, taking daily emtricitabine and tenofovir for prevention of HIV infection is safe. No clinically significant renal, bone, or other toxicity has been reported, although there is concern about potential toxicity after decades of use.^22,23 A recent narrative review from the David Geffen School of Medicine at the University of California Los Angeles compared safety findings from 5 major studies on PrEP with 2 major studies on aspirin safety and found that PrEP is as safe as aspirin, although the authors cautioned that more study on long-term use is needed.²⁴

Continue to: What to tell patients

What to tell patients. Tell patients that within the first weeks of starting PrEP, they might experience a start-up syndrome that typically manifests as gastrointestinal symptoms, headache, and fatigue. These symptoms usually resolve without the need to discontinue the medications.²⁵

Any other concerns about PrEP?

When PrEP was first approved by the FDA, many physicians raised concern about the possibility that PrEP use would lead to increased community-level HIV drug resistance and that behavioral disinhibition might diminish the benefit of PrEP and lead to rampant STIs.²⁶ To date, these fears have not been borne out.

When medication adherence is high, PrEP can reduce new HIV infections by more than 90% in high-risk populations.

Acquired drug resistance, which happens after a person becomes HIV-positive, is a real concern, particularly among people who are screened with antibody-only HIV tests that cannot detect HIV in the so-called window period and who then start PrEP during acute HIV infection. If a person is truly HIV-negative when he (she) starts PrEP, the risk of either acquired or transmitted HIV drug resistance is low and is far outweighed by the preventive benefit of PrEP.²⁷

Similarly, there is a suggestion that syphilis infection is increasing among HIV-negative MSM due to decreased HIV-related stigma and increased mixing between HIV-negative and HIV-positive people. The evidence that PrEP has led to an increase in STI rates²⁸ is mixed, however, and is confounded by temporal increases in STI rates and increased detection of asymptomatic STIs among people on PrEP as a result of regular screening.²⁹

Who pays for PrEP?

The cost of PrEP medications and associated clinical care is covered by nearly all private, employer, and public health insurance. Prior authorization might be required to ensure that testing has excluded HIV infection before prescribing and then refilling prescriptions.

Continue to: For patients who have health insurance...

For patients who have health insurance, assistance with copays or coinsurance is available through the producer of PrEP (Gilead Sciences, Inc.) and other national foundations. Many people who seek PrEP might be eligible for Medicaid if they are otherwise uninsured. Other low-income and uninsured people, including those who are not legal residents or US citizens, usually qualify for the PrEP medication assistance program; the application for this benefit must be completed by the physician.

One way to identify patients for whom PrEP might be appropriate is to talk to subsets of potentially high-risk patients, such as men who have sex with men and transgender patients.

A billing guide on PrEP for physicians is available to assist with International Classification of Disease (ICD)-10 coding.^30,31 If a patient has difficulty with laboratory copays, free HIV and STI testing might be available at local STI clinics and acquired immunodeficiency syndrome (AIDS) service organizations.

Providing PrEP within a primary care setting

The unmet need for PrEP highlights how important it is for family medicine and other primary care practices to incorporate HIV prevention into their suite of services.³²

Patients are most likely to experience adverse effects during the first month of taking PrEP—the same period in which they are establishing their pattern of adherence. It might be helpful to check in with patients at the end of the first month to assess their symptoms and adherence. After this phase, quarterly follow-up is simple, with routine lab monitoring and check-in about continued risk of HIV and adherence challenges (TABLE 3¹⁰).

At our local Ryan White HIV/AIDS Program-funded HIV clinic, which also provides PrEP, computer-ordering checklists (so-called smartsets) for the PrEP initial visit and follow-up visits are programmed into the records system (TABLE 4¹⁵). Other clinics also have developed templates for PrEP visit notes. Adherence monitoring, behavioral counseling, and other preventive services can be integrated into the regular paper- or computer-based intake survey, so that conversations are focused on areas of need.⁶ Family physicians in large practices can develop in-office protocols, based on CDC PrEP guidelines, to assign roles (eg, paperwork assistant, behavioral counselor, prescriber) to staff members.

Continue to: Partnering with HIV specialists, organizations, and pharmacists

Family physicians who are unsure about initiating PrEP might consider referring complex patients, such as those with unclear eligibility or active HBV infection, to an infectious disease or HIV specialist or clinic for the initial evaluation. Once a patient has been started on PrEP, quarterly monitoring is simple and can be easily completed in a family medicine practice.

Depending on location and available services, pharmacists and local HIV and AIDS organizations might provide behavioral and adherence counseling and repeat testing during follow-up appointments. In our experience, working with a primary pharmacy that is familiar with patient assistance programs and prior authorization requirements facilitates smoother prescribing. The result? Lower cost to patients because of knowledge of copays and other assistance programs and willingness to use these secondary payers.

Bringing PrEP into the practice is workable

Providing PrEP is well within your scope of practice as a family physician. To assist you in making PrEP an effective component of your practice, we provide a list of sources of PrEP support in TABLE 5.

Because some physicians might still be reluctant to prescribe PrEP for patients who maintain their risk of HIV acquisition, we recommend that you think of PrEP as you do about statins. Discussing diet and exercise as a means of reducing cardiovascular events for every patient with hyperlipidemia is often insufficient; most physicians therefore also prescribe medication for patients who cannot change behaviors sufficiently to modify their cardiovascular risk factors. Similarly, you now have a preventive for HIV—a costly, lifelong infection—that is as cost-effective as statins are.^26,33

CORRESPONDENCE
Joanne D. Stekler, MD, MPH, Box 359931, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104; [email protected].

The 2012 US Food and Drug Administration (FDA) approval of daily emtricitabine plus tenofovir disoproxil fumarate as HIV pre-exposure prophylaxis (PrEP) re-energized the field of human immunodeficiency virus (HIV) prevention. In subsequent years, PrEP uptake has increased, particularly in people at high risk of HIV infection.

However, since 2012, progress in controlling the HIV epidemic has been uneven across communities and populations. For instance, in 2014, the southern United States accounted for an estimated 50% of infections, but PrEP uptake has remained low there, with only 1% of the estimated number of eligible people taking PrEP.^1,2 Among African American men who have sex with men (MSM), it is predicted that 1 of every 2 will become infected in his lifetime; among Latino MSM, the prediction is 1 of every 5.³ The expanding opioid epidemic is further jeopardizing the progress made in reducing HIV infection among people who inject drugs.

A “test and treat” strategy is insufficient. Mathematical modeling suggests that “test and treat” without a higher level of coverage is insufficient to control the HIV epidemic.⁴ In the absence of an HIV vaccine, these models find that widespread uptake of PrEP among people at risk of HIV acquisition is needed—in combination with HIV treatment as prevention, condom promotion, and needle exchange—to realize the potential to end the HIV epidemic.⁴

A recent proposal by the US Department of Health and Human Services would establish an initiative to address the continuing HIV public health crisis, with a goal of reducing the numbers of incident HIV infections in the United States by 75% in 5 years and then by 90% in 10 years. That strategic initiative includes 4 “pillars” for preventing HIV acquisition—one of which is the use of PrEP by at-risk people.⁵

Although PrEP is often prescribed by HIV specialists and in sexually transmitted infection (STI) clinics, many patients seek PrEP from family physicians (and other primary care clinicians), who are now also being called on to identify patients in their practice at risk of HIV infection⁶ and to offer them PrEP. In this article, we provide an overview of PrEP and discuss how best to integrate PrEP into a family medicine practice.

Understanding PrEP and how it is used

PrEP is one of 2 related biomedical interventions to prevent HIV acquisition. Many clinicians are familiar with postexposure prophylaxis, a regimen of 3 anti-HIV medications given for 1 month to patients who are within 72 hours of a possible exposure. In contrast, PrEP is a once-daily, fixed-dose combination of 2 medications commonly used in the treatment of HIV infection: emtricitabine, 200 mg, and tenofovir disoproxil fumarate, 300 mg. This combination is the only FDA-approved regimen for daily use as PrEP in the United States.

At-risk patients should take PrEP daily—regardless of how often they engage in risky behaviors.

PrEP is indicated for people whose ongoing sexual or drug injection behaviors put them at substantial risk of HIV infection, and should be taken daily regardless of the frequency of risk-taking behavior. Since 2010, several randomized placebo-controlled trials (RCTs) have reported that, when medication adherence is high (measured by drug levels in blood), PrEP can reduce new HIV infections by more than 90% in high-risk populations.⁷ In clinical practice, HIV infection is uncommon because of the effectiveness of daily PrEP; when infections have occurred, almost all have been in patients not taking the medications as prescribed.⁸

Continue to: Infection with HIV...

Infection with HIV in which viral mutations are associated with emtricitabine or tenofovir resistance is rare among the few people infected with HIV after starting PrEP.⁹ In RCTs, most drug resistance occurred among people who started PrEP when they were already HIV-positive (because they were screened with antibody-only HIV tests that did not detect recent infection).¹⁰

Other medications, routes of administration, and dosing schedules are being studied for safety and efficacy as PrEP for HIV infection.^11,12

For whom should PrEP be prescribed? There are 2 ways to identify candidates for PrEP:

• Passive prescribing relies on patients self-identifying as being at risk of HIV infection and asking about PrEP. Many at-risk patients do not recognize their need for PrEP, however.¹³
• Active screening requires that physicians, or their staff, take a sexual history from all patients. However, reviewing detailed sexual histories with every patient in a busy practice can be overwhelming. One way to begin identifying patients for whom PrEP is appropriate is to commit to talking to subsets of potentially high-risk patients, such as MSM or transgender patients.⁶ Sexual orientation and gender identity are not direct risk factors; a nuanced sexual history is often needed to understand potential exposures. A diagnosis of syphilis or other bacterial STI is a marker of high risk of HIV acquisition.¹⁴

To help identify which of your patients might benefit from PrEP, the PrEP guidelines from the Centers for Disease Control and Prevention (CDC)¹⁵ and tools developed by other sources^16,17 recommend several key screening questions about sexual behavior and substance abuse (TABLE 1^15-17).

Familiarity with PrEP and comfort taking a sexual history to screen for risk of HIV acquisition are essential first steps in prescribing PrEP under CDC guidelines.^6,18 In primary care, female patients are routinely questioned to assess their need for contraception; similarly, screening questions to assess PrEP eligibility can be easily incorporated into practice.

Continue to: What are the indications for PrEP?

Patients in whom PrEP is indicated include sexually active adults and adolescents (> 35 kg)¹⁹ whose use of a condom is inconsistent or who have had multiple recent sex partners; those with a recent bacterial STI; and men or women with a sexual or injection partner known to be HIV-infected (TABLE 2).¹⁵

What steps should be taken before and after initiating PrEP?

Providing PrEP is a harm-reduction strategy similar to prescribing other common preventive medications, such as statins to reduce hyperlipidemia and prevent myocardial infarction; oral contraceptives to prevent unwanted pregnancy; and metformin to prevent complications of diabetes. There are a few screening criteria prior to initiating PrEP (TABLE 3)¹⁰:

• A patient starting PrEP should be (1) HIV-negative, ideally screened by a laboratory-based antigen–antibody (ie, fourth-generation) HIV test or HIV RNA test, and (2) without symptoms of acute HIV infection.²⁰ (Note: Do not hold off PrEP and HIV testing until the patient has achieved a period of sexual abstinence.)
• A patient starting PrEP should have normal renal function and should not be taking contraindicated medications, such as long-term high-dose nonsteroidal anti-inflammatory agents.
• Hepatitis B virus (HBV) surface antigen, surface antibody, and core antibody should be tested because both emtricitabine and tenofovir are active against HBV. For a patient who has active HBV infection, particularly with cirrhosis, there is a theoretical concern that starting and stopping PrEP can lead to flares of HBV infection. Patients who are not HBV-immune should be vaccinated.
• Baseline hepatitis C virus testing is recommended for patients who inject drugs, MSM, or those who were born between 1945 and 1965; annual hepatitis C virus testing is recommended for patients who inject drugs.¹⁵

When it has been determined that a patient is eligible for PrEP, a prescription is written for no longer than 90 days to ensure regular monitoring for HIV infection, STIs, and renal function.

Adherence counseling is a key component of PrEP delivery—as it is with oral contraception, antihypertensive medical therapy, and other medications. As noted, HIV acquisition in PrEP users is most often reported in patients with poor adherence,⁸ especially among adolescents.²¹ PrEP is part of comprehensive sexual health care, and safer sex behaviors, such as condom use, should be encouraged to reduce the risk of acquiring other STIs. Condom use should not, however, be a requirement for continuing to receive PrEP.

Is PrEP safe?

Although PrEP might be new to many family physicians and their patients, trials and observational studies have repeatedly shown that for people without HIV infection, taking daily emtricitabine and tenofovir for prevention of HIV infection is safe. No clinically significant renal, bone, or other toxicity has been reported, although there is concern about potential toxicity after decades of use.^22,23 A recent narrative review from the David Geffen School of Medicine at the University of California Los Angeles compared safety findings from 5 major studies on PrEP with 2 major studies on aspirin safety and found that PrEP is as safe as aspirin, although the authors cautioned that more study on long-term use is needed.²⁴

Continue to: What to tell patients

What to tell patients. Tell patients that within the first weeks of starting PrEP, they might experience a start-up syndrome that typically manifests as gastrointestinal symptoms, headache, and fatigue. These symptoms usually resolve without the need to discontinue the medications.²⁵

Any other concerns about PrEP?

When PrEP was first approved by the FDA, many physicians raised concern about the possibility that PrEP use would lead to increased community-level HIV drug resistance and that behavioral disinhibition might diminish the benefit of PrEP and lead to rampant STIs.²⁶ To date, these fears have not been borne out.

When medication adherence is high, PrEP can reduce new HIV infections by more than 90% in high-risk populations.

Acquired drug resistance, which happens after a person becomes HIV-positive, is a real concern, particularly among people who are screened with antibody-only HIV tests that cannot detect HIV in the so-called window period and who then start PrEP during acute HIV infection. If a person is truly HIV-negative when he (she) starts PrEP, the risk of either acquired or transmitted HIV drug resistance is low and is far outweighed by the preventive benefit of PrEP.²⁷

Similarly, there is a suggestion that syphilis infection is increasing among HIV-negative MSM due to decreased HIV-related stigma and increased mixing between HIV-negative and HIV-positive people. The evidence that PrEP has led to an increase in STI rates²⁸ is mixed, however, and is confounded by temporal increases in STI rates and increased detection of asymptomatic STIs among people on PrEP as a result of regular screening.²⁹

Who pays for PrEP?

The cost of PrEP medications and associated clinical care is covered by nearly all private, employer, and public health insurance. Prior authorization might be required to ensure that testing has excluded HIV infection before prescribing and then refilling prescriptions.

Continue to: For patients who have health insurance...

For patients who have health insurance, assistance with copays or coinsurance is available through the producer of PrEP (Gilead Sciences, Inc.) and other national foundations. Many people who seek PrEP might be eligible for Medicaid if they are otherwise uninsured. Other low-income and uninsured people, including those who are not legal residents or US citizens, usually qualify for the PrEP medication assistance program; the application for this benefit must be completed by the physician.

One way to identify patients for whom PrEP might be appropriate is to talk to subsets of potentially high-risk patients, such as men who have sex with men and transgender patients.

A billing guide on PrEP for physicians is available to assist with International Classification of Disease (ICD)-10 coding.^30,31 If a patient has difficulty with laboratory copays, free HIV and STI testing might be available at local STI clinics and acquired immunodeficiency syndrome (AIDS) service organizations.

Providing PrEP within a primary care setting

The unmet need for PrEP highlights how important it is for family medicine and other primary care practices to incorporate HIV prevention into their suite of services.³²

Patients are most likely to experience adverse effects during the first month of taking PrEP—the same period in which they are establishing their pattern of adherence. It might be helpful to check in with patients at the end of the first month to assess their symptoms and adherence. After this phase, quarterly follow-up is simple, with routine lab monitoring and check-in about continued risk of HIV and adherence challenges (TABLE 3¹⁰).

At our local Ryan White HIV/AIDS Program-funded HIV clinic, which also provides PrEP, computer-ordering checklists (so-called smartsets) for the PrEP initial visit and follow-up visits are programmed into the records system (TABLE 4¹⁵). Other clinics also have developed templates for PrEP visit notes. Adherence monitoring, behavioral counseling, and other preventive services can be integrated into the regular paper- or computer-based intake survey, so that conversations are focused on areas of need.⁶ Family physicians in large practices can develop in-office protocols, based on CDC PrEP guidelines, to assign roles (eg, paperwork assistant, behavioral counselor, prescriber) to staff members.

Continue to: Partnering with HIV specialists, organizations, and pharmacists

Family physicians who are unsure about initiating PrEP might consider referring complex patients, such as those with unclear eligibility or active HBV infection, to an infectious disease or HIV specialist or clinic for the initial evaluation. Once a patient has been started on PrEP, quarterly monitoring is simple and can be easily completed in a family medicine practice.

Depending on location and available services, pharmacists and local HIV and AIDS organizations might provide behavioral and adherence counseling and repeat testing during follow-up appointments. In our experience, working with a primary pharmacy that is familiar with patient assistance programs and prior authorization requirements facilitates smoother prescribing. The result? Lower cost to patients because of knowledge of copays and other assistance programs and willingness to use these secondary payers.

Bringing PrEP into the practice is workable

Providing PrEP is well within your scope of practice as a family physician. To assist you in making PrEP an effective component of your practice, we provide a list of sources of PrEP support in TABLE 5.

Because some physicians might still be reluctant to prescribe PrEP for patients who maintain their risk of HIV acquisition, we recommend that you think of PrEP as you do about statins. Discussing diet and exercise as a means of reducing cardiovascular events for every patient with hyperlipidemia is often insufficient; most physicians therefore also prescribe medication for patients who cannot change behaviors sufficiently to modify their cardiovascular risk factors. Similarly, you now have a preventive for HIV—a costly, lifelong infection—that is as cost-effective as statins are.^26,33

CORRESPONDENCE
Joanne D. Stekler, MD, MPH, Box 359931, Harborview Medical Center, 325 9th Avenue, Seattle, WA 98104; [email protected].

The prevalence of allergic disease in the general population is quite high; 8.3% of adults and children have asthma and 11.4% of children have skin allergies.¹ Food allergies are present in 8% of children and 5% of adults,² and up to 10% of anaphylactic reactions in the United States are due to stinging insects.³

Allergy immunotherapy has been shown to produce a 2.7- to 13.7-fold overall improvement in hypersensitivity reactions.

Moderate-to-severe food and environmental allergies can negatively affect multiple organ systems and significantly impact morbidity and mortality.⁴ Quality of life and the financial well-being of patients with allergic diseases, as well as that of their families, can also be significantly impacted by these conditions.^4,5 High prevalence and burden of disease mandate that family physicians (FPs) stay up-to-date on the full array of treatment options for allergic diseases. What follows are 6 common questions about allergy immunotherapy (AIT) and the evidence-based answers that will help you to identify and treat appropriate candidates, as well as educate them along the way.

IMAGE: © ALICIA BUELOW

Who is a candidate for AIT?

Patients with moderate-to-severe immunoglobulin (Ig)E-mediated allergies whose symptoms are not adequately controlled by medications and allergen trigger avoidance are candidates for AIT.^6-8 Skin prick/puncture testing provides the most reliable and cost-effective confirmation of allergies that are suspected, based on patient history and clinical assessment for allergic symptoms.⁹ Life-threatening reactions to skin prick/puncture testing are rare.⁹ While in vitro (laboratory) testing for IgE levels to specific antigens may be more convenient for patients and less invasive than skin prick/puncture testing, it is also less sensitive and less reliable at quantifying the severity of sensitization.⁹

What constitutes AIT?

AIT is a disease-modifying treatment that, along with allergen avoidance, can provide long-term remission of allergic disease in certain circumstances.^6,7 Consistent gradual exposure to an allergen helps to dampen the inflammatory reaction driven by T cells and B cells, producing clinical tolerance or desensitization that persists after the discontinuation of AIT.⁸ While subcutaneous immunotherapy (SCIT) is the most widely known type of AIT (ie, allergy shots), there are additional ways that AIT can be administered. These include sublingual immunotherapy (SLIT), venom immunotherapy (VIT), and oral immunotherapy (OIT). The selection of the route of administration depends on the exact nature and symptoms of the allergic condition being treated (TABLE^6,8-12).

AIT involves 2 phases

The first phase is the induction or buildup phase during which patients are given gradually increasing amounts of allergen to induce a protective immunologic response.⁶ After 8 to 28 weeks, the maintenance phase begins, during which continued, consistent allergen exposure is designed to prevent relapse of, and facilitate continued remission of, allergy symptoms.⁶ The maintenance phase of AIT can last 24 to 48 months.^6,10 Certain patients may qualify for an expedited AIT regimen called cluster or rush immunotherapy.⁶

While lab testing may be more convenient for patients and less invasive than skin prick/ puncture testing, it is also less sensitive and less reliable at quantifying the severity of sensitization.

Conventional schedules for AIT involve increasing the dose of allergen given at each visit (1-3 doses/wk), whereas rush dosing involves multiple, increasing doses given in a single extended visit to reach therapeutic desensitization faster.⁶ AIT has been shown to produce a 2.7- to 13.7-fold overall improvement in hypersensitivity reactions.¹⁰

Length of therapy must be individualized

Experts recommend that the length of treatment with AIT be customized for each patient based on the severity of pretreatment allergy symptoms, the benefit experienced with AIT, the inconvenience of AIT to the patient, and the anticipated impact of symptom relapse.^6,10 There are no physiologic symptoms or objective tests that predict which patients will remain in remission after discontinuing AIT; thus, a joint task force of allergy experts suggests that the decision to restart AIT in patients who have a relapse in allergic symptoms should be made based on the same factors used to determine the duration of the maintenance phase.⁶

Continue to: These allergans are appropriate for AIT

Allergens may be described in terms of mechanism and chronicity of exposure. While avoidance of offending allergens is recommended for those who are sensitized, avoidance is not always possible.^6,7,9,13 AIT has been studied as a therapeutic modality to prevent exposure-related symptoms associated with each of the following types of allergens.^6,7,9,11,14

Inhalant allergens circulate in disturbed and undisturbed air and may be seasonal (eg, pollen), perennial (eg, cat/dog allergens), and/or occupational.⁹ They can derive from the indoors (eg, cockroach, cat, dog, dust mite) or outdoors (eg, tree, grass, or weed pollen ),^6,7,9,11 and serve as triggers for many allergic diseases such as allergic rhinitis (AR), allergic rhinoconjunctivitis, allergic dermatitis, and asthma.^7,13

Food allergens. Sensitization to food allergens may produce a range of symptoms.^6,7 One person may experience nothing more than tingling of the lips when eating a peach, while another may experience throat tightness and anaphylaxis due to the aroma of shellfish cooking.

Occupational allergens. Exposure to occupational allergens varies depending on the setting. Those who work in health care or with animals can be exposed to allergens (eg, latex and animal proteins, respectively) that can cause skin or respiratory hypersensitivity reactions. Occupational allergens can also include chemicals; workers in agriculture or housekeeping may be particularly at risk.

Insect allergens. Envenomation by stinging insects of the order Hymenoptera (bees, yellow jackets, hornets, wasps, fire ants) most commonly causes a pruritic, painful local reaction, but patients sensitized to Hymenoptera venom experience systemic allergic reactions that range from mild to life-threatening.^3,6,7

Continue to: When should you use AIT?

Allergic rhinitis (AR). AR can be triggered by exposure to indoor or outdoor inhalant allergens. Research has shown AIT to be an effective treatment for AR and the conjunctivitis caused by inhaled environmental allergens.^15-17 AIT results in improved symptom control and decreased use of rescue medication (standardized mean difference [SMD] -0.32; 95% confidence interval [CI], -0.23 to -0.33, favoring AIT intervention) in patients with seasonal or perennial AR.^15-17

SCIT effectiveness has been demonstrated in sensitized patients who have symptoms associated with pollen, animal allergens, dust mites, and mold/fungi,^15,16 and SCIT may be effective for the treatment of symptoms associated with cockroach exposure.¹¹ SLIT is approved by the US Food and Drug Administration (FDA) for the treatment of several pollen allergens with efficacy rates similar to those of SCIT and with no significant difference in adverse events (AEs).^8,15,16 Direct comparison studies of SCIT and SLIT preparations for treating grass allergy, while of low quality, showed comparable reductions in allergic rhinoconjunctival symptoms.¹⁵

Asthma. AIT (SCIT and SLIT) has been shown to be effective and safe in patients with mild-to-moderate asthma associated with inhalant allergens. Asthma should be controlled prior to initiation of AIT.^6,8,10 Well-known allergic triggers for asthma exacerbation include indoor inhaled allergens (eg, house dust mite, animal dander, cockroach), outdoor inhalant allergens (plants, pollen), and occupational inhaled allergens (silkworm, weevil).^11,13

In one meta-analysis of 796 patients with asthma from 19 different randomized controlled trials, SCIT significantly decreased asthma-related symptom scores (SMD = -0.94; 95% CI, -1.58 to -0.29; P = .004), as well as asthma medication scores (SMD = -1.06; 95% CI, -1.70 to -0.42; P = .001).¹⁸ While AIT has not been shown to improve lung function, meta-analyses have shown that adults with asthma treated with AIT experience fewer/less severe exacerbations and use less rescue medication when compared with those taking placebo.^19,20 Furthermore, studies have shown that SCIT and SLIT reduce asthma symptoms and asthma medication use compared with placebo or usual care in the pediatric population.²⁰

Adults with asthma treated with allergy immunotherapy use less rescue medication when compared to those taking placebo.

As helpful as AIT can be for some patients with mild-to-moderate asthma, patients with severe asthma experience more severe adverse reactions with AIT.²¹ Therefore, most experts recommend against administering AIT to patients with severe asthma.^6,8,21

Continue to: Stinging insects

Stinging insects. VIT is used for patients with hypersensitivity to the venom from insects of the order Hymenoptera (see previous list of insects).^3,11,22 A meta-analysis concluded, based on limited evidence from low-quality studies, that VIT has the potential to substantially reduce the incidence of severe allergic reactions in patients with Hymenoptera sensitivity with 72% of patients benefitting from VIT (number needed to treat [NNT] = 1.4).²² VIT reduces the risk of a systemic reaction, as well as the size and duration of large local reactions (LLRs).^6,22 Immunotherapy for stinging insects also has been shown to improve disease-specific quality of life (risk difference = 1.41 strongly favoring VIT).^6,22

Insect allergens. Research has shown AIT to be an effective therapy for many allergens even though the potency and effectiveness for some allergens are not standardized or regulated.^6,7,11,14 For example, AIT is available for some inhaled insect allergens; however, because the extracts are not standardized, AIT produces inconsistent outcomes.^11,14 As another example, certain occupations lead to exposure to inhaled insect allergens such as silkworm and weevils. AIT is not indicated for either because available silkworm extracts are used only for allergy testing.¹¹ There are no extracts to test for or treat weevil allergy.¹¹

Food. IgE-mediated food allergy can result in oral allergy syndrome, angioedema, urticaria, and/or anaphylaxis.^2,7,8 There is some evidence that AIT raises the threshold of reactivity in children with IgE-mediated food allergies.^6,7,23-25 But the studies available for meta-analyses (some of which involved OIT) were deemed to be of low quality due to a high risk of bias and a small number of participants.^24,25 AIT for food allergies is associated with a substantially increased incidence of moderate adverse reactions, including upper respiratory, gastrointestinal, and skin symptoms, with a probability of 46% during the buildup phase and a number needed to harm (NNH) of 2.1 (95% CI, 1.8-2.5; P < .0001).^6,25 Therefore, experts consider AIT in any form for food hypersensitivity to be investigational.^6,10

Allergen immunotherapy for allergic rhinitis has proven to be effective at improving quality of life and symptom control and decreasing comorbid disease and use of rescue medication.

But preliminary data from a recent phase 3 trial of OIT for peanut allergy involving 499 children and teens are promising; 67.2% tolerated the food challenge of ≥ 600 mg of peanut protein at the completion of peanut OIT without dose-limiting symptoms (difference = 63.2 percentage points; 95% CI, 53-73.3; P < .001).²⁶ More than twice as many participants in the placebo group vs the treatment group experienced AEs that were moderate (59% vs 25%, respectively) or severe (11% vs 5%, respectively).

There are ongoing trials of SCIT, SLIT, and OIT using modified food allergens to make participants less allergic while maintaining immunogenicity.^2,27 Additional trials include adjunctive treatments like probiotics to create safer, more effective options for children with food allergies.^2,27 Keep in mind that children with food allergies often have concomitant allergies (eg, inhalant allergies) that can benefit from AIT.

Continue to: Other clinical practice strategies include...

Other clinical practice strategies include the introduction of extensively heated (baked) milk and egg products, which benefit the majority of milk- and egg-allergic children.^2,28 An American Academy of Allergy, Asthma and Immunology (AAAAI)-sponsored Task Force and the European Academy of Allergy and Clinical Immunology (EAACI) support exclusive breastfeeding for the first 4 to 6 months of life to decrease the risk of developing food allergies.^6,7

Atopic dermatitis (AD). AD is an IgE-mediated skin disease that affects children and adults. AD is associated with asthma, AR, and food allergy.¹³ Early studies showed that AIT reduced topical corticosteroid use and improved the SCORAD (SCORing Atopic Dermatitis; see www.scorad.corti.li/) score.¹⁰ However, Cochrane reviews of studies involving children and adults with AD undergoing AIT via SCIT, SLIT, or OIT routes found that AIT was not effective in treating AD when accounting for the quality and heterogeneity of the studies.^12,29 In addition, there were no significant differences in SCORAD scores.^10,12

Contact allergens. Contact allergens, including plant resins (eg, poison ivy) and metals (eg, nickel) cause local dermatitis through a cell-mediated, delayed hypersensitivity response. AIT is not indicated for contact dermatitis.^6,9

Why use AIT?

First, AIT has been shown to modify disease. Second, because of its disease-modifying properties, AIT may provide cost savings over standard drug treatment in patients with asthma and AR.^17,20,30 In fact, individual studies have demonstrated ≥ 80% cost savings of AIT over standard drug regimens, although meta-analyses have been unable to demonstrate the same.^30,31

In addition, initial studies suggested that AIT might help to prevent the development of new allergen sensitizations.³² One meta-analysis found that AIT decreased the short-term risk of developing asthma in children with AR; however, subsequent studies showed that AIT did not have efficacy in preventing new allergic disease.^31,33

Continue to: How do you administer AIT?

FPs may be asked to administer AIT to their patients. Patients will typically have weekly office visits during the induction phase of AIT and should have appointments every 6 to 12 months during the maintenance phase.^6,8

While allergy immunotherapy has not been shown to improve lung function in patients with asthma, studies have shown that patients experience fewer exacerbations.

Collaboration with an allergy specialist is wise for dosing schedules and possibly for information regarding adverse reactions during administration. It is essential that AIT be administered by clinicians who are knowledgeable about the signs and symptoms of minor allergic reactions (eg, pruritus, mild erythema, and swelling at the administration site) and severe ones (eg, angioedema, shock, anaphylaxis), as well as who have immediate access to emergency medications and resuscitation, should it be needed.^6-8,34

Most (86%) adverse reactions will occur within 30 minutes of administration of AIT; hence, the recommendation is to observe patients for 30 minutes following AIT administration.^6,7,34 Continual training and “mock” severe reaction responses are beneficial for staff administering AIT to ensure appropriate equipment is available and that appropriate procedures are followed. Late-phase reactions can occur and usually present within 6 to 12 hours of administration; thus, it is essential for patients to be educated on the signs and symptoms of adverse reactions and on symptomatic and emergent treatment.^9,34

Experts consider allergy immunotherapy in any form for food hypersensitivity to be investigational.

Rush immunotherapy regimens for inhalant allergens are associated with increased AEs; therefore, pretreatment with antihistamines, leukotriene antagonists, the monoclonal antibody omalizumab, corticosteroids, or combinations of these agents is often used.^6,34 In contrast to inhaled allergens, rush VIT has not been associated with an increased risk of adverse reactions in meta-analyses.^6,22,34 Most experts recommend that AIT be discontinued if anaphylaxis occurs.^8,34

Is AIT safe?

AIT is a proven safe and effective disease-modifying treatment option.^6-8,31,35 Even when AIT is initiated within the season of increased allergen exposure, meta-analyses reveal no increase in adverse events in patients undergoing AIT.³⁵ Given the lack of high-quality evidence confirming the safety of AIT in the following specific situations, both the AAAAI and EAACI have concluded that these conditions/situations are absolute contraindications for AIT due to the risk of severe reactions by activation of underlying disease^8,21,36:

• severe asthma;
• acquired immune deficiency syndrome (AIDS); and
• initiation of AIT during pregnancy.

Continue to: Patients with a history of transplantation...

Patients with a history of transplantation, cancer in remission, human immunodeficiency virus (HIV) without AIDS, and cardiovascular disease have been safely treated with AIT with a < 1.5% incidence of serious adverse events.^6,21,36 It is possible to give patients taking beta-blockers and/or angiotensin converting enzyme inhibitors (ACEIs) AIT with appropriate consideration. Both classes of drugs can interfere with emergency treatment, so one should consider substitution with an agent from another class if possible during AIT.^6,8,20,34 Patients taking ACEIs receiving VIT had substantially increased adverse reactions compared with other forms of AIT; thus, individual risks and benefits must be weighed carefully before initiating VIT.^6,34

Looking ahead

Studies evaluating the indications for AIT in oral allergy syndrome, food allergy, latex allergy, AD, and venom allergy are ongoing.^2,7,10,26 Although the incidence of severe adverse allergy reactions during AIT is rare, there are investigations of using various immune-modifying agents to improve the safety and efficacy of AIT.³⁷ Application of allergen preparation using skin patches, intralymphatic injections, and chemically modified allergens to make them less immunologically reactive are being researched to further improve safety profiles and make AIT less time consuming.³⁸ In Europe and the United States, there is a call for more rigid studies using standardized SLIT preparations. This will allow for an increased number of AIT studies with decreased heterogeneity.

CORRESPONDENCE
Dellyse Bright, MD, Carolinas Medical Center Family Medicine Residency Program, Atrium Health, 2001 Vail Avenue, Suite 400B, Charlotte, NC 28207; [email protected].

The prevalence of allergic disease in the general population is quite high; 8.3% of adults and children have asthma and 11.4% of children have skin allergies.¹ Food allergies are present in 8% of children and 5% of adults,² and up to 10% of anaphylactic reactions in the United States are due to stinging insects.³

Allergy immunotherapy has been shown to produce a 2.7- to 13.7-fold overall improvement in hypersensitivity reactions.

Moderate-to-severe food and environmental allergies can negatively affect multiple organ systems and significantly impact morbidity and mortality.⁴ Quality of life and the financial well-being of patients with allergic diseases, as well as that of their families, can also be significantly impacted by these conditions.^4,5 High prevalence and burden of disease mandate that family physicians (FPs) stay up-to-date on the full array of treatment options for allergic diseases. What follows are 6 common questions about allergy immunotherapy (AIT) and the evidence-based answers that will help you to identify and treat appropriate candidates, as well as educate them along the way.

IMAGE: © ALICIA BUELOW

Who is a candidate for AIT?

Patients with moderate-to-severe immunoglobulin (Ig)E-mediated allergies whose symptoms are not adequately controlled by medications and allergen trigger avoidance are candidates for AIT.^6-8 Skin prick/puncture testing provides the most reliable and cost-effective confirmation of allergies that are suspected, based on patient history and clinical assessment for allergic symptoms.⁹ Life-threatening reactions to skin prick/puncture testing are rare.⁹ While in vitro (laboratory) testing for IgE levels to specific antigens may be more convenient for patients and less invasive than skin prick/puncture testing, it is also less sensitive and less reliable at quantifying the severity of sensitization.⁹

What constitutes AIT?

AIT is a disease-modifying treatment that, along with allergen avoidance, can provide long-term remission of allergic disease in certain circumstances.^6,7 Consistent gradual exposure to an allergen helps to dampen the inflammatory reaction driven by T cells and B cells, producing clinical tolerance or desensitization that persists after the discontinuation of AIT.⁸ While subcutaneous immunotherapy (SCIT) is the most widely known type of AIT (ie, allergy shots), there are additional ways that AIT can be administered. These include sublingual immunotherapy (SLIT), venom immunotherapy (VIT), and oral immunotherapy (OIT). The selection of the route of administration depends on the exact nature and symptoms of the allergic condition being treated (TABLE^6,8-12).

AIT involves 2 phases

The first phase is the induction or buildup phase during which patients are given gradually increasing amounts of allergen to induce a protective immunologic response.⁶ After 8 to 28 weeks, the maintenance phase begins, during which continued, consistent allergen exposure is designed to prevent relapse of, and facilitate continued remission of, allergy symptoms.⁶ The maintenance phase of AIT can last 24 to 48 months.^6,10 Certain patients may qualify for an expedited AIT regimen called cluster or rush immunotherapy.⁶

While lab testing may be more convenient for patients and less invasive than skin prick/ puncture testing, it is also less sensitive and less reliable at quantifying the severity of sensitization.

Conventional schedules for AIT involve increasing the dose of allergen given at each visit (1-3 doses/wk), whereas rush dosing involves multiple, increasing doses given in a single extended visit to reach therapeutic desensitization faster.⁶ AIT has been shown to produce a 2.7- to 13.7-fold overall improvement in hypersensitivity reactions.¹⁰

Length of therapy must be individualized

Experts recommend that the length of treatment with AIT be customized for each patient based on the severity of pretreatment allergy symptoms, the benefit experienced with AIT, the inconvenience of AIT to the patient, and the anticipated impact of symptom relapse.^6,10 There are no physiologic symptoms or objective tests that predict which patients will remain in remission after discontinuing AIT; thus, a joint task force of allergy experts suggests that the decision to restart AIT in patients who have a relapse in allergic symptoms should be made based on the same factors used to determine the duration of the maintenance phase.⁶

Continue to: These allergans are appropriate for AIT

Allergens may be described in terms of mechanism and chronicity of exposure. While avoidance of offending allergens is recommended for those who are sensitized, avoidance is not always possible.^6,7,9,13 AIT has been studied as a therapeutic modality to prevent exposure-related symptoms associated with each of the following types of allergens.^6,7,9,11,14

Inhalant allergens circulate in disturbed and undisturbed air and may be seasonal (eg, pollen), perennial (eg, cat/dog allergens), and/or occupational.⁹ They can derive from the indoors (eg, cockroach, cat, dog, dust mite) or outdoors (eg, tree, grass, or weed pollen ),^6,7,9,11 and serve as triggers for many allergic diseases such as allergic rhinitis (AR), allergic rhinoconjunctivitis, allergic dermatitis, and asthma.^7,13

Food allergens. Sensitization to food allergens may produce a range of symptoms.^6,7 One person may experience nothing more than tingling of the lips when eating a peach, while another may experience throat tightness and anaphylaxis due to the aroma of shellfish cooking.

Occupational allergens. Exposure to occupational allergens varies depending on the setting. Those who work in health care or with animals can be exposed to allergens (eg, latex and animal proteins, respectively) that can cause skin or respiratory hypersensitivity reactions. Occupational allergens can also include chemicals; workers in agriculture or housekeeping may be particularly at risk.

Insect allergens. Envenomation by stinging insects of the order Hymenoptera (bees, yellow jackets, hornets, wasps, fire ants) most commonly causes a pruritic, painful local reaction, but patients sensitized to Hymenoptera venom experience systemic allergic reactions that range from mild to life-threatening.^3,6,7

Continue to: When should you use AIT?

Allergic rhinitis (AR). AR can be triggered by exposure to indoor or outdoor inhalant allergens. Research has shown AIT to be an effective treatment for AR and the conjunctivitis caused by inhaled environmental allergens.^15-17 AIT results in improved symptom control and decreased use of rescue medication (standardized mean difference [SMD] -0.32; 95% confidence interval [CI], -0.23 to -0.33, favoring AIT intervention) in patients with seasonal or perennial AR.^15-17

SCIT effectiveness has been demonstrated in sensitized patients who have symptoms associated with pollen, animal allergens, dust mites, and mold/fungi,^15,16 and SCIT may be effective for the treatment of symptoms associated with cockroach exposure.¹¹ SLIT is approved by the US Food and Drug Administration (FDA) for the treatment of several pollen allergens with efficacy rates similar to those of SCIT and with no significant difference in adverse events (AEs).^8,15,16 Direct comparison studies of SCIT and SLIT preparations for treating grass allergy, while of low quality, showed comparable reductions in allergic rhinoconjunctival symptoms.¹⁵

Asthma. AIT (SCIT and SLIT) has been shown to be effective and safe in patients with mild-to-moderate asthma associated with inhalant allergens. Asthma should be controlled prior to initiation of AIT.^6,8,10 Well-known allergic triggers for asthma exacerbation include indoor inhaled allergens (eg, house dust mite, animal dander, cockroach), outdoor inhalant allergens (plants, pollen), and occupational inhaled allergens (silkworm, weevil).^11,13

In one meta-analysis of 796 patients with asthma from 19 different randomized controlled trials, SCIT significantly decreased asthma-related symptom scores (SMD = -0.94; 95% CI, -1.58 to -0.29; P = .004), as well as asthma medication scores (SMD = -1.06; 95% CI, -1.70 to -0.42; P = .001).¹⁸ While AIT has not been shown to improve lung function, meta-analyses have shown that adults with asthma treated with AIT experience fewer/less severe exacerbations and use less rescue medication when compared with those taking placebo.^19,20 Furthermore, studies have shown that SCIT and SLIT reduce asthma symptoms and asthma medication use compared with placebo or usual care in the pediatric population.²⁰

Adults with asthma treated with allergy immunotherapy use less rescue medication when compared to those taking placebo.

As helpful as AIT can be for some patients with mild-to-moderate asthma, patients with severe asthma experience more severe adverse reactions with AIT.²¹ Therefore, most experts recommend against administering AIT to patients with severe asthma.^6,8,21

Continue to: Stinging insects

Stinging insects. VIT is used for patients with hypersensitivity to the venom from insects of the order Hymenoptera (see previous list of insects).^3,11,22 A meta-analysis concluded, based on limited evidence from low-quality studies, that VIT has the potential to substantially reduce the incidence of severe allergic reactions in patients with Hymenoptera sensitivity with 72% of patients benefitting from VIT (number needed to treat [NNT] = 1.4).²² VIT reduces the risk of a systemic reaction, as well as the size and duration of large local reactions (LLRs).^6,22 Immunotherapy for stinging insects also has been shown to improve disease-specific quality of life (risk difference = 1.41 strongly favoring VIT).^6,22

Insect allergens. Research has shown AIT to be an effective therapy for many allergens even though the potency and effectiveness for some allergens are not standardized or regulated.^6,7,11,14 For example, AIT is available for some inhaled insect allergens; however, because the extracts are not standardized, AIT produces inconsistent outcomes.^11,14 As another example, certain occupations lead to exposure to inhaled insect allergens such as silkworm and weevils. AIT is not indicated for either because available silkworm extracts are used only for allergy testing.¹¹ There are no extracts to test for or treat weevil allergy.¹¹

Food. IgE-mediated food allergy can result in oral allergy syndrome, angioedema, urticaria, and/or anaphylaxis.^2,7,8 There is some evidence that AIT raises the threshold of reactivity in children with IgE-mediated food allergies.^6,7,23-25 But the studies available for meta-analyses (some of which involved OIT) were deemed to be of low quality due to a high risk of bias and a small number of participants.^24,25 AIT for food allergies is associated with a substantially increased incidence of moderate adverse reactions, including upper respiratory, gastrointestinal, and skin symptoms, with a probability of 46% during the buildup phase and a number needed to harm (NNH) of 2.1 (95% CI, 1.8-2.5; P < .0001).^6,25 Therefore, experts consider AIT in any form for food hypersensitivity to be investigational.^6,10

Allergen immunotherapy for allergic rhinitis has proven to be effective at improving quality of life and symptom control and decreasing comorbid disease and use of rescue medication.

But preliminary data from a recent phase 3 trial of OIT for peanut allergy involving 499 children and teens are promising; 67.2% tolerated the food challenge of ≥ 600 mg of peanut protein at the completion of peanut OIT without dose-limiting symptoms (difference = 63.2 percentage points; 95% CI, 53-73.3; P < .001).²⁶ More than twice as many participants in the placebo group vs the treatment group experienced AEs that were moderate (59% vs 25%, respectively) or severe (11% vs 5%, respectively).

There are ongoing trials of SCIT, SLIT, and OIT using modified food allergens to make participants less allergic while maintaining immunogenicity.^2,27 Additional trials include adjunctive treatments like probiotics to create safer, more effective options for children with food allergies.^2,27 Keep in mind that children with food allergies often have concomitant allergies (eg, inhalant allergies) that can benefit from AIT.

Continue to: Other clinical practice strategies include...

Other clinical practice strategies include the introduction of extensively heated (baked) milk and egg products, which benefit the majority of milk- and egg-allergic children.^2,28 An American Academy of Allergy, Asthma and Immunology (AAAAI)-sponsored Task Force and the European Academy of Allergy and Clinical Immunology (EAACI) support exclusive breastfeeding for the first 4 to 6 months of life to decrease the risk of developing food allergies.^6,7

Atopic dermatitis (AD). AD is an IgE-mediated skin disease that affects children and adults. AD is associated with asthma, AR, and food allergy.¹³ Early studies showed that AIT reduced topical corticosteroid use and improved the SCORAD (SCORing Atopic Dermatitis; see www.scorad.corti.li/) score.¹⁰ However, Cochrane reviews of studies involving children and adults with AD undergoing AIT via SCIT, SLIT, or OIT routes found that AIT was not effective in treating AD when accounting for the quality and heterogeneity of the studies.^12,29 In addition, there were no significant differences in SCORAD scores.^10,12

Contact allergens. Contact allergens, including plant resins (eg, poison ivy) and metals (eg, nickel) cause local dermatitis through a cell-mediated, delayed hypersensitivity response. AIT is not indicated for contact dermatitis.^6,9

Why use AIT?

First, AIT has been shown to modify disease. Second, because of its disease-modifying properties, AIT may provide cost savings over standard drug treatment in patients with asthma and AR.^17,20,30 In fact, individual studies have demonstrated ≥ 80% cost savings of AIT over standard drug regimens, although meta-analyses have been unable to demonstrate the same.^30,31

In addition, initial studies suggested that AIT might help to prevent the development of new allergen sensitizations.³² One meta-analysis found that AIT decreased the short-term risk of developing asthma in children with AR; however, subsequent studies showed that AIT did not have efficacy in preventing new allergic disease.^31,33

Continue to: How do you administer AIT?

FPs may be asked to administer AIT to their patients. Patients will typically have weekly office visits during the induction phase of AIT and should have appointments every 6 to 12 months during the maintenance phase.^6,8

While allergy immunotherapy has not been shown to improve lung function in patients with asthma, studies have shown that patients experience fewer exacerbations.

Collaboration with an allergy specialist is wise for dosing schedules and possibly for information regarding adverse reactions during administration. It is essential that AIT be administered by clinicians who are knowledgeable about the signs and symptoms of minor allergic reactions (eg, pruritus, mild erythema, and swelling at the administration site) and severe ones (eg, angioedema, shock, anaphylaxis), as well as who have immediate access to emergency medications and resuscitation, should it be needed.^6-8,34

Most (86%) adverse reactions will occur within 30 minutes of administration of AIT; hence, the recommendation is to observe patients for 30 minutes following AIT administration.^6,7,34 Continual training and “mock” severe reaction responses are beneficial for staff administering AIT to ensure appropriate equipment is available and that appropriate procedures are followed. Late-phase reactions can occur and usually present within 6 to 12 hours of administration; thus, it is essential for patients to be educated on the signs and symptoms of adverse reactions and on symptomatic and emergent treatment.^9,34

Experts consider allergy immunotherapy in any form for food hypersensitivity to be investigational.

Rush immunotherapy regimens for inhalant allergens are associated with increased AEs; therefore, pretreatment with antihistamines, leukotriene antagonists, the monoclonal antibody omalizumab, corticosteroids, or combinations of these agents is often used.^6,34 In contrast to inhaled allergens, rush VIT has not been associated with an increased risk of adverse reactions in meta-analyses.^6,22,34 Most experts recommend that AIT be discontinued if anaphylaxis occurs.^8,34

Is AIT safe?

AIT is a proven safe and effective disease-modifying treatment option.^6-8,31,35 Even when AIT is initiated within the season of increased allergen exposure, meta-analyses reveal no increase in adverse events in patients undergoing AIT.³⁵ Given the lack of high-quality evidence confirming the safety of AIT in the following specific situations, both the AAAAI and EAACI have concluded that these conditions/situations are absolute contraindications for AIT due to the risk of severe reactions by activation of underlying disease^8,21,36:

• severe asthma;
• acquired immune deficiency syndrome (AIDS); and
• initiation of AIT during pregnancy.

Continue to: Patients with a history of transplantation...

Patients with a history of transplantation, cancer in remission, human immunodeficiency virus (HIV) without AIDS, and cardiovascular disease have been safely treated with AIT with a < 1.5% incidence of serious adverse events.^6,21,36 It is possible to give patients taking beta-blockers and/or angiotensin converting enzyme inhibitors (ACEIs) AIT with appropriate consideration. Both classes of drugs can interfere with emergency treatment, so one should consider substitution with an agent from another class if possible during AIT.^6,8,20,34 Patients taking ACEIs receiving VIT had substantially increased adverse reactions compared with other forms of AIT; thus, individual risks and benefits must be weighed carefully before initiating VIT.^6,34

Looking ahead

Studies evaluating the indications for AIT in oral allergy syndrome, food allergy, latex allergy, AD, and venom allergy are ongoing.^2,7,10,26 Although the incidence of severe adverse allergy reactions during AIT is rare, there are investigations of using various immune-modifying agents to improve the safety and efficacy of AIT.³⁷ Application of allergen preparation using skin patches, intralymphatic injections, and chemically modified allergens to make them less immunologically reactive are being researched to further improve safety profiles and make AIT less time consuming.³⁸ In Europe and the United States, there is a call for more rigid studies using standardized SLIT preparations. This will allow for an increased number of AIT studies with decreased heterogeneity.

CORRESPONDENCE
Dellyse Bright, MD, Carolinas Medical Center Family Medicine Residency Program, Atrium Health, 2001 Vail Avenue, Suite 400B, Charlotte, NC 28207; [email protected].

The prevalence of allergic disease in the general population is quite high; 8.3% of adults and children have asthma and 11.4% of children have skin allergies.¹ Food allergies are present in 8% of children and 5% of adults,² and up to 10% of anaphylactic reactions in the United States are due to stinging insects.³

Allergy immunotherapy has been shown to produce a 2.7- to 13.7-fold overall improvement in hypersensitivity reactions.

Moderate-to-severe food and environmental allergies can negatively affect multiple organ systems and significantly impact morbidity and mortality.⁴ Quality of life and the financial well-being of patients with allergic diseases, as well as that of their families, can also be significantly impacted by these conditions.^4,5 High prevalence and burden of disease mandate that family physicians (FPs) stay up-to-date on the full array of treatment options for allergic diseases. What follows are 6 common questions about allergy immunotherapy (AIT) and the evidence-based answers that will help you to identify and treat appropriate candidates, as well as educate them along the way.

IMAGE: © ALICIA BUELOW

Who is a candidate for AIT?

Patients with moderate-to-severe immunoglobulin (Ig)E-mediated allergies whose symptoms are not adequately controlled by medications and allergen trigger avoidance are candidates for AIT.^6-8 Skin prick/puncture testing provides the most reliable and cost-effective confirmation of allergies that are suspected, based on patient history and clinical assessment for allergic symptoms.⁹ Life-threatening reactions to skin prick/puncture testing are rare.⁹ While in vitro (laboratory) testing for IgE levels to specific antigens may be more convenient for patients and less invasive than skin prick/puncture testing, it is also less sensitive and less reliable at quantifying the severity of sensitization.⁹

What constitutes AIT?

AIT is a disease-modifying treatment that, along with allergen avoidance, can provide long-term remission of allergic disease in certain circumstances.^6,7 Consistent gradual exposure to an allergen helps to dampen the inflammatory reaction driven by T cells and B cells, producing clinical tolerance or desensitization that persists after the discontinuation of AIT.⁸ While subcutaneous immunotherapy (SCIT) is the most widely known type of AIT (ie, allergy shots), there are additional ways that AIT can be administered. These include sublingual immunotherapy (SLIT), venom immunotherapy (VIT), and oral immunotherapy (OIT). The selection of the route of administration depends on the exact nature and symptoms of the allergic condition being treated (TABLE^6,8-12).

AIT involves 2 phases

The first phase is the induction or buildup phase during which patients are given gradually increasing amounts of allergen to induce a protective immunologic response.⁶ After 8 to 28 weeks, the maintenance phase begins, during which continued, consistent allergen exposure is designed to prevent relapse of, and facilitate continued remission of, allergy symptoms.⁶ The maintenance phase of AIT can last 24 to 48 months.^6,10 Certain patients may qualify for an expedited AIT regimen called cluster or rush immunotherapy.⁶

While lab testing may be more convenient for patients and less invasive than skin prick/ puncture testing, it is also less sensitive and less reliable at quantifying the severity of sensitization.

Conventional schedules for AIT involve increasing the dose of allergen given at each visit (1-3 doses/wk), whereas rush dosing involves multiple, increasing doses given in a single extended visit to reach therapeutic desensitization faster.⁶ AIT has been shown to produce a 2.7- to 13.7-fold overall improvement in hypersensitivity reactions.¹⁰

Length of therapy must be individualized

Experts recommend that the length of treatment with AIT be customized for each patient based on the severity of pretreatment allergy symptoms, the benefit experienced with AIT, the inconvenience of AIT to the patient, and the anticipated impact of symptom relapse.^6,10 There are no physiologic symptoms or objective tests that predict which patients will remain in remission after discontinuing AIT; thus, a joint task force of allergy experts suggests that the decision to restart AIT in patients who have a relapse in allergic symptoms should be made based on the same factors used to determine the duration of the maintenance phase.⁶

Continue to: These allergans are appropriate for AIT

Allergens may be described in terms of mechanism and chronicity of exposure. While avoidance of offending allergens is recommended for those who are sensitized, avoidance is not always possible.^6,7,9,13 AIT has been studied as a therapeutic modality to prevent exposure-related symptoms associated with each of the following types of allergens.^6,7,9,11,14

Inhalant allergens circulate in disturbed and undisturbed air and may be seasonal (eg, pollen), perennial (eg, cat/dog allergens), and/or occupational.⁹ They can derive from the indoors (eg, cockroach, cat, dog, dust mite) or outdoors (eg, tree, grass, or weed pollen ),^6,7,9,11 and serve as triggers for many allergic diseases such as allergic rhinitis (AR), allergic rhinoconjunctivitis, allergic dermatitis, and asthma.^7,13

Food allergens. Sensitization to food allergens may produce a range of symptoms.^6,7 One person may experience nothing more than tingling of the lips when eating a peach, while another may experience throat tightness and anaphylaxis due to the aroma of shellfish cooking.

Occupational allergens. Exposure to occupational allergens varies depending on the setting. Those who work in health care or with animals can be exposed to allergens (eg, latex and animal proteins, respectively) that can cause skin or respiratory hypersensitivity reactions. Occupational allergens can also include chemicals; workers in agriculture or housekeeping may be particularly at risk.

Insect allergens. Envenomation by stinging insects of the order Hymenoptera (bees, yellow jackets, hornets, wasps, fire ants) most commonly causes a pruritic, painful local reaction, but patients sensitized to Hymenoptera venom experience systemic allergic reactions that range from mild to life-threatening.^3,6,7

Continue to: When should you use AIT?

Allergic rhinitis (AR). AR can be triggered by exposure to indoor or outdoor inhalant allergens. Research has shown AIT to be an effective treatment for AR and the conjunctivitis caused by inhaled environmental allergens.^15-17 AIT results in improved symptom control and decreased use of rescue medication (standardized mean difference [SMD] -0.32; 95% confidence interval [CI], -0.23 to -0.33, favoring AIT intervention) in patients with seasonal or perennial AR.^15-17

SCIT effectiveness has been demonstrated in sensitized patients who have symptoms associated with pollen, animal allergens, dust mites, and mold/fungi,^15,16 and SCIT may be effective for the treatment of symptoms associated with cockroach exposure.¹¹ SLIT is approved by the US Food and Drug Administration (FDA) for the treatment of several pollen allergens with efficacy rates similar to those of SCIT and with no significant difference in adverse events (AEs).^8,15,16 Direct comparison studies of SCIT and SLIT preparations for treating grass allergy, while of low quality, showed comparable reductions in allergic rhinoconjunctival symptoms.¹⁵

Asthma. AIT (SCIT and SLIT) has been shown to be effective and safe in patients with mild-to-moderate asthma associated with inhalant allergens. Asthma should be controlled prior to initiation of AIT.^6,8,10 Well-known allergic triggers for asthma exacerbation include indoor inhaled allergens (eg, house dust mite, animal dander, cockroach), outdoor inhalant allergens (plants, pollen), and occupational inhaled allergens (silkworm, weevil).^11,13

In one meta-analysis of 796 patients with asthma from 19 different randomized controlled trials, SCIT significantly decreased asthma-related symptom scores (SMD = -0.94; 95% CI, -1.58 to -0.29; P = .004), as well as asthma medication scores (SMD = -1.06; 95% CI, -1.70 to -0.42; P = .001).¹⁸ While AIT has not been shown to improve lung function, meta-analyses have shown that adults with asthma treated with AIT experience fewer/less severe exacerbations and use less rescue medication when compared with those taking placebo.^19,20 Furthermore, studies have shown that SCIT and SLIT reduce asthma symptoms and asthma medication use compared with placebo or usual care in the pediatric population.²⁰

Adults with asthma treated with allergy immunotherapy use less rescue medication when compared to those taking placebo.

As helpful as AIT can be for some patients with mild-to-moderate asthma, patients with severe asthma experience more severe adverse reactions with AIT.²¹ Therefore, most experts recommend against administering AIT to patients with severe asthma.^6,8,21

Continue to: Stinging insects

Stinging insects. VIT is used for patients with hypersensitivity to the venom from insects of the order Hymenoptera (see previous list of insects).^3,11,22 A meta-analysis concluded, based on limited evidence from low-quality studies, that VIT has the potential to substantially reduce the incidence of severe allergic reactions in patients with Hymenoptera sensitivity with 72% of patients benefitting from VIT (number needed to treat [NNT] = 1.4).²² VIT reduces the risk of a systemic reaction, as well as the size and duration of large local reactions (LLRs).^6,22 Immunotherapy for stinging insects also has been shown to improve disease-specific quality of life (risk difference = 1.41 strongly favoring VIT).^6,22

Insect allergens. Research has shown AIT to be an effective therapy for many allergens even though the potency and effectiveness for some allergens are not standardized or regulated.^6,7,11,14 For example, AIT is available for some inhaled insect allergens; however, because the extracts are not standardized, AIT produces inconsistent outcomes.^11,14 As another example, certain occupations lead to exposure to inhaled insect allergens such as silkworm and weevils. AIT is not indicated for either because available silkworm extracts are used only for allergy testing.¹¹ There are no extracts to test for or treat weevil allergy.¹¹

Food. IgE-mediated food allergy can result in oral allergy syndrome, angioedema, urticaria, and/or anaphylaxis.^2,7,8 There is some evidence that AIT raises the threshold of reactivity in children with IgE-mediated food allergies.^6,7,23-25 But the studies available for meta-analyses (some of which involved OIT) were deemed to be of low quality due to a high risk of bias and a small number of participants.^24,25 AIT for food allergies is associated with a substantially increased incidence of moderate adverse reactions, including upper respiratory, gastrointestinal, and skin symptoms, with a probability of 46% during the buildup phase and a number needed to harm (NNH) of 2.1 (95% CI, 1.8-2.5; P < .0001).^6,25 Therefore, experts consider AIT in any form for food hypersensitivity to be investigational.^6,10

Allergen immunotherapy for allergic rhinitis has proven to be effective at improving quality of life and symptom control and decreasing comorbid disease and use of rescue medication.

But preliminary data from a recent phase 3 trial of OIT for peanut allergy involving 499 children and teens are promising; 67.2% tolerated the food challenge of ≥ 600 mg of peanut protein at the completion of peanut OIT without dose-limiting symptoms (difference = 63.2 percentage points; 95% CI, 53-73.3; P < .001).²⁶ More than twice as many participants in the placebo group vs the treatment group experienced AEs that were moderate (59% vs 25%, respectively) or severe (11% vs 5%, respectively).

There are ongoing trials of SCIT, SLIT, and OIT using modified food allergens to make participants less allergic while maintaining immunogenicity.^2,27 Additional trials include adjunctive treatments like probiotics to create safer, more effective options for children with food allergies.^2,27 Keep in mind that children with food allergies often have concomitant allergies (eg, inhalant allergies) that can benefit from AIT.

Continue to: Other clinical practice strategies include...

Other clinical practice strategies include the introduction of extensively heated (baked) milk and egg products, which benefit the majority of milk- and egg-allergic children.^2,28 An American Academy of Allergy, Asthma and Immunology (AAAAI)-sponsored Task Force and the European Academy of Allergy and Clinical Immunology (EAACI) support exclusive breastfeeding for the first 4 to 6 months of life to decrease the risk of developing food allergies.^6,7

Atopic dermatitis (AD). AD is an IgE-mediated skin disease that affects children and adults. AD is associated with asthma, AR, and food allergy.¹³ Early studies showed that AIT reduced topical corticosteroid use and improved the SCORAD (SCORing Atopic Dermatitis; see www.scorad.corti.li/) score.¹⁰ However, Cochrane reviews of studies involving children and adults with AD undergoing AIT via SCIT, SLIT, or OIT routes found that AIT was not effective in treating AD when accounting for the quality and heterogeneity of the studies.^12,29 In addition, there were no significant differences in SCORAD scores.^10,12

Contact allergens. Contact allergens, including plant resins (eg, poison ivy) and metals (eg, nickel) cause local dermatitis through a cell-mediated, delayed hypersensitivity response. AIT is not indicated for contact dermatitis.^6,9

Why use AIT?

First, AIT has been shown to modify disease. Second, because of its disease-modifying properties, AIT may provide cost savings over standard drug treatment in patients with asthma and AR.^17,20,30 In fact, individual studies have demonstrated ≥ 80% cost savings of AIT over standard drug regimens, although meta-analyses have been unable to demonstrate the same.^30,31

In addition, initial studies suggested that AIT might help to prevent the development of new allergen sensitizations.³² One meta-analysis found that AIT decreased the short-term risk of developing asthma in children with AR; however, subsequent studies showed that AIT did not have efficacy in preventing new allergic disease.^31,33

Continue to: How do you administer AIT?

FPs may be asked to administer AIT to their patients. Patients will typically have weekly office visits during the induction phase of AIT and should have appointments every 6 to 12 months during the maintenance phase.^6,8

While allergy immunotherapy has not been shown to improve lung function in patients with asthma, studies have shown that patients experience fewer exacerbations.

Collaboration with an allergy specialist is wise for dosing schedules and possibly for information regarding adverse reactions during administration. It is essential that AIT be administered by clinicians who are knowledgeable about the signs and symptoms of minor allergic reactions (eg, pruritus, mild erythema, and swelling at the administration site) and severe ones (eg, angioedema, shock, anaphylaxis), as well as who have immediate access to emergency medications and resuscitation, should it be needed.^6-8,34

Most (86%) adverse reactions will occur within 30 minutes of administration of AIT; hence, the recommendation is to observe patients for 30 minutes following AIT administration.^6,7,34 Continual training and “mock” severe reaction responses are beneficial for staff administering AIT to ensure appropriate equipment is available and that appropriate procedures are followed. Late-phase reactions can occur and usually present within 6 to 12 hours of administration; thus, it is essential for patients to be educated on the signs and symptoms of adverse reactions and on symptomatic and emergent treatment.^9,34

Experts consider allergy immunotherapy in any form for food hypersensitivity to be investigational.

Rush immunotherapy regimens for inhalant allergens are associated with increased AEs; therefore, pretreatment with antihistamines, leukotriene antagonists, the monoclonal antibody omalizumab, corticosteroids, or combinations of these agents is often used.^6,34 In contrast to inhaled allergens, rush VIT has not been associated with an increased risk of adverse reactions in meta-analyses.^6,22,34 Most experts recommend that AIT be discontinued if anaphylaxis occurs.^8,34

Is AIT safe?

AIT is a proven safe and effective disease-modifying treatment option.^6-8,31,35 Even when AIT is initiated within the season of increased allergen exposure, meta-analyses reveal no increase in adverse events in patients undergoing AIT.³⁵ Given the lack of high-quality evidence confirming the safety of AIT in the following specific situations, both the AAAAI and EAACI have concluded that these conditions/situations are absolute contraindications for AIT due to the risk of severe reactions by activation of underlying disease^8,21,36:

• severe asthma;
• acquired immune deficiency syndrome (AIDS); and
• initiation of AIT during pregnancy.

Continue to: Patients with a history of transplantation...

Patients with a history of transplantation, cancer in remission, human immunodeficiency virus (HIV) without AIDS, and cardiovascular disease have been safely treated with AIT with a < 1.5% incidence of serious adverse events.^6,21,36 It is possible to give patients taking beta-blockers and/or angiotensin converting enzyme inhibitors (ACEIs) AIT with appropriate consideration. Both classes of drugs can interfere with emergency treatment, so one should consider substitution with an agent from another class if possible during AIT.^6,8,20,34 Patients taking ACEIs receiving VIT had substantially increased adverse reactions compared with other forms of AIT; thus, individual risks and benefits must be weighed carefully before initiating VIT.^6,34

Looking ahead

Studies evaluating the indications for AIT in oral allergy syndrome, food allergy, latex allergy, AD, and venom allergy are ongoing.^2,7,10,26 Although the incidence of severe adverse allergy reactions during AIT is rare, there are investigations of using various immune-modifying agents to improve the safety and efficacy of AIT.³⁷ Application of allergen preparation using skin patches, intralymphatic injections, and chemically modified allergens to make them less immunologically reactive are being researched to further improve safety profiles and make AIT less time consuming.³⁸ In Europe and the United States, there is a call for more rigid studies using standardized SLIT preparations. This will allow for an increased number of AIT studies with decreased heterogeneity.

CORRESPONDENCE
Dellyse Bright, MD, Carolinas Medical Center Family Medicine Residency Program, Atrium Health, 2001 Vail Avenue, Suite 400B, Charlotte, NC 28207; [email protected].