Clinical Inquiries

Evidence summary

Sebaceous cysts—more correctly referred to as epidermal inclusion cysts—are benign lesions of the skin. They rarely require intervention out of medical necessity, but are removed for cosmetic reasons. If the cysts become inflamed, secondary to internal discharge of the cysts’ contents, or grow so large that they interfere with the patient’s functioning, they may need to be removed.¹

Traditional wide excision—involving dissection and removal of the cyst completely from the surrounding tissue through an elliptical incision—is considered the gold standard of treatment. This time-consuming endeavor frequently leads to significant scarring in comparison with minimal excision or punch biopsy, but has almost no recurrence when the cyst wall is entirely removed.²

Minimal excision and punch biopsy techniques are purported to produce minimal bleeding, have faster healing times, and produce less scarring.² Though both techniques offer a shorter procedural time, they appear to have a slightly higher rates of recurrence.

The minimal incision technique involves kneading the lesion following injection of anesthetic and expressing the cyst contents through a 2- to 3-mm incision. Following expulsion of the cyst contents, the loosened capsule is delivered through the small opening. Closure with suture is optional.³

Punch biopsy excision is similar to the minimal excision technique except that the incision is made using a single-use disposable dermal punch following injection of lidocaine. Expulsion of the cyst contents, with cyst wall, via lateral pressure is performed and occasionally followed by closure with one suture.²

The majority of authors agree that inflamed cysts should be allowed to convalesce prior to attempted removal, though one group (Kitamura et al⁴) suggests primary resection, wound lavage, and primary suture without drainage for infected epidermal cysts. Rarely are these cysts truly infected. The inflammation is secondary to sebaceous cyst wall rupture with leakage of cyst contents, which elicits the inflammatory response.⁵

A small study points to cosmetic benefits of punch biopsy

To date, no randomized controlled trials have been published that compare the 3 most common techniques for treatment of sebaceous cysts. Only 1 small (n=60) randomized study compared traditional wide excision with punch biopsy.⁶ They found punch biopsy to be less time-consuming and to offer superior cosmetic results. However, cysts larger than 2 cm took longer with the punch biopsy technique.

Only a single dermatologist performed all of the surgeries, which could introduce bias. There was no mention of blinding of the researcher that subsequently measured the wounds. Of the 31 patients randomized to the punch biopsy technique, there was 1 recurrence in the 16 months of follow-up compared with none in the wide excision arm. This study excluded patients with infected, inflamed, or recurrent cysts.

Recommendations from others

UpToDate does not recommend excision of an inflamed cyst, suggesting that the inflamed cyst wall is more friable and, therefore, more difficult to remove completely.⁷ This may lead to a higher rate of recurrence.

Lookingbill and Marks in Principles of Dermatology⁸ suggest that, frequently, no therapy is indicated for these lesions. If removal is desired or indicated, every effort should be made to remove the entire cyst lining in order to prevent recurrence of the cyst. They recommend removal of the cyst via the traditional wide excision technique. If the cyst ruptures accidentally during the procedure they suggest removing the remaining contents and wall with a curette.

Evidence summary

Sebaceous cysts—more correctly referred to as epidermal inclusion cysts—are benign lesions of the skin. They rarely require intervention out of medical necessity, but are removed for cosmetic reasons. If the cysts become inflamed, secondary to internal discharge of the cysts’ contents, or grow so large that they interfere with the patient’s functioning, they may need to be removed.¹

Traditional wide excision—involving dissection and removal of the cyst completely from the surrounding tissue through an elliptical incision—is considered the gold standard of treatment. This time-consuming endeavor frequently leads to significant scarring in comparison with minimal excision or punch biopsy, but has almost no recurrence when the cyst wall is entirely removed.²

Minimal excision and punch biopsy techniques are purported to produce minimal bleeding, have faster healing times, and produce less scarring.² Though both techniques offer a shorter procedural time, they appear to have a slightly higher rates of recurrence.

The minimal incision technique involves kneading the lesion following injection of anesthetic and expressing the cyst contents through a 2- to 3-mm incision. Following expulsion of the cyst contents, the loosened capsule is delivered through the small opening. Closure with suture is optional.³

Punch biopsy excision is similar to the minimal excision technique except that the incision is made using a single-use disposable dermal punch following injection of lidocaine. Expulsion of the cyst contents, with cyst wall, via lateral pressure is performed and occasionally followed by closure with one suture.²

The majority of authors agree that inflamed cysts should be allowed to convalesce prior to attempted removal, though one group (Kitamura et al⁴) suggests primary resection, wound lavage, and primary suture without drainage for infected epidermal cysts. Rarely are these cysts truly infected. The inflammation is secondary to sebaceous cyst wall rupture with leakage of cyst contents, which elicits the inflammatory response.⁵

A small study points to cosmetic benefits of punch biopsy

To date, no randomized controlled trials have been published that compare the 3 most common techniques for treatment of sebaceous cysts. Only 1 small (n=60) randomized study compared traditional wide excision with punch biopsy.⁶ They found punch biopsy to be less time-consuming and to offer superior cosmetic results. However, cysts larger than 2 cm took longer with the punch biopsy technique.

Only a single dermatologist performed all of the surgeries, which could introduce bias. There was no mention of blinding of the researcher that subsequently measured the wounds. Of the 31 patients randomized to the punch biopsy technique, there was 1 recurrence in the 16 months of follow-up compared with none in the wide excision arm. This study excluded patients with infected, inflamed, or recurrent cysts.

Recommendations from others

UpToDate does not recommend excision of an inflamed cyst, suggesting that the inflamed cyst wall is more friable and, therefore, more difficult to remove completely.⁷ This may lead to a higher rate of recurrence.

Lookingbill and Marks in Principles of Dermatology⁸ suggest that, frequently, no therapy is indicated for these lesions. If removal is desired or indicated, every effort should be made to remove the entire cyst lining in order to prevent recurrence of the cyst. They recommend removal of the cyst via the traditional wide excision technique. If the cyst ruptures accidentally during the procedure they suggest removing the remaining contents and wall with a curette.

Evidence summary

Sebaceous cysts—more correctly referred to as epidermal inclusion cysts—are benign lesions of the skin. They rarely require intervention out of medical necessity, but are removed for cosmetic reasons. If the cysts become inflamed, secondary to internal discharge of the cysts’ contents, or grow so large that they interfere with the patient’s functioning, they may need to be removed.¹

Traditional wide excision—involving dissection and removal of the cyst completely from the surrounding tissue through an elliptical incision—is considered the gold standard of treatment. This time-consuming endeavor frequently leads to significant scarring in comparison with minimal excision or punch biopsy, but has almost no recurrence when the cyst wall is entirely removed.²

Minimal excision and punch biopsy techniques are purported to produce minimal bleeding, have faster healing times, and produce less scarring.² Though both techniques offer a shorter procedural time, they appear to have a slightly higher rates of recurrence.

The minimal incision technique involves kneading the lesion following injection of anesthetic and expressing the cyst contents through a 2- to 3-mm incision. Following expulsion of the cyst contents, the loosened capsule is delivered through the small opening. Closure with suture is optional.³

Punch biopsy excision is similar to the minimal excision technique except that the incision is made using a single-use disposable dermal punch following injection of lidocaine. Expulsion of the cyst contents, with cyst wall, via lateral pressure is performed and occasionally followed by closure with one suture.²

The majority of authors agree that inflamed cysts should be allowed to convalesce prior to attempted removal, though one group (Kitamura et al⁴) suggests primary resection, wound lavage, and primary suture without drainage for infected epidermal cysts. Rarely are these cysts truly infected. The inflammation is secondary to sebaceous cyst wall rupture with leakage of cyst contents, which elicits the inflammatory response.⁵

A small study points to cosmetic benefits of punch biopsy

To date, no randomized controlled trials have been published that compare the 3 most common techniques for treatment of sebaceous cysts. Only 1 small (n=60) randomized study compared traditional wide excision with punch biopsy.⁶ They found punch biopsy to be less time-consuming and to offer superior cosmetic results. However, cysts larger than 2 cm took longer with the punch biopsy technique.

Only a single dermatologist performed all of the surgeries, which could introduce bias. There was no mention of blinding of the researcher that subsequently measured the wounds. Of the 31 patients randomized to the punch biopsy technique, there was 1 recurrence in the 16 months of follow-up compared with none in the wide excision arm. This study excluded patients with infected, inflamed, or recurrent cysts.

Recommendations from others

UpToDate does not recommend excision of an inflamed cyst, suggesting that the inflamed cyst wall is more friable and, therefore, more difficult to remove completely.⁷ This may lead to a higher rate of recurrence.

Lookingbill and Marks in Principles of Dermatology⁸ suggest that, frequently, no therapy is indicated for these lesions. If removal is desired or indicated, every effort should be made to remove the entire cyst lining in order to prevent recurrence of the cyst. They recommend removal of the cyst via the traditional wide excision technique. If the cyst ruptures accidentally during the procedure they suggest removing the remaining contents and wall with a curette.

Evidence summary

Numerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head trials of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mortality, in the treatment of hypertension.

No effect on lung function, but fatigue is a factor

A Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.^3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimetic activity for patients with lung disease.

That said, beta-blockers do have side effects. One meta-analysis found no difference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.⁵ They reported that the risk of fatigue was only 18 per 1000 patients (95% confidence interval [CI], 5–30) and the risk for sexual dysfunction was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs nonlipophilic and found no difference in side effect frequency.

Adverse outcomes data give reason to pause

Two recent meta-analyses^6,7 on beta-blockers have called into question the effectiveness of these agents in preventing adverse outcomes in treating hypertension.

The first meta-analysis⁶ reviewed 4 studies that compared atenolol with placebo or no treatment, and 5 that compared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, followed for a mean of 4.6 years. There was no difference in all-cause mortality (relative risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the atenolol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms.

The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were followed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents.

The second meta-analysis⁷ covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality.

An age divide appears with adverse events

A subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovascular morbidity and mortality.⁸ Researchers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05).

In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other antihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The primary outcome researchers evaluated was a composite of stroke, myocardial infarction, and death.

Calcium channel blockers beat beta-blockers in recent review

Finally, a more recent systematic review found beta blockers to be inferior to calcium channel blockers and renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardiovascular mortality.⁹ This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR=1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54).

Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers reduced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in total cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coronary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel blockers (RR=1.24, 1.11–1.40) and renin-angiotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovascular events was less than that of calcium-channel blockers (RR=1.18, 1.08–1.29).

Recommendations from others

The Joint National Committee on Hypertension (JNC-7) states that excellent clinical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.¹⁰

The European Society of Cardiology recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.¹¹

Evidence summary

Numerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head trials of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mortality, in the treatment of hypertension.

No effect on lung function, but fatigue is a factor

A Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.^3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimetic activity for patients with lung disease.

That said, beta-blockers do have side effects. One meta-analysis found no difference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.⁵ They reported that the risk of fatigue was only 18 per 1000 patients (95% confidence interval [CI], 5–30) and the risk for sexual dysfunction was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs nonlipophilic and found no difference in side effect frequency.

Adverse outcomes data give reason to pause

Two recent meta-analyses^6,7 on beta-blockers have called into question the effectiveness of these agents in preventing adverse outcomes in treating hypertension.

The first meta-analysis⁶ reviewed 4 studies that compared atenolol with placebo or no treatment, and 5 that compared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, followed for a mean of 4.6 years. There was no difference in all-cause mortality (relative risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the atenolol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms.

The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were followed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents.

The second meta-analysis⁷ covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality.

An age divide appears with adverse events

A subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovascular morbidity and mortality.⁸ Researchers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05).

In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other antihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The primary outcome researchers evaluated was a composite of stroke, myocardial infarction, and death.

Calcium channel blockers beat beta-blockers in recent review

Finally, a more recent systematic review found beta blockers to be inferior to calcium channel blockers and renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardiovascular mortality.⁹ This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR=1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54).

Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers reduced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in total cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coronary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel blockers (RR=1.24, 1.11–1.40) and renin-angiotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovascular events was less than that of calcium-channel blockers (RR=1.18, 1.08–1.29).

Recommendations from others

The Joint National Committee on Hypertension (JNC-7) states that excellent clinical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.¹⁰

The European Society of Cardiology recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.¹¹

Evidence summary

Numerous trials have shown that beta-blockers lower blood pressure for patients with hypertension. No head-to-head trials of beta-blockers have been conducted that reveal differences in terms of patient-oriented outcomes, such as all-cause mortality, in the treatment of hypertension.

No effect on lung function, but fatigue is a factor

A Cochrane review on the cardioselective beta-blockers atenolol (Tenormin), bisoprolol (Zebeta), and metoprolol (Lopressor) found that single-dose and multiple-treatment studies showed no decline in lung function among patients with mild to moderate reversible airway disease or chronic obstructive pulmonary disease.^3,4 The analysis was not able to identify any differential effect of these beta-blockers with or without intrinsic sympathomimetic activity for patients with lung disease.

That said, beta-blockers do have side effects. One meta-analysis found no difference in the development of depression with beta-blocker therapy; however, first-generation beta-blockers (propranolol and timolol) had higher rates of fatigue than did the later beta-blockers.⁵ They reported that the risk of fatigue was only 18 per 1000 patients (95% confidence interval [CI], 5–30) and the risk for sexual dysfunction was 5 per 1000 patients (95% CI, 2–8) for all beta-blockers as a class. Importantly, they also stratified side-effect findings on the basis of lipophilic vs nonlipophilic and found no difference in side effect frequency.

Adverse outcomes data give reason to pause

Two recent meta-analyses^6,7 on beta-blockers have called into question the effectiveness of these agents in preventing adverse outcomes in treating hypertension.

The first meta-analysis⁶ reviewed 4 studies that compared atenolol with placebo or no treatment, and 5 that compared atenolol with other antihypertensive drugs. They found no outcome differences between atenolol and placebo in the 4 studies, comprising 6825 patients, followed for a mean of 4.6 years. There was no difference in all-cause mortality (relative risk [RR]=1.01; 95% CI, 0.89–1.15), cardiovascular mortality (RR=0.99; 95% CI, 0.83–1.18), or myocardial infarction (RR=0.99; 95% CI, 0.83–1.19). The risk of stroke appeared to be lower in the atenolol than in the placebo group (RR=0.85; 95% CI, 0.72–1.01). When atenolol was compared with other antihypertensives, there were no major differences in blood pressure lowering between the treatment arms.

The authors found a significantly higher mortality (RR=1.13; 95% CI, 1.02–1.25) with atenolol treatment than with other active treatment, in 5 studies comprising 17,671 patients who were followed up for a mean of 4.6 years. Stroke was also more frequent with atenolol in comparison with other agents.

The second meta-analysis⁷ covered 13 randomized controlled trials (n=105,951) comparing treatment with beta-blockers with other antihypertensive drugs. Seven studies (n=27,433) were included in a comparison of beta-blockers and placebo or no treatment. The relative risk of stroke was 16% higher for beta-blockers (95% CI, 4%–30%) than for other drugs. No difference was seen for myocardial infarction. When the effect of beta-blockers was compared with that of placebo or no treatment, the relative risk of stroke was reduced by 19% for all beta-blockers (95% CI, 7%–29%). There was no difference for myocardial infarction or mortality.

An age divide appears with adverse events

A subsequent meta-analysis found that beta-blocker therapy in younger patients (less than 60 years of age) is associated with a significant reduction in cardiovascular morbidity and mortality.⁸ Researchers used data from 145,811 participants in 21 hypertension trials, beta-blockers reduced major cardiovascular outcomes in younger patients (risk ratio=0.86; 95% CI, 0.74–0.99) but not in older patients (risk ratio=0.89; 95% CI, 0.75–1.05).

In active comparator trials, beta-blockers demonstrated similar reductions in morbidity and mortality to other antihypertensive agents in younger patients (risk ratio=0.97; 95% CI, 0.88–1.07) but not in older patients (risk ratio=1.06; 95% CI, 1.01–1.10), with the excess risk being particularly marked for strokes (risk ratio=1.18; 95% CI, 1.07–1.30). The primary outcome researchers evaluated was a composite of stroke, myocardial infarction, and death.

Calcium channel blockers beat beta-blockers in recent review

Finally, a more recent systematic review found beta blockers to be inferior to calcium channel blockers and renin-angiotensin system inhibitors (ACE inhibitors or ARBs) for major endpoints of all-cause mortality, coronary heart disease, stroke, total cardiovascular events, and cardiovascular mortality.⁹ This review found beta-blockers had similar outcomes as diuretics but were less well tolerated than diuretics (RR=1.80; 95% CI, 1.33–2.42) or renin-angiotensin system inhibitors (RR=1.41; 1.29–1.54).

Thirteen trials with 91,561 participants, meeting inclusion criteria, compared beta-blockers with placebo (4 trials; n=23,613), diuretics (5 trials; n=18,241), calcium-channel blockers (4 trials; n=44,825), and renin-angiotensin system inhibitors (3 trials; n=10,828). Compared with placebo, beta-blockers reduced the risk of stroke (RR=0.80; 95% CI, 0.66–0.96) with a marginal fall in total cardiovascular events (RR=0.88; 95% CI, 0.79–0.97), but did not affect all-cause mortality (RR=0.99, 0.88–1.11), coronary heart disease (RR=0.93, 0.81–1.07), or cardiovascular mortality (RR=0.93, 0.80–1.09). The effect on stroke was less than that of calcium-channel blockers (RR=1.24, 1.11–1.40) and renin-angiotensin system inhibitors (RR=1.30, 1.11–1.53). The effect on total cardiovascular events was less than that of calcium-channel blockers (RR=1.18, 1.08–1.29).

Recommendations from others

The Joint National Committee on Hypertension (JNC-7) states that excellent clinical trial data demonstrate that lowering blood pressure with beta-blockers (and several other drug classes) will reduce the complications of hypertension.¹⁰

The European Society of Cardiology recommends beta-blockers as the first choice for antihypertensive therapy, alone or in combination, for patients with previous myocardial infarction, ischemic heart disease, arrhythmias or heart failure, asymptomatic left ventricular dysfunction, diabetes, or high risk of coronary disease, based on the efficacy of these drugs in these patient populations.¹¹

Evidence summary

Lupus anticoagulant and anticardiolipin antibodies are known to increase risk of both arterial and venous thromboembolic events.

One study prospectively followed patients ≥15 years old recruited from 16 hospitals in Sweden, who had their first or second episode of a VTE. Patients with malignancy or a known congenital deficiency of an inhibitor of coagulation were excluded. These patients were followed for 4 years. Each received at least 6 months of warfarin therapy (INR=2.0–2.85) after initial diagnosis of a VTE.

After treatment, the 4-year recurrence rate for VTEs was 29% for patients with aPL (20/68) vs 14% for patients without (47/344) (relative risk [RR]=2.1; 95% confidence interval [CI], 1.3–3.3). The risk of death for those patients with aPL was 15% (10/68) vs 6% for those without (20/324) (RR=1.8; 95% CI, 0.9–3.6).

In the same study, those with an aPL and a second clot were randomized to a second 6 months of therapy vs indefinite therapy (INR=2.0–2.85). After 4 years, their risk of another recurrence was 20% (3/15) with 6 months of therapy vs 5% (1/19) with indefinite therapy. This underpowered study did not show a statistical difference under intention-to-treat analysis; however, the single failure in the treatment group had stopped the warfarin prior to the event.⁴

Moderate intensity therapy does the job

Two recent randomized controlled trials have shown that moderate-intensity warfarin therapy (INR=2.0–3.0) is equally efficacious to high-intensity therapy (INR=3.0–4.0).^5,6 In these small studies, those with aPL were randomized to moderate-intensity vs high-intensity therapy and followed for approximately 3 years. A meta-analysis of these studies (done in conjunction with the second study) remained insufficiently powered to show any significant differences between high- and moderate-intensity therapy, but there was a trend towards increased thrombosis and bleeding events in the high-intensity groups.⁶ Of note, the relative risk for developing a VTE was lower in these studies than in those with time-limited treatment, suggesting that indefinite treatment may be indicated.

Warfarin probably isn’t best for primary prevention

Wahl et al⁷ constructed a decision analysis of antithrombotic therapy for patients with systemic lupus erythematosus with and without aPL. They compared observation alone with aspirin and with warfarin for the primary prevention of VTE. Using a decision analysis based on the best available efficacy rates, they recommended that the benefits of prophylactic aspirin outweigh the risks. However, due to high complication rates, warfarin’s benefits are outweighed by the risks. This analysis has not been validated in an actual patient population and remains theoretical in nature, but is the best available evidence regarding primary prevention of VTE for patients with aPL.

Recommendations from others

Guidelines from the American College of Chest Physicians recommend at least 12 months of treatment with warfarin and suggest indefinite treatment for patients with a VTE and antiphospholipid antibodies. The guidelines also suggest a target INR of 3.0 (range, 2.5–3.5) for patients with recurrent VTEs or additional risk factors, and a therapeutic INR of 2.5 (range, 2.0–3.0) for patients with a VTE and lupus anticoagulant but no additional risk factors.⁸

The Thrombosis Interest Group of Canada also recommends considering indefinite treatment for those with a VTE and a positive test for any of the antiphospholipid antibodies.⁹

Evidence summary

Lupus anticoagulant and anticardiolipin antibodies are known to increase risk of both arterial and venous thromboembolic events.

One study prospectively followed patients ≥15 years old recruited from 16 hospitals in Sweden, who had their first or second episode of a VTE. Patients with malignancy or a known congenital deficiency of an inhibitor of coagulation were excluded. These patients were followed for 4 years. Each received at least 6 months of warfarin therapy (INR=2.0–2.85) after initial diagnosis of a VTE.

After treatment, the 4-year recurrence rate for VTEs was 29% for patients with aPL (20/68) vs 14% for patients without (47/344) (relative risk [RR]=2.1; 95% confidence interval [CI], 1.3–3.3). The risk of death for those patients with aPL was 15% (10/68) vs 6% for those without (20/324) (RR=1.8; 95% CI, 0.9–3.6).

In the same study, those with an aPL and a second clot were randomized to a second 6 months of therapy vs indefinite therapy (INR=2.0–2.85). After 4 years, their risk of another recurrence was 20% (3/15) with 6 months of therapy vs 5% (1/19) with indefinite therapy. This underpowered study did not show a statistical difference under intention-to-treat analysis; however, the single failure in the treatment group had stopped the warfarin prior to the event.⁴

Moderate intensity therapy does the job

Two recent randomized controlled trials have shown that moderate-intensity warfarin therapy (INR=2.0–3.0) is equally efficacious to high-intensity therapy (INR=3.0–4.0).^5,6 In these small studies, those with aPL were randomized to moderate-intensity vs high-intensity therapy and followed for approximately 3 years. A meta-analysis of these studies (done in conjunction with the second study) remained insufficiently powered to show any significant differences between high- and moderate-intensity therapy, but there was a trend towards increased thrombosis and bleeding events in the high-intensity groups.⁶ Of note, the relative risk for developing a VTE was lower in these studies than in those with time-limited treatment, suggesting that indefinite treatment may be indicated.

Warfarin probably isn’t best for primary prevention

Wahl et al⁷ constructed a decision analysis of antithrombotic therapy for patients with systemic lupus erythematosus with and without aPL. They compared observation alone with aspirin and with warfarin for the primary prevention of VTE. Using a decision analysis based on the best available efficacy rates, they recommended that the benefits of prophylactic aspirin outweigh the risks. However, due to high complication rates, warfarin’s benefits are outweighed by the risks. This analysis has not been validated in an actual patient population and remains theoretical in nature, but is the best available evidence regarding primary prevention of VTE for patients with aPL.

Recommendations from others

Guidelines from the American College of Chest Physicians recommend at least 12 months of treatment with warfarin and suggest indefinite treatment for patients with a VTE and antiphospholipid antibodies. The guidelines also suggest a target INR of 3.0 (range, 2.5–3.5) for patients with recurrent VTEs or additional risk factors, and a therapeutic INR of 2.5 (range, 2.0–3.0) for patients with a VTE and lupus anticoagulant but no additional risk factors.⁸

The Thrombosis Interest Group of Canada also recommends considering indefinite treatment for those with a VTE and a positive test for any of the antiphospholipid antibodies.⁹

Evidence summary

Lupus anticoagulant and anticardiolipin antibodies are known to increase risk of both arterial and venous thromboembolic events.

One study prospectively followed patients ≥15 years old recruited from 16 hospitals in Sweden, who had their first or second episode of a VTE. Patients with malignancy or a known congenital deficiency of an inhibitor of coagulation were excluded. These patients were followed for 4 years. Each received at least 6 months of warfarin therapy (INR=2.0–2.85) after initial diagnosis of a VTE.

After treatment, the 4-year recurrence rate for VTEs was 29% for patients with aPL (20/68) vs 14% for patients without (47/344) (relative risk [RR]=2.1; 95% confidence interval [CI], 1.3–3.3). The risk of death for those patients with aPL was 15% (10/68) vs 6% for those without (20/324) (RR=1.8; 95% CI, 0.9–3.6).

In the same study, those with an aPL and a second clot were randomized to a second 6 months of therapy vs indefinite therapy (INR=2.0–2.85). After 4 years, their risk of another recurrence was 20% (3/15) with 6 months of therapy vs 5% (1/19) with indefinite therapy. This underpowered study did not show a statistical difference under intention-to-treat analysis; however, the single failure in the treatment group had stopped the warfarin prior to the event.⁴

Moderate intensity therapy does the job

Two recent randomized controlled trials have shown that moderate-intensity warfarin therapy (INR=2.0–3.0) is equally efficacious to high-intensity therapy (INR=3.0–4.0).^5,6 In these small studies, those with aPL were randomized to moderate-intensity vs high-intensity therapy and followed for approximately 3 years. A meta-analysis of these studies (done in conjunction with the second study) remained insufficiently powered to show any significant differences between high- and moderate-intensity therapy, but there was a trend towards increased thrombosis and bleeding events in the high-intensity groups.⁶ Of note, the relative risk for developing a VTE was lower in these studies than in those with time-limited treatment, suggesting that indefinite treatment may be indicated.

Warfarin probably isn’t best for primary prevention

Wahl et al⁷ constructed a decision analysis of antithrombotic therapy for patients with systemic lupus erythematosus with and without aPL. They compared observation alone with aspirin and with warfarin for the primary prevention of VTE. Using a decision analysis based on the best available efficacy rates, they recommended that the benefits of prophylactic aspirin outweigh the risks. However, due to high complication rates, warfarin’s benefits are outweighed by the risks. This analysis has not been validated in an actual patient population and remains theoretical in nature, but is the best available evidence regarding primary prevention of VTE for patients with aPL.

Recommendations from others

Guidelines from the American College of Chest Physicians recommend at least 12 months of treatment with warfarin and suggest indefinite treatment for patients with a VTE and antiphospholipid antibodies. The guidelines also suggest a target INR of 3.0 (range, 2.5–3.5) for patients with recurrent VTEs or additional risk factors, and a therapeutic INR of 2.5 (range, 2.0–3.0) for patients with a VTE and lupus anticoagulant but no additional risk factors.⁸

The Thrombosis Interest Group of Canada also recommends considering indefinite treatment for those with a VTE and a positive test for any of the antiphospholipid antibodies.⁹

Evidence summary

Sexual dysfunction includes desire, arousal, orgasmic, and sex pain disorders. In the US, 43% of women and 31% of men experience sexual dysfunction. Since sexual dysfunction increases with age, the prevalence will likely increase with the aging American population.²

Testosterone helps men, but long-term risks are unclear

Several cross-sectional and longitudinal studies^3,4 demonstrate that serum total and free testosterone concentrations in men decline with age. Although the decline is gradual, by the eighth decade 30% of men have total testosterone values in the hypogonadal range and 50% have low free testosterone values.⁴

In randomized, placebo-controlled trials^5,6 of older men with low testosterone concentrations, testosterone administration was associated with a sustained increase in testosterone levels over 1 to 3 years. Regardless of the route of administration (gel, transdermal patch, or intramuscular injection), testosterone replacement results in improved libido and sexual function for men with low testosterone levels.^6-8 The caveat, though, is that testosterone trials of older men are characterized by very small sample sizes (n=10–50), disparate outcome measures, and the inclusion of men who were not uniformly testosterone-deficient and were asymptomatic.

In addition, these studies did not have sufficient power to detect either meaningful gains in patient-important outcomes or changes in prostate or cardiovascular event rates.^5,6,8,9 Thus, the long-term benefit/risk ratio of testosterone replacement therapy for aging hypogonadal men is unknown.

Less evidence for women

Up to 50% of postmenopausal women experience sexual dysfunction,¹⁰ and a low testosterone level is correlated with a decreased coital frequency.¹¹ Some studies suggest that testosterone at supraphysiological doses—by injections, implants, or pill (in combination with estrogen)—improves libido and sexual function.^12-14

The downside is that these studies are very small and have several methodological shortcomings. The pharmacokinetics of testosterone formulations for women are unclear, and the assays for the measurement of total and free testosterone concentrations in women lack accuracy and sensitivity. Long-term safety studies on breast cancer and cardiovascular events are lacking.

Testosterone’s major adverse effects include virilization (oily skin, acne, hirsutism, alopecia, deep voice), liver toxicity, polycythemia, breast carcinoma, and unfavorable changes in cardiovascular risk markers such as reduction in high-density lipoprotein cholesterol or insulin sensitivity.^5-8,12-15

Recommendations from others

American Association of Clinical Endocrinologists guidelines for menopause¹⁶ recommends against the general use of testosterone therapy at menopause, except for women with continuing symptoms during adequate estrogen therapy.

The Endocrine Society¹⁷ recommends that clinicians consider offering testosterone therapy on an individualized basis to older men with low testosterone levels and significant symptoms of testosterone androgen deficiency. Before administration, it’s important to discuss the uncertainties, risks, and benefits of testosterone therapy in older men.

The Endocrine Society also recommends against starting testosterone therapy for patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen >3 ng/mL without further urological evaluation, erythrocytosis (hematocrit >50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with an International Prostate Symptom Score (IPSS) >19, or class III or IV heart failure. When testosterone therapy is instituted, the goal should be to achieve testosterone levels in the midnormal range. This guideline recommends evaluating the patient 3 months after treatment initiation and then annually to assess whether he or she has responded to treatment and whether the patient is suffering any adverse effects.¹⁷

The Institute of Medicine examined the effectiveness and safety of testosterone therapy for older men. The report¹⁸ states that its use is appropriate only for those conditions approved by the FDA (primary and secondary hypogonadism among men), and that it is inappropriate to use testosterone replacement therapy to prevent possible future disease for otherwise healthy older men. The committee found no compelling evidence of major adverse effects resulting from testosterone therapy.¹⁸

Evidence summary

Sexual dysfunction includes desire, arousal, orgasmic, and sex pain disorders. In the US, 43% of women and 31% of men experience sexual dysfunction. Since sexual dysfunction increases with age, the prevalence will likely increase with the aging American population.²

Testosterone helps men, but long-term risks are unclear

Several cross-sectional and longitudinal studies^3,4 demonstrate that serum total and free testosterone concentrations in men decline with age. Although the decline is gradual, by the eighth decade 30% of men have total testosterone values in the hypogonadal range and 50% have low free testosterone values.⁴

In randomized, placebo-controlled trials^5,6 of older men with low testosterone concentrations, testosterone administration was associated with a sustained increase in testosterone levels over 1 to 3 years. Regardless of the route of administration (gel, transdermal patch, or intramuscular injection), testosterone replacement results in improved libido and sexual function for men with low testosterone levels.^6-8 The caveat, though, is that testosterone trials of older men are characterized by very small sample sizes (n=10–50), disparate outcome measures, and the inclusion of men who were not uniformly testosterone-deficient and were asymptomatic.

In addition, these studies did not have sufficient power to detect either meaningful gains in patient-important outcomes or changes in prostate or cardiovascular event rates.^5,6,8,9 Thus, the long-term benefit/risk ratio of testosterone replacement therapy for aging hypogonadal men is unknown.

Less evidence for women

Up to 50% of postmenopausal women experience sexual dysfunction,¹⁰ and a low testosterone level is correlated with a decreased coital frequency.¹¹ Some studies suggest that testosterone at supraphysiological doses—by injections, implants, or pill (in combination with estrogen)—improves libido and sexual function.^12-14

The downside is that these studies are very small and have several methodological shortcomings. The pharmacokinetics of testosterone formulations for women are unclear, and the assays for the measurement of total and free testosterone concentrations in women lack accuracy and sensitivity. Long-term safety studies on breast cancer and cardiovascular events are lacking.

Testosterone’s major adverse effects include virilization (oily skin, acne, hirsutism, alopecia, deep voice), liver toxicity, polycythemia, breast carcinoma, and unfavorable changes in cardiovascular risk markers such as reduction in high-density lipoprotein cholesterol or insulin sensitivity.^5-8,12-15

Recommendations from others

American Association of Clinical Endocrinologists guidelines for menopause¹⁶ recommends against the general use of testosterone therapy at menopause, except for women with continuing symptoms during adequate estrogen therapy.

The Endocrine Society¹⁷ recommends that clinicians consider offering testosterone therapy on an individualized basis to older men with low testosterone levels and significant symptoms of testosterone androgen deficiency. Before administration, it’s important to discuss the uncertainties, risks, and benefits of testosterone therapy in older men.

The Endocrine Society also recommends against starting testosterone therapy for patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen >3 ng/mL without further urological evaluation, erythrocytosis (hematocrit >50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with an International Prostate Symptom Score (IPSS) >19, or class III or IV heart failure. When testosterone therapy is instituted, the goal should be to achieve testosterone levels in the midnormal range. This guideline recommends evaluating the patient 3 months after treatment initiation and then annually to assess whether he or she has responded to treatment and whether the patient is suffering any adverse effects.¹⁷

The Institute of Medicine examined the effectiveness and safety of testosterone therapy for older men. The report¹⁸ states that its use is appropriate only for those conditions approved by the FDA (primary and secondary hypogonadism among men), and that it is inappropriate to use testosterone replacement therapy to prevent possible future disease for otherwise healthy older men. The committee found no compelling evidence of major adverse effects resulting from testosterone therapy.¹⁸

Evidence summary

Sexual dysfunction includes desire, arousal, orgasmic, and sex pain disorders. In the US, 43% of women and 31% of men experience sexual dysfunction. Since sexual dysfunction increases with age, the prevalence will likely increase with the aging American population.²

Testosterone helps men, but long-term risks are unclear

Several cross-sectional and longitudinal studies^3,4 demonstrate that serum total and free testosterone concentrations in men decline with age. Although the decline is gradual, by the eighth decade 30% of men have total testosterone values in the hypogonadal range and 50% have low free testosterone values.⁴

In randomized, placebo-controlled trials^5,6 of older men with low testosterone concentrations, testosterone administration was associated with a sustained increase in testosterone levels over 1 to 3 years. Regardless of the route of administration (gel, transdermal patch, or intramuscular injection), testosterone replacement results in improved libido and sexual function for men with low testosterone levels.^6-8 The caveat, though, is that testosterone trials of older men are characterized by very small sample sizes (n=10–50), disparate outcome measures, and the inclusion of men who were not uniformly testosterone-deficient and were asymptomatic.

In addition, these studies did not have sufficient power to detect either meaningful gains in patient-important outcomes or changes in prostate or cardiovascular event rates.^5,6,8,9 Thus, the long-term benefit/risk ratio of testosterone replacement therapy for aging hypogonadal men is unknown.

Less evidence for women

Up to 50% of postmenopausal women experience sexual dysfunction,¹⁰ and a low testosterone level is correlated with a decreased coital frequency.¹¹ Some studies suggest that testosterone at supraphysiological doses—by injections, implants, or pill (in combination with estrogen)—improves libido and sexual function.^12-14

The downside is that these studies are very small and have several methodological shortcomings. The pharmacokinetics of testosterone formulations for women are unclear, and the assays for the measurement of total and free testosterone concentrations in women lack accuracy and sensitivity. Long-term safety studies on breast cancer and cardiovascular events are lacking.

Testosterone’s major adverse effects include virilization (oily skin, acne, hirsutism, alopecia, deep voice), liver toxicity, polycythemia, breast carcinoma, and unfavorable changes in cardiovascular risk markers such as reduction in high-density lipoprotein cholesterol or insulin sensitivity.^5-8,12-15

Recommendations from others

American Association of Clinical Endocrinologists guidelines for menopause¹⁶ recommends against the general use of testosterone therapy at menopause, except for women with continuing symptoms during adequate estrogen therapy.

The Endocrine Society¹⁷ recommends that clinicians consider offering testosterone therapy on an individualized basis to older men with low testosterone levels and significant symptoms of testosterone androgen deficiency. Before administration, it’s important to discuss the uncertainties, risks, and benefits of testosterone therapy in older men.

The Endocrine Society also recommends against starting testosterone therapy for patients with breast or prostate cancer, a palpable prostate nodule or induration or prostate-specific antigen >3 ng/mL without further urological evaluation, erythrocytosis (hematocrit >50%), hyperviscosity, untreated obstructive sleep apnea, severe lower urinary tract symptoms with an International Prostate Symptom Score (IPSS) >19, or class III or IV heart failure. When testosterone therapy is instituted, the goal should be to achieve testosterone levels in the midnormal range. This guideline recommends evaluating the patient 3 months after treatment initiation and then annually to assess whether he or she has responded to treatment and whether the patient is suffering any adverse effects.¹⁷

The Institute of Medicine examined the effectiveness and safety of testosterone therapy for older men. The report¹⁸ states that its use is appropriate only for those conditions approved by the FDA (primary and secondary hypogonadism among men), and that it is inappropriate to use testosterone replacement therapy to prevent possible future disease for otherwise healthy older men. The committee found no compelling evidence of major adverse effects resulting from testosterone therapy.¹⁸

Evidence summary

Only 5% to 10% of adults and 20% to 25% of children presenting in an office setting with acute pharyngitis actually have GABHS pharyngitis.¹ The prevalence of GABHS pharyngitis is higher for patients presenting to urgent care centers or emergency rooms than office practices.

Clinical prediction rules can help

Useful and well-validated clinical prediction rules (such as the Centor score) can help you make more informed decisions about testing. According to 1 meta-analysis, a history of exposure to strep in the previous 2 weeks had a sensitivity of 19%, with a specificity ranging from 87% to 94%.¹ This results in a likelihood ratio (LR) of 1.9 if the patient has an exposure (eg, the patient’s odds of having strep are 1.9 times higher than baseline), and a patient without an exposure has an LR of 0.94. (Typically, LRs of 0.5 to 2.0 are not helpful for diagnostic testing.) In a population at a 10% risk of GABHS as the cause of pharyngitis, the positive predictive value of streptococcal exposure was 17%, and the negative predictive value of no known exposure was 91%.

Of the primary clinical prediction rules for pharyngitis, only the Walsh Diagnostic Algorithm explicitly includes a history of streptococcal exposure. In that algorithm, only patients with tender or enlarged cervical lymph nodes who either had exudative pharyngitis or a recent exposure were in the highest risk category (23% prevalence of GABHS).¹

Since no clinical prediction rules have been validated for telephone management of pharyngitis, the diagnosis of GABHS pharyngitis by telephone is inherently less accurate than clinical (nonlaboratory) diagnosis in the office setting, since the pharynx and cervical lymph nodes cannot be physically examined. Moreover, while patients may report their sore throat symptoms reliably, they have a tendency to over-report physical signs.²

Diagnosis won’t be accurate without a physical exam

All of the clinical prediction rules were derived from an in-person encounter, and relied partially on the physician’s findings. It is unlikely the accuracy of the clinical prediction rules would be maintained in the absence of a physician’s exam. The lack of clinical confirmation of physical signs potentially reduces the precision of the clinical prediction rules to the point that they become nearly useless.

For example, an adult patient (with a 10% baseline risk of GABHS) who presents with a fever but no cough could have a pretest probability for GABHS pharyngitis ranging from 8% to 41%, depending on the presence of exudates and adenopathy.

The number needed to treat (NNT) for antibiotics given to GABHS-positive patients is 3.5 for resolution of symptoms by day 3; for GABHS-negative patients it is 5.5, and for patients who did not have a culture, it is 14.5. When properly prescribed, antibiotics decrease communicability of GABHS to 24 hours, and symptoms by 1 day (NNT=5 patients to decrease symptoms).

Antibiotics also decrease the incidence of rheumatic heart disease (NNT=100) and peritonsillar abscesses. Due to the decreased incidence of glomerulonephritis, the evidence is inadequate to determine the role of antibiotics in preventing this complication.³

Recommendations from others

Although guidelines do not specifically address the treatment of symptomatic family members over the phone, the Infectious Disease Society of America states that the diagnosis of GABHS pharyngitis be confirmed by appropriate laboratory testing after clinical and epidemiological suspicion.⁴ The American College of Physicians state that a positive confirmatory laboratory test or Centor score of 4 could reasonably warrant treatment.³

Evidence summary

Only 5% to 10% of adults and 20% to 25% of children presenting in an office setting with acute pharyngitis actually have GABHS pharyngitis.¹ The prevalence of GABHS pharyngitis is higher for patients presenting to urgent care centers or emergency rooms than office practices.

Clinical prediction rules can help

Useful and well-validated clinical prediction rules (such as the Centor score) can help you make more informed decisions about testing. According to 1 meta-analysis, a history of exposure to strep in the previous 2 weeks had a sensitivity of 19%, with a specificity ranging from 87% to 94%.¹ This results in a likelihood ratio (LR) of 1.9 if the patient has an exposure (eg, the patient’s odds of having strep are 1.9 times higher than baseline), and a patient without an exposure has an LR of 0.94. (Typically, LRs of 0.5 to 2.0 are not helpful for diagnostic testing.) In a population at a 10% risk of GABHS as the cause of pharyngitis, the positive predictive value of streptococcal exposure was 17%, and the negative predictive value of no known exposure was 91%.

Of the primary clinical prediction rules for pharyngitis, only the Walsh Diagnostic Algorithm explicitly includes a history of streptococcal exposure. In that algorithm, only patients with tender or enlarged cervical lymph nodes who either had exudative pharyngitis or a recent exposure were in the highest risk category (23% prevalence of GABHS).¹

Since no clinical prediction rules have been validated for telephone management of pharyngitis, the diagnosis of GABHS pharyngitis by telephone is inherently less accurate than clinical (nonlaboratory) diagnosis in the office setting, since the pharynx and cervical lymph nodes cannot be physically examined. Moreover, while patients may report their sore throat symptoms reliably, they have a tendency to over-report physical signs.²

Diagnosis won’t be accurate without a physical exam

All of the clinical prediction rules were derived from an in-person encounter, and relied partially on the physician’s findings. It is unlikely the accuracy of the clinical prediction rules would be maintained in the absence of a physician’s exam. The lack of clinical confirmation of physical signs potentially reduces the precision of the clinical prediction rules to the point that they become nearly useless.

For example, an adult patient (with a 10% baseline risk of GABHS) who presents with a fever but no cough could have a pretest probability for GABHS pharyngitis ranging from 8% to 41%, depending on the presence of exudates and adenopathy.

The number needed to treat (NNT) for antibiotics given to GABHS-positive patients is 3.5 for resolution of symptoms by day 3; for GABHS-negative patients it is 5.5, and for patients who did not have a culture, it is 14.5. When properly prescribed, antibiotics decrease communicability of GABHS to 24 hours, and symptoms by 1 day (NNT=5 patients to decrease symptoms).

Antibiotics also decrease the incidence of rheumatic heart disease (NNT=100) and peritonsillar abscesses. Due to the decreased incidence of glomerulonephritis, the evidence is inadequate to determine the role of antibiotics in preventing this complication.³

Recommendations from others

Although guidelines do not specifically address the treatment of symptomatic family members over the phone, the Infectious Disease Society of America states that the diagnosis of GABHS pharyngitis be confirmed by appropriate laboratory testing after clinical and epidemiological suspicion.⁴ The American College of Physicians state that a positive confirmatory laboratory test or Centor score of 4 could reasonably warrant treatment.³

Evidence summary

Only 5% to 10% of adults and 20% to 25% of children presenting in an office setting with acute pharyngitis actually have GABHS pharyngitis.¹ The prevalence of GABHS pharyngitis is higher for patients presenting to urgent care centers or emergency rooms than office practices.

Clinical prediction rules can help

Useful and well-validated clinical prediction rules (such as the Centor score) can help you make more informed decisions about testing. According to 1 meta-analysis, a history of exposure to strep in the previous 2 weeks had a sensitivity of 19%, with a specificity ranging from 87% to 94%.¹ This results in a likelihood ratio (LR) of 1.9 if the patient has an exposure (eg, the patient’s odds of having strep are 1.9 times higher than baseline), and a patient without an exposure has an LR of 0.94. (Typically, LRs of 0.5 to 2.0 are not helpful for diagnostic testing.) In a population at a 10% risk of GABHS as the cause of pharyngitis, the positive predictive value of streptococcal exposure was 17%, and the negative predictive value of no known exposure was 91%.

Of the primary clinical prediction rules for pharyngitis, only the Walsh Diagnostic Algorithm explicitly includes a history of streptococcal exposure. In that algorithm, only patients with tender or enlarged cervical lymph nodes who either had exudative pharyngitis or a recent exposure were in the highest risk category (23% prevalence of GABHS).¹

Since no clinical prediction rules have been validated for telephone management of pharyngitis, the diagnosis of GABHS pharyngitis by telephone is inherently less accurate than clinical (nonlaboratory) diagnosis in the office setting, since the pharynx and cervical lymph nodes cannot be physically examined. Moreover, while patients may report their sore throat symptoms reliably, they have a tendency to over-report physical signs.²

Diagnosis won’t be accurate without a physical exam

All of the clinical prediction rules were derived from an in-person encounter, and relied partially on the physician’s findings. It is unlikely the accuracy of the clinical prediction rules would be maintained in the absence of a physician’s exam. The lack of clinical confirmation of physical signs potentially reduces the precision of the clinical prediction rules to the point that they become nearly useless.

For example, an adult patient (with a 10% baseline risk of GABHS) who presents with a fever but no cough could have a pretest probability for GABHS pharyngitis ranging from 8% to 41%, depending on the presence of exudates and adenopathy.

The number needed to treat (NNT) for antibiotics given to GABHS-positive patients is 3.5 for resolution of symptoms by day 3; for GABHS-negative patients it is 5.5, and for patients who did not have a culture, it is 14.5. When properly prescribed, antibiotics decrease communicability of GABHS to 24 hours, and symptoms by 1 day (NNT=5 patients to decrease symptoms).

Antibiotics also decrease the incidence of rheumatic heart disease (NNT=100) and peritonsillar abscesses. Due to the decreased incidence of glomerulonephritis, the evidence is inadequate to determine the role of antibiotics in preventing this complication.³

Recommendations from others

Although guidelines do not specifically address the treatment of symptomatic family members over the phone, the Infectious Disease Society of America states that the diagnosis of GABHS pharyngitis be confirmed by appropriate laboratory testing after clinical and epidemiological suspicion.⁴ The American College of Physicians state that a positive confirmatory laboratory test or Centor score of 4 could reasonably warrant treatment.³

Evidence summary

Cradle cap is a form of seborrheic dermatitis that manifests as greasy patches of scaling on the scalp of infants between the second week and sixth month of life.^1,2 Untreated, it usually resolves at 8 months.¹ It’s generally nonpruritic and doesn’t bother the infant, though it can be a stressor for parents.¹

Researchers have noted a potential link with increased concentrations of the yeast Malassezia furfur (formerly Pityrosporum ovale), but a causative mechanism has not been identified.^1,2 Overnight use of emollients such as mineral oil to soften scales followed by gentle brushing and washing with baby shampoo is an accepted treatment, although no trials could be found to show its efficacy for infants.^1,3

Numerous treatments for seborrheic dermatitis with proven efficacy for adults have been adopted for use for infants. These include topical antifungals, anti-dandruff shampoos with zinc pyrithione or selenium sulfide, coal tar preparations, and episodic topical corticosteroids.^1,4 Although each of these agents is used for infants with cradle cap, significantly sized randomized controlled trials in this age group are essentially absent.

Although limited evidence exists for seborrhea treatment in any age group, ketoconazole shampoo appears to be backed by the strongest evidence. For example, an uncontrolled multicenter trial with 575 adults found ketoconazole shampoo was superior to placebo for treatment of scalp seborrheic dermatitis with an 88% “excellent response” rate (P<.0001, no relative risk or confidence intervals given).⁴

Based on small studies, ketoconazole appears safe and effective for infants. A small (n=13) phase I safety trial of infants demonstrated that ketoconazole shampoo applied twice weekly for 1 month resulted in no detectable serum ketoconazole levels or elevation in liver function tests.⁵ In another small (n=19) uncontrolled study of once-daily ketoconazole 2% cream, 79% of infants affected with seborrheic dermatitis of the scalp and diaper area showed good response by day 10 (no statistical methods reported). Peak plasma ketoconazole levels in this study were only 1% to 2% of those documented after systemic administration.⁶

Studies conducted on topical steroids have also shown weak data. An unblinded uncontrolled comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis revealed no statistical difference (31% vs 35%) in severity for 48 infants. All skin lesions in both treatment groups were cleared by the end of the second week of treatment.²

Multiple authors note safety concerns when considering treatment for mild and self-limited conditions such as cradle cap. Several studies have demonstrated systemic absorption and, in some cases, adrenocortical suppression when using mild topical steroids such as 1% hydrocortisone cream in pediatric populations.^1,3,7

Recommendations from others

The guidance from PRODIGY (the UK’s National Health Service primary care database) recommends regular washing with baby shampoo followed by gentle brushing. Alternatively, softening the scale with mineral oil, followed by gentle brushing and shampooing is an alternative approach. Ketoconazole 2% shampoo or cream once a day has been shown to be effective; PRODIGY recommends avoiding topical corticosteroids.¹

A review article recommends daily shampooing with an unmedicated shampoo. If this doesn’t work, the authors recommend trying a dandruff shampoo and softening the scales with mineral oil before washing.⁸ While the American Academy of Dermatology has no official guidelines on this subject, their patient-oriented pamphlet Dermatology Insights suggests that “cradle cap is treated with anti-dandruff or baby shampoo, with or without hydrocortisone lotion or cream, depending on the severity.”⁹

Acknowledgments

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Cradle cap is a form of seborrheic dermatitis that manifests as greasy patches of scaling on the scalp of infants between the second week and sixth month of life.^1,2 Untreated, it usually resolves at 8 months.¹ It’s generally nonpruritic and doesn’t bother the infant, though it can be a stressor for parents.¹

Researchers have noted a potential link with increased concentrations of the yeast Malassezia furfur (formerly Pityrosporum ovale), but a causative mechanism has not been identified.^1,2 Overnight use of emollients such as mineral oil to soften scales followed by gentle brushing and washing with baby shampoo is an accepted treatment, although no trials could be found to show its efficacy for infants.^1,3

Numerous treatments for seborrheic dermatitis with proven efficacy for adults have been adopted for use for infants. These include topical antifungals, anti-dandruff shampoos with zinc pyrithione or selenium sulfide, coal tar preparations, and episodic topical corticosteroids.^1,4 Although each of these agents is used for infants with cradle cap, significantly sized randomized controlled trials in this age group are essentially absent.

Although limited evidence exists for seborrhea treatment in any age group, ketoconazole shampoo appears to be backed by the strongest evidence. For example, an uncontrolled multicenter trial with 575 adults found ketoconazole shampoo was superior to placebo for treatment of scalp seborrheic dermatitis with an 88% “excellent response” rate (P<.0001, no relative risk or confidence intervals given).⁴

Based on small studies, ketoconazole appears safe and effective for infants. A small (n=13) phase I safety trial of infants demonstrated that ketoconazole shampoo applied twice weekly for 1 month resulted in no detectable serum ketoconazole levels or elevation in liver function tests.⁵ In another small (n=19) uncontrolled study of once-daily ketoconazole 2% cream, 79% of infants affected with seborrheic dermatitis of the scalp and diaper area showed good response by day 10 (no statistical methods reported). Peak plasma ketoconazole levels in this study were only 1% to 2% of those documented after systemic administration.⁶

Studies conducted on topical steroids have also shown weak data. An unblinded uncontrolled comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis revealed no statistical difference (31% vs 35%) in severity for 48 infants. All skin lesions in both treatment groups were cleared by the end of the second week of treatment.²

Multiple authors note safety concerns when considering treatment for mild and self-limited conditions such as cradle cap. Several studies have demonstrated systemic absorption and, in some cases, adrenocortical suppression when using mild topical steroids such as 1% hydrocortisone cream in pediatric populations.^1,3,7

Recommendations from others

The guidance from PRODIGY (the UK’s National Health Service primary care database) recommends regular washing with baby shampoo followed by gentle brushing. Alternatively, softening the scale with mineral oil, followed by gentle brushing and shampooing is an alternative approach. Ketoconazole 2% shampoo or cream once a day has been shown to be effective; PRODIGY recommends avoiding topical corticosteroids.¹

A review article recommends daily shampooing with an unmedicated shampoo. If this doesn’t work, the authors recommend trying a dandruff shampoo and softening the scales with mineral oil before washing.⁸ While the American Academy of Dermatology has no official guidelines on this subject, their patient-oriented pamphlet Dermatology Insights suggests that “cradle cap is treated with anti-dandruff or baby shampoo, with or without hydrocortisone lotion or cream, depending on the severity.”⁹

Acknowledgments

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Cradle cap is a form of seborrheic dermatitis that manifests as greasy patches of scaling on the scalp of infants between the second week and sixth month of life.^1,2 Untreated, it usually resolves at 8 months.¹ It’s generally nonpruritic and doesn’t bother the infant, though it can be a stressor for parents.¹

Researchers have noted a potential link with increased concentrations of the yeast Malassezia furfur (formerly Pityrosporum ovale), but a causative mechanism has not been identified.^1,2 Overnight use of emollients such as mineral oil to soften scales followed by gentle brushing and washing with baby shampoo is an accepted treatment, although no trials could be found to show its efficacy for infants.^1,3

Numerous treatments for seborrheic dermatitis with proven efficacy for adults have been adopted for use for infants. These include topical antifungals, anti-dandruff shampoos with zinc pyrithione or selenium sulfide, coal tar preparations, and episodic topical corticosteroids.^1,4 Although each of these agents is used for infants with cradle cap, significantly sized randomized controlled trials in this age group are essentially absent.

Although limited evidence exists for seborrhea treatment in any age group, ketoconazole shampoo appears to be backed by the strongest evidence. For example, an uncontrolled multicenter trial with 575 adults found ketoconazole shampoo was superior to placebo for treatment of scalp seborrheic dermatitis with an 88% “excellent response” rate (P<.0001, no relative risk or confidence intervals given).⁴

Based on small studies, ketoconazole appears safe and effective for infants. A small (n=13) phase I safety trial of infants demonstrated that ketoconazole shampoo applied twice weekly for 1 month resulted in no detectable serum ketoconazole levels or elevation in liver function tests.⁵ In another small (n=19) uncontrolled study of once-daily ketoconazole 2% cream, 79% of infants affected with seborrheic dermatitis of the scalp and diaper area showed good response by day 10 (no statistical methods reported). Peak plasma ketoconazole levels in this study were only 1% to 2% of those documented after systemic administration.⁶

Studies conducted on topical steroids have also shown weak data. An unblinded uncontrolled comparative study of 2% ketoconazole cream and 1% hydrocortisone cream in the treatment of infantile seborrheic dermatitis revealed no statistical difference (31% vs 35%) in severity for 48 infants. All skin lesions in both treatment groups were cleared by the end of the second week of treatment.²

Multiple authors note safety concerns when considering treatment for mild and self-limited conditions such as cradle cap. Several studies have demonstrated systemic absorption and, in some cases, adrenocortical suppression when using mild topical steroids such as 1% hydrocortisone cream in pediatric populations.^1,3,7

Recommendations from others

The guidance from PRODIGY (the UK’s National Health Service primary care database) recommends regular washing with baby shampoo followed by gentle brushing. Alternatively, softening the scale with mineral oil, followed by gentle brushing and shampooing is an alternative approach. Ketoconazole 2% shampoo or cream once a day has been shown to be effective; PRODIGY recommends avoiding topical corticosteroids.¹

A review article recommends daily shampooing with an unmedicated shampoo. If this doesn’t work, the authors recommend trying a dandruff shampoo and softening the scales with mineral oil before washing.⁸ While the American Academy of Dermatology has no official guidelines on this subject, their patient-oriented pamphlet Dermatology Insights suggests that “cradle cap is treated with anti-dandruff or baby shampoo, with or without hydrocortisone lotion or cream, depending on the severity.”⁹

Acknowledgments

The opinions and assertions contained herein are the private views of the authors and not to be construed as official, or as reflecting the views of the US Air Force Medical Service or the US Air Force at large.

Evidence summary

Self-care can be defined as activities that a patient undertakes with the intention of improving health or preventing disease. Self-care for hypertension includes taking medicine as prescribed, monitoring blood pressure response to therapy, and adopting lifestyle recommendations—increasing exercise, decreasing salt intake, and increasing fruits and vegetable consumption.

Keeping meds simple improves adherence

Various interventions have been developed with the goal of improving medication adherence among patients with hypertension. A Cochrane review included 38 randomized controlled trials (RCTs) of 58 various types of interventions (some tested in factorial trials) designed to improve patient adherence to antihypertensive medications in ambulatory settings.¹ The quality of the studies was generally low due to inadequate allocation concealment, lack of blinding of outcome assessors, loss to follow-up, and the small number of participants in trials.

The authors grouped interventions into 4 broad categories: simplification of dosing regimens; patient education; patient motivation, support, and reminders; and complex interventions. Comparison groups received either no intervention, usual care, or—in the case of simplification of dosing regimens—a daily regimen consisting of more than 1 pill per day vs a once-daily regimen. Because of various types of interventions and different methods of assessing outcomes, pooling of results was, appropriately, not done.

Of all the interventions, simplification of dosing regimens had the most evidence of effectiveness, with 7 out of 9 studies demonstrating a statistically significant improvement in adherence in the intervention group. In the other 2 studies, improved adherence was observed in the intervention group; however, the effect was either not statistically significant or not reported.

Five of the studies used a system that electronically recorded the time and date when a medicine container was opened. All studies using this rigorous system for outcome measurement demonstrated statistically significant improvement in adherence with once-daily vs twice-daily dosage regimens. Relative improvement in adherence ranged from 8% to 20%.

Educational strategies alone were largely ineffective in improving adherence. Only 1 of 6 studies of patient education intervention demonstrated improved adherence, but the trial was small (n=110), and the effect was not seen in the other studies (total of 1103 patients).

Research on motivating patients is inconsistent

Motivation and support strategies consisted of interventions such as drug reminder charts, self-recording of blood pressure, mail reminders, and home visits.

Overall, out of 24 RCTs studying motivational, support, and reminder interventions, 10 demonstrated statistically significant but small improvements in adherence. These studies relied on measures such as pill counts and self-report to assess adherence rather than electronic monitoring. The marked inconsistency among the body of evidence makes it difficult to determine whether motivational, support, and reminder interventions alone are effective in improving adherence.

Out of 18 studies of interventions classified as complex health and organizational interventions, including many with an educational or motivational component, interventions in 8 studies led to a statistically significant improvement in adherence. Complex interventions included structured hypertension management programs such as worksite care provided by trained nurses. An example of an intervention given in combination is a program of home visits, education, and specialized dosing devices. Because these interventions varied considerably, an overall statement of effectiveness is not appropriate.

Modest success seen in improving diet

A Cochrane review of dietary advice for reducing cardiovascular disease risk among healthy adults included 29 trials.² Individuals or groups of patients received verbal or printed dietary advice over 1 or more personal contacts. They also received advice by telephone. Ten RCTs of dietary advice in 4328 participants or groups of participants assessed self-reported dietary fat intake.

Overall, intake of dietary fat (expressed as a percentage of total caloric intake) fell by 6.2% (95% confidence interval [CI], reduced 8.4% to increased 4.0%) with dietary intervention over 6 to 48 months. Due to significant heterogeneity between the studies, this overall estimate must be viewed with caution.

Eight RCT studies in 3952 participants or groups of participants assessed self-reported fruit and vegetable intake as an outcome. Overall, intake of fruits and vegetables increased by 1.2 servings per day (95% CI, 0.43–2.1) with interventions over 6 to 48 months. Again, there was significant heterogeneity between the studies. Therefore, this overall estimate must be viewed with caution.

In general, the quality of the studies included in this systematic review was low due to poor descriptions of randomization, lack of allocation concealment, and lack of blinding of outcome assessment. The use of food frequency questionnaires to measure fat and fruit/vegetable intake likely led to reporting bias in these dietary intervention studies. Also, the trials were in healthy adults and not specific to hypertensive patients.

Motiviating patents to exercise remains a challenge

We found 1 randomized trial that evaluated the effectiveness of a physician’s advice to increase physical activity among patients with hypertension in a general practice setting.³ Physical activity was measured using a validated questionnaire. Patients given the advice as part of self-care for hypertension (n=192) were no more likely to have increased their physical activity than those not given the advice (n=108) at 2- and 6-month follow-ups.

Recommendations from others

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) states that self-measurement of blood pressure may benefit patients by providing information on response to antihypertensive medication and improving adherence with therapy.⁴

The report also notes that the patient and clinician must agree on blood pressure goals, and that patient motivation to adopt lifestyle changes and take prescribed medication improves when patients have positive experiences and trust their clinicians.

Evidence summary

Self-care can be defined as activities that a patient undertakes with the intention of improving health or preventing disease. Self-care for hypertension includes taking medicine as prescribed, monitoring blood pressure response to therapy, and adopting lifestyle recommendations—increasing exercise, decreasing salt intake, and increasing fruits and vegetable consumption.

Keeping meds simple improves adherence

Various interventions have been developed with the goal of improving medication adherence among patients with hypertension. A Cochrane review included 38 randomized controlled trials (RCTs) of 58 various types of interventions (some tested in factorial trials) designed to improve patient adherence to antihypertensive medications in ambulatory settings.¹ The quality of the studies was generally low due to inadequate allocation concealment, lack of blinding of outcome assessors, loss to follow-up, and the small number of participants in trials.

The authors grouped interventions into 4 broad categories: simplification of dosing regimens; patient education; patient motivation, support, and reminders; and complex interventions. Comparison groups received either no intervention, usual care, or—in the case of simplification of dosing regimens—a daily regimen consisting of more than 1 pill per day vs a once-daily regimen. Because of various types of interventions and different methods of assessing outcomes, pooling of results was, appropriately, not done.

Of all the interventions, simplification of dosing regimens had the most evidence of effectiveness, with 7 out of 9 studies demonstrating a statistically significant improvement in adherence in the intervention group. In the other 2 studies, improved adherence was observed in the intervention group; however, the effect was either not statistically significant or not reported.

Five of the studies used a system that electronically recorded the time and date when a medicine container was opened. All studies using this rigorous system for outcome measurement demonstrated statistically significant improvement in adherence with once-daily vs twice-daily dosage regimens. Relative improvement in adherence ranged from 8% to 20%.

Educational strategies alone were largely ineffective in improving adherence. Only 1 of 6 studies of patient education intervention demonstrated improved adherence, but the trial was small (n=110), and the effect was not seen in the other studies (total of 1103 patients).

Research on motivating patients is inconsistent

Motivation and support strategies consisted of interventions such as drug reminder charts, self-recording of blood pressure, mail reminders, and home visits.

Overall, out of 24 RCTs studying motivational, support, and reminder interventions, 10 demonstrated statistically significant but small improvements in adherence. These studies relied on measures such as pill counts and self-report to assess adherence rather than electronic monitoring. The marked inconsistency among the body of evidence makes it difficult to determine whether motivational, support, and reminder interventions alone are effective in improving adherence.

Out of 18 studies of interventions classified as complex health and organizational interventions, including many with an educational or motivational component, interventions in 8 studies led to a statistically significant improvement in adherence. Complex interventions included structured hypertension management programs such as worksite care provided by trained nurses. An example of an intervention given in combination is a program of home visits, education, and specialized dosing devices. Because these interventions varied considerably, an overall statement of effectiveness is not appropriate.

Modest success seen in improving diet

A Cochrane review of dietary advice for reducing cardiovascular disease risk among healthy adults included 29 trials.² Individuals or groups of patients received verbal or printed dietary advice over 1 or more personal contacts. They also received advice by telephone. Ten RCTs of dietary advice in 4328 participants or groups of participants assessed self-reported dietary fat intake.

Overall, intake of dietary fat (expressed as a percentage of total caloric intake) fell by 6.2% (95% confidence interval [CI], reduced 8.4% to increased 4.0%) with dietary intervention over 6 to 48 months. Due to significant heterogeneity between the studies, this overall estimate must be viewed with caution.

Eight RCT studies in 3952 participants or groups of participants assessed self-reported fruit and vegetable intake as an outcome. Overall, intake of fruits and vegetables increased by 1.2 servings per day (95% CI, 0.43–2.1) with interventions over 6 to 48 months. Again, there was significant heterogeneity between the studies. Therefore, this overall estimate must be viewed with caution.

In general, the quality of the studies included in this systematic review was low due to poor descriptions of randomization, lack of allocation concealment, and lack of blinding of outcome assessment. The use of food frequency questionnaires to measure fat and fruit/vegetable intake likely led to reporting bias in these dietary intervention studies. Also, the trials were in healthy adults and not specific to hypertensive patients.

Motiviating patents to exercise remains a challenge

We found 1 randomized trial that evaluated the effectiveness of a physician’s advice to increase physical activity among patients with hypertension in a general practice setting.³ Physical activity was measured using a validated questionnaire. Patients given the advice as part of self-care for hypertension (n=192) were no more likely to have increased their physical activity than those not given the advice (n=108) at 2- and 6-month follow-ups.

Recommendations from others

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) states that self-measurement of blood pressure may benefit patients by providing information on response to antihypertensive medication and improving adherence with therapy.⁴

The report also notes that the patient and clinician must agree on blood pressure goals, and that patient motivation to adopt lifestyle changes and take prescribed medication improves when patients have positive experiences and trust their clinicians.

Evidence summary

Self-care can be defined as activities that a patient undertakes with the intention of improving health or preventing disease. Self-care for hypertension includes taking medicine as prescribed, monitoring blood pressure response to therapy, and adopting lifestyle recommendations—increasing exercise, decreasing salt intake, and increasing fruits and vegetable consumption.

Keeping meds simple improves adherence

Various interventions have been developed with the goal of improving medication adherence among patients with hypertension. A Cochrane review included 38 randomized controlled trials (RCTs) of 58 various types of interventions (some tested in factorial trials) designed to improve patient adherence to antihypertensive medications in ambulatory settings.¹ The quality of the studies was generally low due to inadequate allocation concealment, lack of blinding of outcome assessors, loss to follow-up, and the small number of participants in trials.

The authors grouped interventions into 4 broad categories: simplification of dosing regimens; patient education; patient motivation, support, and reminders; and complex interventions. Comparison groups received either no intervention, usual care, or—in the case of simplification of dosing regimens—a daily regimen consisting of more than 1 pill per day vs a once-daily regimen. Because of various types of interventions and different methods of assessing outcomes, pooling of results was, appropriately, not done.

Of all the interventions, simplification of dosing regimens had the most evidence of effectiveness, with 7 out of 9 studies demonstrating a statistically significant improvement in adherence in the intervention group. In the other 2 studies, improved adherence was observed in the intervention group; however, the effect was either not statistically significant or not reported.

Five of the studies used a system that electronically recorded the time and date when a medicine container was opened. All studies using this rigorous system for outcome measurement demonstrated statistically significant improvement in adherence with once-daily vs twice-daily dosage regimens. Relative improvement in adherence ranged from 8% to 20%.

Educational strategies alone were largely ineffective in improving adherence. Only 1 of 6 studies of patient education intervention demonstrated improved adherence, but the trial was small (n=110), and the effect was not seen in the other studies (total of 1103 patients).

Research on motivating patients is inconsistent

Motivation and support strategies consisted of interventions such as drug reminder charts, self-recording of blood pressure, mail reminders, and home visits.

Overall, out of 24 RCTs studying motivational, support, and reminder interventions, 10 demonstrated statistically significant but small improvements in adherence. These studies relied on measures such as pill counts and self-report to assess adherence rather than electronic monitoring. The marked inconsistency among the body of evidence makes it difficult to determine whether motivational, support, and reminder interventions alone are effective in improving adherence.

Out of 18 studies of interventions classified as complex health and organizational interventions, including many with an educational or motivational component, interventions in 8 studies led to a statistically significant improvement in adherence. Complex interventions included structured hypertension management programs such as worksite care provided by trained nurses. An example of an intervention given in combination is a program of home visits, education, and specialized dosing devices. Because these interventions varied considerably, an overall statement of effectiveness is not appropriate.

Modest success seen in improving diet

A Cochrane review of dietary advice for reducing cardiovascular disease risk among healthy adults included 29 trials.² Individuals or groups of patients received verbal or printed dietary advice over 1 or more personal contacts. They also received advice by telephone. Ten RCTs of dietary advice in 4328 participants or groups of participants assessed self-reported dietary fat intake.

Overall, intake of dietary fat (expressed as a percentage of total caloric intake) fell by 6.2% (95% confidence interval [CI], reduced 8.4% to increased 4.0%) with dietary intervention over 6 to 48 months. Due to significant heterogeneity between the studies, this overall estimate must be viewed with caution.

Eight RCT studies in 3952 participants or groups of participants assessed self-reported fruit and vegetable intake as an outcome. Overall, intake of fruits and vegetables increased by 1.2 servings per day (95% CI, 0.43–2.1) with interventions over 6 to 48 months. Again, there was significant heterogeneity between the studies. Therefore, this overall estimate must be viewed with caution.

In general, the quality of the studies included in this systematic review was low due to poor descriptions of randomization, lack of allocation concealment, and lack of blinding of outcome assessment. The use of food frequency questionnaires to measure fat and fruit/vegetable intake likely led to reporting bias in these dietary intervention studies. Also, the trials were in healthy adults and not specific to hypertensive patients.

Motiviating patents to exercise remains a challenge

We found 1 randomized trial that evaluated the effectiveness of a physician’s advice to increase physical activity among patients with hypertension in a general practice setting.³ Physical activity was measured using a validated questionnaire. Patients given the advice as part of self-care for hypertension (n=192) were no more likely to have increased their physical activity than those not given the advice (n=108) at 2- and 6-month follow-ups.

Recommendations from others

The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) states that self-measurement of blood pressure may benefit patients by providing information on response to antihypertensive medication and improving adherence with therapy.⁴

The report also notes that the patient and clinician must agree on blood pressure goals, and that patient motivation to adopt lifestyle changes and take prescribed medication improves when patients have positive experiences and trust their clinicians.

Evidence summary

Urinary tract infections (UTIs) are common in reproductive-aged women. In lactating women, it’s important to select a therapy that is not only effective, but also safe for the breastfeeding infant. No studies in the literature address the safety or efficacy of UTI treatments in lactating women and their infants. Therefore, recommendations are extrapolated from studies of efficacy in the general population, studies of antibiotic penetration into breast milk, and effects of antibiotics given to infants directly.

How the efficacy of UTI treatments stack up

The best evidence for efficacy of UTI treatments comes from a 1999 meta-analysis of uncomplicated UTI in nonpregnant, nonlactating women.¹ They found TMP/SMX to be the most widely studied antibiotic and to have a 93% bacterial eradication rate; it was therefore used as a standard for comparison of other treatments. Nitrofurantoin and quinolones (ofloxacin, ciprofloxacin, and others) had comparable eradication rates to TMP/SMX in the same study; 7-day courses of nitrofurantoin were more efficacious than shorter ones. TMP/SMX is not recommended if the local resistance rate is more than 10% to 20%.²

Three-day therapy for uncomplicated UTI is more effective than single-dose therapy and equal to longer courses for most antibiotics.¹ A longer course (7 days) may be required for nitrofurantoin. Beta-lactams are associated with high levels of resistance and therefore not recommended in empiric treatment of UTI.²

A look at penetration into breast milk

Most of the data regarding antibiotic penetration into breast milk come from case series. One South African series measured breast milk levels of both trimethoprim and sulfamethoxazole among 50 Bantu women treated with TMP/SMX for various infections (including UTI).³ The women received 160 mg TMP and 800 mg SMX 2 or 3 times daily for up to 5 days. The average level of TMP in breast milk was 2 mcg/mL, and the level of SMX was 4.7 mcg/mL. Researchers calculated that the average breastfeeding infant would ingest only 1 mg of TMP and 2.5 mg of SMX per day. TMP/SMX is generally considered safe for infants in the absence of G6PD deficiency.

In a case series, 9 lactating mothers were given nitrofurantoin 100 mg orally every 6 hours for 1 day.⁴ On day 2, after a single 100 to 200 mg dose, drug levels in the breast milk 2 hours post-dose ranged from none (in 6 of the 9 women) to a maximum of 0.5 mcg/mL in one. Since even a very small amount of the drug may trigger a hemolytic reaction among G6PD-deficient individuals, the researchers called for caution when prescribing to mothers from high-risk populations.

A final case seriesadministered ciprofloxacin 750 mg, pefloxacin 400 mg, or ofloxacin 400 mg twice daily to 3 groups of 10 women each.⁵ Milk samples were obtained 6 times over 24 hours following the third dose of antibiotic. Maximum levels in breast milk occurred 2 hours after the dose, and were 3.79, 3.54, and 2.41 mcg/mL for ciprofloxacin, pefloxacin, and ofloxacin respectively. All 3 quinolones achieved higher concentrations in breast milk than in serum.

But are these drugs safe for children?

While TMP/SMX and nitrofurantoin are generally considered safe when given to infants and children (barring G6PD deficiency), data are mixed regarding the safety of quinolones. Ciprofloxacin’s FDA indication for pediatric patients is limited to postexposure anthrax prophylaxis due to evidence of fluoroquinolone-induced joint toxicity in animal studies.⁶ Despite this, they have been prescribed to tens of thousands of children for select scenarios such as chemotherapy-induced immuno-compromise, cystic fibrosis, complicated UTIs, and salmonella infections.⁷

A report was published summarizing safety data from the Bayer database of compassionate use of ciprofloxacin.⁸ The report indicates that 2030 treatment courses of ciprofloxacin were given to 1795 children up to age 17 for a variety of infections; only 3% were under age 5. Most patients received 21 to 40 mg/kg of ciprofloxacin per day; treatment duration was from 1 to 303 days. Arthralgia occurred in 1.5% of patients, most of whom had cystic fibrosis. Of the 31 patients affected, arthralgias resolved in 25, improved in 1, and remained unchanged in 1. (Data regarding resolution were unavailable for 4 patients.)

Recommendations from others

The American Academy of Pediatrics’ Committee on Drugsconsiders the following antibiotics typically used for UTI to be compatible with breastfeeding: ciprofloxacin, ofloxacin, nitrofurantoin (caution for infants with G6PD deficiency), and TMP/SMX.⁹

Drugs in Pregnancy and Lactation considers trimethoprim and sulfamethoxazole to be compatible with breastfeeding but cautions against sulfamethoxazole use in infants with known G6PD deficiency. The authors categorize nitrofurantoin, ciprofloxacin, and ofloxacin as “probably compatible/limited human data,” and advise caution with nitrofurantoin for infants with G6PD deficiency.¹⁰

Evidence summary

Urinary tract infections (UTIs) are common in reproductive-aged women. In lactating women, it’s important to select a therapy that is not only effective, but also safe for the breastfeeding infant. No studies in the literature address the safety or efficacy of UTI treatments in lactating women and their infants. Therefore, recommendations are extrapolated from studies of efficacy in the general population, studies of antibiotic penetration into breast milk, and effects of antibiotics given to infants directly.

How the efficacy of UTI treatments stack up

The best evidence for efficacy of UTI treatments comes from a 1999 meta-analysis of uncomplicated UTI in nonpregnant, nonlactating women.¹ They found TMP/SMX to be the most widely studied antibiotic and to have a 93% bacterial eradication rate; it was therefore used as a standard for comparison of other treatments. Nitrofurantoin and quinolones (ofloxacin, ciprofloxacin, and others) had comparable eradication rates to TMP/SMX in the same study; 7-day courses of nitrofurantoin were more efficacious than shorter ones. TMP/SMX is not recommended if the local resistance rate is more than 10% to 20%.²

Three-day therapy for uncomplicated UTI is more effective than single-dose therapy and equal to longer courses for most antibiotics.¹ A longer course (7 days) may be required for nitrofurantoin. Beta-lactams are associated with high levels of resistance and therefore not recommended in empiric treatment of UTI.²

A look at penetration into breast milk

Most of the data regarding antibiotic penetration into breast milk come from case series. One South African series measured breast milk levels of both trimethoprim and sulfamethoxazole among 50 Bantu women treated with TMP/SMX for various infections (including UTI).³ The women received 160 mg TMP and 800 mg SMX 2 or 3 times daily for up to 5 days. The average level of TMP in breast milk was 2 mcg/mL, and the level of SMX was 4.7 mcg/mL. Researchers calculated that the average breastfeeding infant would ingest only 1 mg of TMP and 2.5 mg of SMX per day. TMP/SMX is generally considered safe for infants in the absence of G6PD deficiency.

In a case series, 9 lactating mothers were given nitrofurantoin 100 mg orally every 6 hours for 1 day.⁴ On day 2, after a single 100 to 200 mg dose, drug levels in the breast milk 2 hours post-dose ranged from none (in 6 of the 9 women) to a maximum of 0.5 mcg/mL in one. Since even a very small amount of the drug may trigger a hemolytic reaction among G6PD-deficient individuals, the researchers called for caution when prescribing to mothers from high-risk populations.

A final case seriesadministered ciprofloxacin 750 mg, pefloxacin 400 mg, or ofloxacin 400 mg twice daily to 3 groups of 10 women each.⁵ Milk samples were obtained 6 times over 24 hours following the third dose of antibiotic. Maximum levels in breast milk occurred 2 hours after the dose, and were 3.79, 3.54, and 2.41 mcg/mL for ciprofloxacin, pefloxacin, and ofloxacin respectively. All 3 quinolones achieved higher concentrations in breast milk than in serum.

But are these drugs safe for children?

While TMP/SMX and nitrofurantoin are generally considered safe when given to infants and children (barring G6PD deficiency), data are mixed regarding the safety of quinolones. Ciprofloxacin’s FDA indication for pediatric patients is limited to postexposure anthrax prophylaxis due to evidence of fluoroquinolone-induced joint toxicity in animal studies.⁶ Despite this, they have been prescribed to tens of thousands of children for select scenarios such as chemotherapy-induced immuno-compromise, cystic fibrosis, complicated UTIs, and salmonella infections.⁷

A report was published summarizing safety data from the Bayer database of compassionate use of ciprofloxacin.⁸ The report indicates that 2030 treatment courses of ciprofloxacin were given to 1795 children up to age 17 for a variety of infections; only 3% were under age 5. Most patients received 21 to 40 mg/kg of ciprofloxacin per day; treatment duration was from 1 to 303 days. Arthralgia occurred in 1.5% of patients, most of whom had cystic fibrosis. Of the 31 patients affected, arthralgias resolved in 25, improved in 1, and remained unchanged in 1. (Data regarding resolution were unavailable for 4 patients.)

Recommendations from others

The American Academy of Pediatrics’ Committee on Drugsconsiders the following antibiotics typically used for UTI to be compatible with breastfeeding: ciprofloxacin, ofloxacin, nitrofurantoin (caution for infants with G6PD deficiency), and TMP/SMX.⁹

Drugs in Pregnancy and Lactation considers trimethoprim and sulfamethoxazole to be compatible with breastfeeding but cautions against sulfamethoxazole use in infants with known G6PD deficiency. The authors categorize nitrofurantoin, ciprofloxacin, and ofloxacin as “probably compatible/limited human data,” and advise caution with nitrofurantoin for infants with G6PD deficiency.¹⁰

Evidence summary

Urinary tract infections (UTIs) are common in reproductive-aged women. In lactating women, it’s important to select a therapy that is not only effective, but also safe for the breastfeeding infant. No studies in the literature address the safety or efficacy of UTI treatments in lactating women and their infants. Therefore, recommendations are extrapolated from studies of efficacy in the general population, studies of antibiotic penetration into breast milk, and effects of antibiotics given to infants directly.

How the efficacy of UTI treatments stack up

The best evidence for efficacy of UTI treatments comes from a 1999 meta-analysis of uncomplicated UTI in nonpregnant, nonlactating women.¹ They found TMP/SMX to be the most widely studied antibiotic and to have a 93% bacterial eradication rate; it was therefore used as a standard for comparison of other treatments. Nitrofurantoin and quinolones (ofloxacin, ciprofloxacin, and others) had comparable eradication rates to TMP/SMX in the same study; 7-day courses of nitrofurantoin were more efficacious than shorter ones. TMP/SMX is not recommended if the local resistance rate is more than 10% to 20%.²

Three-day therapy for uncomplicated UTI is more effective than single-dose therapy and equal to longer courses for most antibiotics.¹ A longer course (7 days) may be required for nitrofurantoin. Beta-lactams are associated with high levels of resistance and therefore not recommended in empiric treatment of UTI.²

A look at penetration into breast milk

Most of the data regarding antibiotic penetration into breast milk come from case series. One South African series measured breast milk levels of both trimethoprim and sulfamethoxazole among 50 Bantu women treated with TMP/SMX for various infections (including UTI).³ The women received 160 mg TMP and 800 mg SMX 2 or 3 times daily for up to 5 days. The average level of TMP in breast milk was 2 mcg/mL, and the level of SMX was 4.7 mcg/mL. Researchers calculated that the average breastfeeding infant would ingest only 1 mg of TMP and 2.5 mg of SMX per day. TMP/SMX is generally considered safe for infants in the absence of G6PD deficiency.

In a case series, 9 lactating mothers were given nitrofurantoin 100 mg orally every 6 hours for 1 day.⁴ On day 2, after a single 100 to 200 mg dose, drug levels in the breast milk 2 hours post-dose ranged from none (in 6 of the 9 women) to a maximum of 0.5 mcg/mL in one. Since even a very small amount of the drug may trigger a hemolytic reaction among G6PD-deficient individuals, the researchers called for caution when prescribing to mothers from high-risk populations.

A final case seriesadministered ciprofloxacin 750 mg, pefloxacin 400 mg, or ofloxacin 400 mg twice daily to 3 groups of 10 women each.⁵ Milk samples were obtained 6 times over 24 hours following the third dose of antibiotic. Maximum levels in breast milk occurred 2 hours after the dose, and were 3.79, 3.54, and 2.41 mcg/mL for ciprofloxacin, pefloxacin, and ofloxacin respectively. All 3 quinolones achieved higher concentrations in breast milk than in serum.

But are these drugs safe for children?

While TMP/SMX and nitrofurantoin are generally considered safe when given to infants and children (barring G6PD deficiency), data are mixed regarding the safety of quinolones. Ciprofloxacin’s FDA indication for pediatric patients is limited to postexposure anthrax prophylaxis due to evidence of fluoroquinolone-induced joint toxicity in animal studies.⁶ Despite this, they have been prescribed to tens of thousands of children for select scenarios such as chemotherapy-induced immuno-compromise, cystic fibrosis, complicated UTIs, and salmonella infections.⁷

A report was published summarizing safety data from the Bayer database of compassionate use of ciprofloxacin.⁸ The report indicates that 2030 treatment courses of ciprofloxacin were given to 1795 children up to age 17 for a variety of infections; only 3% were under age 5. Most patients received 21 to 40 mg/kg of ciprofloxacin per day; treatment duration was from 1 to 303 days. Arthralgia occurred in 1.5% of patients, most of whom had cystic fibrosis. Of the 31 patients affected, arthralgias resolved in 25, improved in 1, and remained unchanged in 1. (Data regarding resolution were unavailable for 4 patients.)

Recommendations from others

The American Academy of Pediatrics’ Committee on Drugsconsiders the following antibiotics typically used for UTI to be compatible with breastfeeding: ciprofloxacin, ofloxacin, nitrofurantoin (caution for infants with G6PD deficiency), and TMP/SMX.⁹

Drugs in Pregnancy and Lactation considers trimethoprim and sulfamethoxazole to be compatible with breastfeeding but cautions against sulfamethoxazole use in infants with known G6PD deficiency. The authors categorize nitrofurantoin, ciprofloxacin, and ofloxacin as “probably compatible/limited human data,” and advise caution with nitrofurantoin for infants with G6PD deficiency.¹⁰

TABLE
Summary of HSV test characteristics

Evidence summary

Our literature search failed to find any randomized controlled trials comparing diagnostic tests for HSV-2 infection among asymptomatic populations. Data from cross-sectional studies, however, are available.

Glycoprotein G ELISA has better specificity

Using the Western blot technique as the gold standard, a total of 158 serum samples from patients with either HSV-1 or HSV-2 infection—without mention of symptomatology—were used to compare the performance of several commercially available ELISA assays.¹ The glycoprotein G and non–glycoprotein G ELISA tests were both found to have sensitivities >90%, but the non–glycoprotein G ELISA tests had specificities under 90%.

In 47% to 82% of the samples tested with non–glycoprotein G ELISA, there was cross-reactivity between HSV-1 and HSV-2 antibodies.¹ The College of American Pathologists found that 46% to 84% of laboratories using non–glycoprotein G ELISA tests incorrectly identified an HSV-1 sample as being HSV-2. All laboratories reporting use of glycoprotein G ELISA tests correctly identified the sample as containing only HSV-1 antibodies.² Neither study included controls, delineated symptom status, or measured patient-oriented outcomes.

Genital culture has poor sensitivity

A prospective cohort study compared the viral shedding by Western blot among 52 asymptomatic seropositive patients with 90 seropositive and symptomatic patients.³ Daily genital swabs were done for 3 months for each patient. The asymptomatic individuals had HSV-2 positive cultures on 3% of culture days.³ Genital culture appears to have a very poor sensitivity (5%) for diagnosis of HSV-2 infection among asymptomatic individuals.

We found no studies that measured patient-oriented harms or benefits arising from testing asymptomatic individuals for HSV-2 infection.

Recommendations from others

The USPSTF recommends against routine serological screening for HSV in asymptomatic adolescents and adults (D recommendation, fair or good evidence that the service is ineffective or that the harms outweigh the benefits).⁴ The California Sexually Transmitted Diseases Controllers Association recommends that serologic testing is likely to benefit HIV-infected patients, those whose sexual partners have genital herpes, and those at high risk of STDs motivated to reduce their sexual risk behavior.⁵

TABLE
Summary of HSV test characteristics

Evidence summary

Our literature search failed to find any randomized controlled trials comparing diagnostic tests for HSV-2 infection among asymptomatic populations. Data from cross-sectional studies, however, are available.

Glycoprotein G ELISA has better specificity

Using the Western blot technique as the gold standard, a total of 158 serum samples from patients with either HSV-1 or HSV-2 infection—without mention of symptomatology—were used to compare the performance of several commercially available ELISA assays.¹ The glycoprotein G and non–glycoprotein G ELISA tests were both found to have sensitivities >90%, but the non–glycoprotein G ELISA tests had specificities under 90%.

In 47% to 82% of the samples tested with non–glycoprotein G ELISA, there was cross-reactivity between HSV-1 and HSV-2 antibodies.¹ The College of American Pathologists found that 46% to 84% of laboratories using non–glycoprotein G ELISA tests incorrectly identified an HSV-1 sample as being HSV-2. All laboratories reporting use of glycoprotein G ELISA tests correctly identified the sample as containing only HSV-1 antibodies.² Neither study included controls, delineated symptom status, or measured patient-oriented outcomes.

Genital culture has poor sensitivity

A prospective cohort study compared the viral shedding by Western blot among 52 asymptomatic seropositive patients with 90 seropositive and symptomatic patients.³ Daily genital swabs were done for 3 months for each patient. The asymptomatic individuals had HSV-2 positive cultures on 3% of culture days.³ Genital culture appears to have a very poor sensitivity (5%) for diagnosis of HSV-2 infection among asymptomatic individuals.

We found no studies that measured patient-oriented harms or benefits arising from testing asymptomatic individuals for HSV-2 infection.

Recommendations from others

The USPSTF recommends against routine serological screening for HSV in asymptomatic adolescents and adults (D recommendation, fair or good evidence that the service is ineffective or that the harms outweigh the benefits).⁴ The California Sexually Transmitted Diseases Controllers Association recommends that serologic testing is likely to benefit HIV-infected patients, those whose sexual partners have genital herpes, and those at high risk of STDs motivated to reduce their sexual risk behavior.⁵

TABLE
Summary of HSV test characteristics

Evidence summary

Our literature search failed to find any randomized controlled trials comparing diagnostic tests for HSV-2 infection among asymptomatic populations. Data from cross-sectional studies, however, are available.

Glycoprotein G ELISA has better specificity

Using the Western blot technique as the gold standard, a total of 158 serum samples from patients with either HSV-1 or HSV-2 infection—without mention of symptomatology—were used to compare the performance of several commercially available ELISA assays.¹ The glycoprotein G and non–glycoprotein G ELISA tests were both found to have sensitivities >90%, but the non–glycoprotein G ELISA tests had specificities under 90%.

In 47% to 82% of the samples tested with non–glycoprotein G ELISA, there was cross-reactivity between HSV-1 and HSV-2 antibodies.¹ The College of American Pathologists found that 46% to 84% of laboratories using non–glycoprotein G ELISA tests incorrectly identified an HSV-1 sample as being HSV-2. All laboratories reporting use of glycoprotein G ELISA tests correctly identified the sample as containing only HSV-1 antibodies.² Neither study included controls, delineated symptom status, or measured patient-oriented outcomes.

Genital culture has poor sensitivity

A prospective cohort study compared the viral shedding by Western blot among 52 asymptomatic seropositive patients with 90 seropositive and symptomatic patients.³ Daily genital swabs were done for 3 months for each patient. The asymptomatic individuals had HSV-2 positive cultures on 3% of culture days.³ Genital culture appears to have a very poor sensitivity (5%) for diagnosis of HSV-2 infection among asymptomatic individuals.

We found no studies that measured patient-oriented harms or benefits arising from testing asymptomatic individuals for HSV-2 infection.

Recommendations from others

The USPSTF recommends against routine serological screening for HSV in asymptomatic adolescents and adults (D recommendation, fair or good evidence that the service is ineffective or that the harms outweigh the benefits).⁴ The California Sexually Transmitted Diseases Controllers Association recommends that serologic testing is likely to benefit HIV-infected patients, those whose sexual partners have genital herpes, and those at high risk of STDs motivated to reduce their sexual risk behavior.⁵

Evidence summary

Our search for articles that examined patient- and primary care–oriented PID diagnostic tests resulted in 2 systematic reviews, no randomized controlled trials, 4 data analyses, and 5 cohort studies, all of which were fair- to good-quality.

Systematic reviews don’t show consistent results

One systematic review of 12 fair- to good-quality studies, based in Europe and the US, included urban populations treated in Ob/Gyn departments, emergency rooms, and sexually transmitted disease clinics. This review supports a thorough evaluation when more severe disease is suspected and the use of sensitive diagnostic tests for suspected mild disease—eg, CRP (74%–93% sensitivity) and ESR (64%–81% sensitivity for value >20 or 15 mm/h).³

Another systematic review of 19 fair-to good-quality cohort studies found a sensitivity of only 64% for laparoscopy, 50% to 87% for endometrial biopsy, and up to 80% for microbiological tests. Results were not consistent for the reported sensitivity of WBC, ESR, or CRP.⁴

Multivariate analyses of Swedish data come to different conclusions

We identified no randomized controlled trials that addressed the diagnosis of PID. Two multivariate analyses of the same Swedish data from the 1960s came to different conclusions.

The Lund analysis includes data collected between 1960 and 1969 at Lund University Hospital in Sweden on women with suspected PID, with about 625 cases included for these analyses. Simms et al⁵ found insufficient evidence from these data for any existing diagnostic criteria.

Looking at the same data, Hagdu et al proposed the use of a clinical criteria model including low abdominal pain and 2 or more of the following other criteria: vaginal discharge, temperature greater than 38°C, vomiting, irregular menses, urologic or proctitis symptoms, pelvic tenderness, adnexal mass or swelling, and ESR ≥15.⁶ This model had a reported sensitivity of 87%, specificity of 52.5%, and false-positive and false-negative rates of 21.2% and 33.3%, respectively.

Looking at adnexal tenderness aids sensitivity of other tests

Cross-sectional analysis of a multisite US randomized treatment trial supported using adnexal tenderness as a minimum clinical criterion to increase sensitivity.¹ Further analysis of that trial suggests that some asymptomatic women are at equivalent risk of developing sequelae compared with symptomatic women diagnosed with PID. Those asymptomatic women who met diagnostic criteria with a positive endometrial biopsy were more likely to have pelvic tenderness than asymptomatic women who were not diagnosed.²

Symptoms >1 week and elevated WBC also helpful

Two small, fair-quality cohort studies (N=61 and 176, respectively) investigated the use of clinical diagnostic criteria for PID. The smaller study compared clinical criteria to several reference standards (laparoscopy, histology, microbiological markers, and transvaginal ultrasound) and found clinical criteria, specifically adnexal tenderness, most sensitive (87%), and laparoscopy most specific (100%).⁷

In the second study, the authors evaluated 176 consecutive admissions for clinically diagnosed PID, 76% of which were laparoscopically confirmed. Reviewing clinical indicators, they found that a combination of adnexal tenderness, symptoms for <1 week, and elevated WBC was the most sensitive set of predictors (sensitivity 86.6%, specificity 45.7%) with positive predictive value of 0.84 and negative predictive value of 0.52.⁸

Useful lab indicators: C-reactive protein, serum CA-125

Three small cohort studies (N=50–152) of fair-quality evaluated various laboratory indicators in the diagnosis of PID. Each used a different reference standard: clinical criteria, laparoscopy, and endometrial biopsy, respectively.

One study found CRP >10 to be 93% sensitive and 83% specific in a cohort of women admitted to the emergency department with an acute gynecological disorder.⁹ This population had a high baseline incidence of PID, pregnancy, and intrauterine device use.

A study of serum CA-125 levels showed a predictive value of 97% for values >16 U/mL in diagnosing salpingitis. This test might therefore be useful in confirming peritoneal involvement when PID is suspected clinically.¹⁰

Another study developed a model using vaginal WBC (the single most sensitive factor at 78%), serum WBC (the single most specific factor at 88%), CRP, and ESR. The model was 100% sensitive if the diagnosis only required 1 positive test, although the specificity was only 18%. The positive predictive value was 65%. If all 4 were positive, specificity was 95%, with 29% sensitivity, a positive predictive value of 90%, and a negative predictive value of 47%. Prevalence was 60% in the group studied.¹¹

Recommendations from others

The CDC recommends empiric treatment of women with lower abdominal or pelvic pain who are at risk for sexually transmitted diseases with uterine, adnexal, or cervical motion tenderness and no other identifiable cause.¹²

Clinical Evidence found no RCTs that compared empiric treatment of suspected PID with waiting for microbiological test results for guidance.¹³

The Agency for Healthcare Research and Quality recommends requiring the presence of lower abdominal, adnexal and cervical tenderness, without alternative diagnosis, for the diagnosis of PID. Temperature >101°F, cervical or vaginal discharge, elevated ESR, and positive gonococcal or chlamydia cultures all increase specificity of diagnosis.¹⁴

The United Kingdom’s national guideline recommends maintaining a low threshold for empirical treatment, citing a lack of definitive diagnostic criteria and potential for sequelae, but does recommend testing for gonorrhea and chlamydia.¹⁵

Evidence summary

Our search for articles that examined patient- and primary care–oriented PID diagnostic tests resulted in 2 systematic reviews, no randomized controlled trials, 4 data analyses, and 5 cohort studies, all of which were fair- to good-quality.

Systematic reviews don’t show consistent results

One systematic review of 12 fair- to good-quality studies, based in Europe and the US, included urban populations treated in Ob/Gyn departments, emergency rooms, and sexually transmitted disease clinics. This review supports a thorough evaluation when more severe disease is suspected and the use of sensitive diagnostic tests for suspected mild disease—eg, CRP (74%–93% sensitivity) and ESR (64%–81% sensitivity for value >20 or 15 mm/h).³

Another systematic review of 19 fair-to good-quality cohort studies found a sensitivity of only 64% for laparoscopy, 50% to 87% for endometrial biopsy, and up to 80% for microbiological tests. Results were not consistent for the reported sensitivity of WBC, ESR, or CRP.⁴

Multivariate analyses of Swedish data come to different conclusions

We identified no randomized controlled trials that addressed the diagnosis of PID. Two multivariate analyses of the same Swedish data from the 1960s came to different conclusions.

The Lund analysis includes data collected between 1960 and 1969 at Lund University Hospital in Sweden on women with suspected PID, with about 625 cases included for these analyses. Simms et al⁵ found insufficient evidence from these data for any existing diagnostic criteria.

Looking at the same data, Hagdu et al proposed the use of a clinical criteria model including low abdominal pain and 2 or more of the following other criteria: vaginal discharge, temperature greater than 38°C, vomiting, irregular menses, urologic or proctitis symptoms, pelvic tenderness, adnexal mass or swelling, and ESR ≥15.⁶ This model had a reported sensitivity of 87%, specificity of 52.5%, and false-positive and false-negative rates of 21.2% and 33.3%, respectively.

Looking at adnexal tenderness aids sensitivity of other tests

Cross-sectional analysis of a multisite US randomized treatment trial supported using adnexal tenderness as a minimum clinical criterion to increase sensitivity.¹ Further analysis of that trial suggests that some asymptomatic women are at equivalent risk of developing sequelae compared with symptomatic women diagnosed with PID. Those asymptomatic women who met diagnostic criteria with a positive endometrial biopsy were more likely to have pelvic tenderness than asymptomatic women who were not diagnosed.²

Symptoms >1 week and elevated WBC also helpful

Two small, fair-quality cohort studies (N=61 and 176, respectively) investigated the use of clinical diagnostic criteria for PID. The smaller study compared clinical criteria to several reference standards (laparoscopy, histology, microbiological markers, and transvaginal ultrasound) and found clinical criteria, specifically adnexal tenderness, most sensitive (87%), and laparoscopy most specific (100%).⁷

In the second study, the authors evaluated 176 consecutive admissions for clinically diagnosed PID, 76% of which were laparoscopically confirmed. Reviewing clinical indicators, they found that a combination of adnexal tenderness, symptoms for <1 week, and elevated WBC was the most sensitive set of predictors (sensitivity 86.6%, specificity 45.7%) with positive predictive value of 0.84 and negative predictive value of 0.52.⁸

Useful lab indicators: C-reactive protein, serum CA-125

Three small cohort studies (N=50–152) of fair-quality evaluated various laboratory indicators in the diagnosis of PID. Each used a different reference standard: clinical criteria, laparoscopy, and endometrial biopsy, respectively.

One study found CRP >10 to be 93% sensitive and 83% specific in a cohort of women admitted to the emergency department with an acute gynecological disorder.⁹ This population had a high baseline incidence of PID, pregnancy, and intrauterine device use.

A study of serum CA-125 levels showed a predictive value of 97% for values >16 U/mL in diagnosing salpingitis. This test might therefore be useful in confirming peritoneal involvement when PID is suspected clinically.¹⁰

Another study developed a model using vaginal WBC (the single most sensitive factor at 78%), serum WBC (the single most specific factor at 88%), CRP, and ESR. The model was 100% sensitive if the diagnosis only required 1 positive test, although the specificity was only 18%. The positive predictive value was 65%. If all 4 were positive, specificity was 95%, with 29% sensitivity, a positive predictive value of 90%, and a negative predictive value of 47%. Prevalence was 60% in the group studied.¹¹

Recommendations from others

The CDC recommends empiric treatment of women with lower abdominal or pelvic pain who are at risk for sexually transmitted diseases with uterine, adnexal, or cervical motion tenderness and no other identifiable cause.¹²

Clinical Evidence found no RCTs that compared empiric treatment of suspected PID with waiting for microbiological test results for guidance.¹³

The Agency for Healthcare Research and Quality recommends requiring the presence of lower abdominal, adnexal and cervical tenderness, without alternative diagnosis, for the diagnosis of PID. Temperature >101°F, cervical or vaginal discharge, elevated ESR, and positive gonococcal or chlamydia cultures all increase specificity of diagnosis.¹⁴

The United Kingdom’s national guideline recommends maintaining a low threshold for empirical treatment, citing a lack of definitive diagnostic criteria and potential for sequelae, but does recommend testing for gonorrhea and chlamydia.¹⁵

Evidence summary

Our search for articles that examined patient- and primary care–oriented PID diagnostic tests resulted in 2 systematic reviews, no randomized controlled trials, 4 data analyses, and 5 cohort studies, all of which were fair- to good-quality.

Systematic reviews don’t show consistent results

One systematic review of 12 fair- to good-quality studies, based in Europe and the US, included urban populations treated in Ob/Gyn departments, emergency rooms, and sexually transmitted disease clinics. This review supports a thorough evaluation when more severe disease is suspected and the use of sensitive diagnostic tests for suspected mild disease—eg, CRP (74%–93% sensitivity) and ESR (64%–81% sensitivity for value >20 or 15 mm/h).³

Another systematic review of 19 fair-to good-quality cohort studies found a sensitivity of only 64% for laparoscopy, 50% to 87% for endometrial biopsy, and up to 80% for microbiological tests. Results were not consistent for the reported sensitivity of WBC, ESR, or CRP.⁴

Multivariate analyses of Swedish data come to different conclusions

We identified no randomized controlled trials that addressed the diagnosis of PID. Two multivariate analyses of the same Swedish data from the 1960s came to different conclusions.

The Lund analysis includes data collected between 1960 and 1969 at Lund University Hospital in Sweden on women with suspected PID, with about 625 cases included for these analyses. Simms et al⁵ found insufficient evidence from these data for any existing diagnostic criteria.

Looking at the same data, Hagdu et al proposed the use of a clinical criteria model including low abdominal pain and 2 or more of the following other criteria: vaginal discharge, temperature greater than 38°C, vomiting, irregular menses, urologic or proctitis symptoms, pelvic tenderness, adnexal mass or swelling, and ESR ≥15.⁶ This model had a reported sensitivity of 87%, specificity of 52.5%, and false-positive and false-negative rates of 21.2% and 33.3%, respectively.

Looking at adnexal tenderness aids sensitivity of other tests

Cross-sectional analysis of a multisite US randomized treatment trial supported using adnexal tenderness as a minimum clinical criterion to increase sensitivity.¹ Further analysis of that trial suggests that some asymptomatic women are at equivalent risk of developing sequelae compared with symptomatic women diagnosed with PID. Those asymptomatic women who met diagnostic criteria with a positive endometrial biopsy were more likely to have pelvic tenderness than asymptomatic women who were not diagnosed.²

Symptoms >1 week and elevated WBC also helpful

Two small, fair-quality cohort studies (N=61 and 176, respectively) investigated the use of clinical diagnostic criteria for PID. The smaller study compared clinical criteria to several reference standards (laparoscopy, histology, microbiological markers, and transvaginal ultrasound) and found clinical criteria, specifically adnexal tenderness, most sensitive (87%), and laparoscopy most specific (100%).⁷

In the second study, the authors evaluated 176 consecutive admissions for clinically diagnosed PID, 76% of which were laparoscopically confirmed. Reviewing clinical indicators, they found that a combination of adnexal tenderness, symptoms for <1 week, and elevated WBC was the most sensitive set of predictors (sensitivity 86.6%, specificity 45.7%) with positive predictive value of 0.84 and negative predictive value of 0.52.⁸

Useful lab indicators: C-reactive protein, serum CA-125

Three small cohort studies (N=50–152) of fair-quality evaluated various laboratory indicators in the diagnosis of PID. Each used a different reference standard: clinical criteria, laparoscopy, and endometrial biopsy, respectively.

One study found CRP >10 to be 93% sensitive and 83% specific in a cohort of women admitted to the emergency department with an acute gynecological disorder.⁹ This population had a high baseline incidence of PID, pregnancy, and intrauterine device use.

A study of serum CA-125 levels showed a predictive value of 97% for values >16 U/mL in diagnosing salpingitis. This test might therefore be useful in confirming peritoneal involvement when PID is suspected clinically.¹⁰

Another study developed a model using vaginal WBC (the single most sensitive factor at 78%), serum WBC (the single most specific factor at 88%), CRP, and ESR. The model was 100% sensitive if the diagnosis only required 1 positive test, although the specificity was only 18%. The positive predictive value was 65%. If all 4 were positive, specificity was 95%, with 29% sensitivity, a positive predictive value of 90%, and a negative predictive value of 47%. Prevalence was 60% in the group studied.¹¹

Recommendations from others

The CDC recommends empiric treatment of women with lower abdominal or pelvic pain who are at risk for sexually transmitted diseases with uterine, adnexal, or cervical motion tenderness and no other identifiable cause.¹²

Clinical Evidence found no RCTs that compared empiric treatment of suspected PID with waiting for microbiological test results for guidance.¹³

The Agency for Healthcare Research and Quality recommends requiring the presence of lower abdominal, adnexal and cervical tenderness, without alternative diagnosis, for the diagnosis of PID. Temperature >101°F, cervical or vaginal discharge, elevated ESR, and positive gonococcal or chlamydia cultures all increase specificity of diagnosis.¹⁴

The United Kingdom’s national guideline recommends maintaining a low threshold for empirical treatment, citing a lack of definitive diagnostic criteria and potential for sequelae, but does recommend testing for gonorrhea and chlamydia.¹⁵