Clinical Inquiries

Evidence summary

CAD is the leading cause of death in the United States and is a significant cause of mortality and morbidity for those aged 65 years and older. Multiple studies have demonstrated the value of lipid-lowering therapy for the primary and secondary prevention of CAD. Most of these studies have not been specifically oriented toward the elderly; however, substantial data from subgroup analyses of older subjects from major lipid treatment trials has consistently demonstrated the beneficial effects of statin therapy in reducing all cardiovascular events for patients with known CAD who are 65 and older.^2-7

Unfortunately, randomized trials of hyperlipidemia treatment with statins have enrolled few people aged 80 and above. Hence, it is unclear whether the benefit of statins on cardiovascular mortality extends to advanced elderly patients. These people comprise the fastest-growing segment of the population, increasing by about 3% per year. They tend to experience concomitant chronic illness, shorter life expectancy, and physical frailty, leading to quality-of-life and end-of-life issues. Is it beneficial and cost-effective to treat these very elderly patients for hyperlipidemia?

The first prospective, randomized trial⁸ of the use of statins among the elderly examined the impact of pravastatin therapy on primary and secondary prevention of cardiovascular and cerebrovascular events for men and women (age 70–82 years), with a history of vascular disease or with risk factors for vascular disease. The sample of 5804 participants was randomized to receive pravastatin 40 mg or placebo, followed for an average of 3.2 years, and monitored for the combined endpoint of myocardial infarction (MI), stroke, and CAD death. The study showed 19% (95% confidence interval [CI], 6–31; P=.006) proportional reduction in the rate of coronary death or nonfatal MI. The absolute risk reduction for coronary death or nonfatal myocardial infarction or nonfatal stroke was significant (2.2%, number needed to treat [NNT]=45). Rates of adverse drug events were similar in the intervention and control groups.⁸

Serum cholesterol normally declines with age; so the benefit of lowering lipids with medication in this age group is unclear. Furthermore, a meta-analysis⁹ showed an inverse relationship between total serum cholesterol and all-cause mortality for people aged 80 and above, raising the possibility that lowering cholesterol may be detrimental in this age group. Two other cohort studies^10,11 found that low cholesterol was related to all-cause mortality, even when adjusted for health status and indicators of frailty. The reasons for this relationship are not clear, but some postulated mechanisms exist. It is possible that lower cholesterol levels can increase the risk of a variety of nonatherosclerotic diseases since cholesterol may play a direct role in immune response. Alternatively, preclinical diseases, chronic inflammation, or malnutrition may suppress cholesterol levels.⁴

Recommendations from others

National Cholesterol Education Program Adult Treatment Panel III guidelines¹ outline risk identification and management of hyperlipidemia in all age groups with no exceptions noted for the very elderly. A recent scientific statement from the American Heart Association¹² outlined the data on the implementation of all primary and secondary prevention guidelines for the elderly and emphasized that the latest cholesterol treatment recommendations should be applied to all eligible adults, with no exceptions for the very elderly.

Evidence summary

CAD is the leading cause of death in the United States and is a significant cause of mortality and morbidity for those aged 65 years and older. Multiple studies have demonstrated the value of lipid-lowering therapy for the primary and secondary prevention of CAD. Most of these studies have not been specifically oriented toward the elderly; however, substantial data from subgroup analyses of older subjects from major lipid treatment trials has consistently demonstrated the beneficial effects of statin therapy in reducing all cardiovascular events for patients with known CAD who are 65 and older.^2-7

Unfortunately, randomized trials of hyperlipidemia treatment with statins have enrolled few people aged 80 and above. Hence, it is unclear whether the benefit of statins on cardiovascular mortality extends to advanced elderly patients. These people comprise the fastest-growing segment of the population, increasing by about 3% per year. They tend to experience concomitant chronic illness, shorter life expectancy, and physical frailty, leading to quality-of-life and end-of-life issues. Is it beneficial and cost-effective to treat these very elderly patients for hyperlipidemia?

The first prospective, randomized trial⁸ of the use of statins among the elderly examined the impact of pravastatin therapy on primary and secondary prevention of cardiovascular and cerebrovascular events for men and women (age 70–82 years), with a history of vascular disease or with risk factors for vascular disease. The sample of 5804 participants was randomized to receive pravastatin 40 mg or placebo, followed for an average of 3.2 years, and monitored for the combined endpoint of myocardial infarction (MI), stroke, and CAD death. The study showed 19% (95% confidence interval [CI], 6–31; P=.006) proportional reduction in the rate of coronary death or nonfatal MI. The absolute risk reduction for coronary death or nonfatal myocardial infarction or nonfatal stroke was significant (2.2%, number needed to treat [NNT]=45). Rates of adverse drug events were similar in the intervention and control groups.⁸

Serum cholesterol normally declines with age; so the benefit of lowering lipids with medication in this age group is unclear. Furthermore, a meta-analysis⁹ showed an inverse relationship between total serum cholesterol and all-cause mortality for people aged 80 and above, raising the possibility that lowering cholesterol may be detrimental in this age group. Two other cohort studies^10,11 found that low cholesterol was related to all-cause mortality, even when adjusted for health status and indicators of frailty. The reasons for this relationship are not clear, but some postulated mechanisms exist. It is possible that lower cholesterol levels can increase the risk of a variety of nonatherosclerotic diseases since cholesterol may play a direct role in immune response. Alternatively, preclinical diseases, chronic inflammation, or malnutrition may suppress cholesterol levels.⁴

Recommendations from others

National Cholesterol Education Program Adult Treatment Panel III guidelines¹ outline risk identification and management of hyperlipidemia in all age groups with no exceptions noted for the very elderly. A recent scientific statement from the American Heart Association¹² outlined the data on the implementation of all primary and secondary prevention guidelines for the elderly and emphasized that the latest cholesterol treatment recommendations should be applied to all eligible adults, with no exceptions for the very elderly.

Evidence summary

CAD is the leading cause of death in the United States and is a significant cause of mortality and morbidity for those aged 65 years and older. Multiple studies have demonstrated the value of lipid-lowering therapy for the primary and secondary prevention of CAD. Most of these studies have not been specifically oriented toward the elderly; however, substantial data from subgroup analyses of older subjects from major lipid treatment trials has consistently demonstrated the beneficial effects of statin therapy in reducing all cardiovascular events for patients with known CAD who are 65 and older.^2-7

Unfortunately, randomized trials of hyperlipidemia treatment with statins have enrolled few people aged 80 and above. Hence, it is unclear whether the benefit of statins on cardiovascular mortality extends to advanced elderly patients. These people comprise the fastest-growing segment of the population, increasing by about 3% per year. They tend to experience concomitant chronic illness, shorter life expectancy, and physical frailty, leading to quality-of-life and end-of-life issues. Is it beneficial and cost-effective to treat these very elderly patients for hyperlipidemia?

The first prospective, randomized trial⁸ of the use of statins among the elderly examined the impact of pravastatin therapy on primary and secondary prevention of cardiovascular and cerebrovascular events for men and women (age 70–82 years), with a history of vascular disease or with risk factors for vascular disease. The sample of 5804 participants was randomized to receive pravastatin 40 mg or placebo, followed for an average of 3.2 years, and monitored for the combined endpoint of myocardial infarction (MI), stroke, and CAD death. The study showed 19% (95% confidence interval [CI], 6–31; P=.006) proportional reduction in the rate of coronary death or nonfatal MI. The absolute risk reduction for coronary death or nonfatal myocardial infarction or nonfatal stroke was significant (2.2%, number needed to treat [NNT]=45). Rates of adverse drug events were similar in the intervention and control groups.⁸

Serum cholesterol normally declines with age; so the benefit of lowering lipids with medication in this age group is unclear. Furthermore, a meta-analysis⁹ showed an inverse relationship between total serum cholesterol and all-cause mortality for people aged 80 and above, raising the possibility that lowering cholesterol may be detrimental in this age group. Two other cohort studies^10,11 found that low cholesterol was related to all-cause mortality, even when adjusted for health status and indicators of frailty. The reasons for this relationship are not clear, but some postulated mechanisms exist. It is possible that lower cholesterol levels can increase the risk of a variety of nonatherosclerotic diseases since cholesterol may play a direct role in immune response. Alternatively, preclinical diseases, chronic inflammation, or malnutrition may suppress cholesterol levels.⁴

Recommendations from others

National Cholesterol Education Program Adult Treatment Panel III guidelines¹ outline risk identification and management of hyperlipidemia in all age groups with no exceptions noted for the very elderly. A recent scientific statement from the American Heart Association¹² outlined the data on the implementation of all primary and secondary prevention guidelines for the elderly and emphasized that the latest cholesterol treatment recommendations should be applied to all eligible adults, with no exceptions for the very elderly.

Evidence summary

Oral therapies for common warts suffer from a lack rigorous clinical data regarding their efficacy. A detailed literature search found multiple trials evaluating various oral agents. However, only 6 trials met the selection criteria of randomized, controlled trials published in English.

Cimetidine (Tagamet) has been compared with placebo in 3 trials^1-3 and was not found superior to placebo. Levamisole (Ergamisol), used in combination with cimetidine, has been compared with cimetidine alone in 2 trials,^4,5 and was found to be effective at speeding regression of warts, with patients in the combination arm showing a mean regression time of 7.8 weeks compared with 11 weeks in the cimetidine alone group. These small studies involved 48 and 44 patients, respectively. In addition, 1 nonrandomized controlled trial⁶ found levamisole at 5 mg/kg for 3 days every 2 weeks to be superior to placebo in achieving complete cure of warts in a group of 40 patients.

Zinc is the only agent to demonstrate efficacy in a completely randomized and placebo-controlled study.⁷ However, this trial was unblinded, had only 40 subjects assigned to each agent, had a dropout rate of 46%, and did not follow intention-to-treat analysis.

Recommendations from others

Clinical Evidence lists cimetidine and levamisole as therapies of unknown effectiveness.⁸ The commentary on both agents notes that the size of each randomized controlled trial cited may have been too small to detect clinically important differences.

Evidence summary

Oral therapies for common warts suffer from a lack rigorous clinical data regarding their efficacy. A detailed literature search found multiple trials evaluating various oral agents. However, only 6 trials met the selection criteria of randomized, controlled trials published in English.

Cimetidine (Tagamet) has been compared with placebo in 3 trials^1-3 and was not found superior to placebo. Levamisole (Ergamisol), used in combination with cimetidine, has been compared with cimetidine alone in 2 trials,^4,5 and was found to be effective at speeding regression of warts, with patients in the combination arm showing a mean regression time of 7.8 weeks compared with 11 weeks in the cimetidine alone group. These small studies involved 48 and 44 patients, respectively. In addition, 1 nonrandomized controlled trial⁶ found levamisole at 5 mg/kg for 3 days every 2 weeks to be superior to placebo in achieving complete cure of warts in a group of 40 patients.

Zinc is the only agent to demonstrate efficacy in a completely randomized and placebo-controlled study.⁷ However, this trial was unblinded, had only 40 subjects assigned to each agent, had a dropout rate of 46%, and did not follow intention-to-treat analysis.

Recommendations from others

Clinical Evidence lists cimetidine and levamisole as therapies of unknown effectiveness.⁸ The commentary on both agents notes that the size of each randomized controlled trial cited may have been too small to detect clinically important differences.

Evidence summary

Oral therapies for common warts suffer from a lack rigorous clinical data regarding their efficacy. A detailed literature search found multiple trials evaluating various oral agents. However, only 6 trials met the selection criteria of randomized, controlled trials published in English.

Cimetidine (Tagamet) has been compared with placebo in 3 trials^1-3 and was not found superior to placebo. Levamisole (Ergamisol), used in combination with cimetidine, has been compared with cimetidine alone in 2 trials,^4,5 and was found to be effective at speeding regression of warts, with patients in the combination arm showing a mean regression time of 7.8 weeks compared with 11 weeks in the cimetidine alone group. These small studies involved 48 and 44 patients, respectively. In addition, 1 nonrandomized controlled trial⁶ found levamisole at 5 mg/kg for 3 days every 2 weeks to be superior to placebo in achieving complete cure of warts in a group of 40 patients.

Zinc is the only agent to demonstrate efficacy in a completely randomized and placebo-controlled study.⁷ However, this trial was unblinded, had only 40 subjects assigned to each agent, had a dropout rate of 46%, and did not follow intention-to-treat analysis.

Recommendations from others

Clinical Evidence lists cimetidine and levamisole as therapies of unknown effectiveness.⁸ The commentary on both agents notes that the size of each randomized controlled trial cited may have been too small to detect clinically important differences.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

TABLE
Differential diagnosis of hyperandrogenism in PCOS

Evidence summary

Polycystic ovarian syndrome is a condition of unexplained hyperandrogenic chronic anovulation that affects at least 4% of women of reproductive age.¹ Because PCOS is a clinical syndrome, no single diagnostic criterion is sufficient for diagnosis.² Clinical features include menstrual irregularities or infertility, hirsutism, male-pattern balding, acne, ovarian enlargement, and signs of insulin resistance (eg, central obesity, acanthosis nigricans). A 2003 international consensus panel concluded that the presence of 2 of 3 criteria (oligo/anovulation, hyperandrogenism, polycystic ovaries), in the absence of other secondary causes, is sufficient to make the diagnosis.² Evidence for hyperandrogenism includes hirsutism, acne, or elevated total testosterone levels.³ A high luteinizing hormone/follicle-stimulating hormone (LH/FSH) ratio supports the diagnosis. However, because this measure varies considerably in relation to ovulation, body-mass index (BMI), and the particular measurement assay used, the consensus panel recommended against its use as a diagnostic criterion.² Based on optimum receiver operator characteristic curve analyses, ultrasound criteria include the presence of 12 or more follicles in each ovary measuring 2 to 9 mm in diameter (sensitivity=75%, specificity=99%, positive predictive value [PPV]=75%, negative predictive value [NPV]=99%, assuming 4% prevalence) or ovarian volume over 7 mL (sensitivity=67.5%, specificity=91.2%, PPV=24%, NPV 99%).^4,5

PCOS is also a diagnosis of exclusion. Secondary causes of hyperandrogenism may be suggested by clinical findings, including 1) abrupt onset, short duration, or sudden progressive worsening of hirsutism; 2) onset of symptoms in the third decade of life or later; or 3) signs of virilization (deepening voice, clitoromegaly).⁶ The differential diagnosis, clinical features and potentially useful diagnostic tests to rule out secondary causes are shown in the TABLE.

Women with PCOS often experience insulin resistance, and are at increased risk for developing type 2 diabetes, dyslipidemia, and cardiovascular disease. One cross-sectional study⁷ of 122 women with PCOS between 13.5 and 40 years of age found that 35% had impaired glucose tolerance, and another 10% had non-insulindependent diabetes. A prospective case-control study⁸ of young women (aged <35 years) found that compared with age- and BMI-matched controls, those with PCOS had higher levels of fasting glucose, insulin, total and low-density lipoprotein cholesterol, and altered left ventricular mass and cardiac function on echocardiogram. Once PCOS is suspected, the diagnostic work-up should include a 2-hour glucose tolerance test and lipid panel to assess cardiovascular risk, particularly among obese women.

Recommendations from others

A 2002 American College of Obstetricians and Gynecologists guideline⁹ adopted the 1990 National Institutes of Health consensus panel criteria for diagnosing PCOS (ie, chronic anovulation and clinical or biochemical signs of hyperandrogenism, excluding other causes), and recommends that all patients have documentation of elevated testosterone levels; thyroid-stimulating hormone (TSH), prolactin, and 17-hydroxyprogesterone levels to exclude secondary causes of hyperandrogenism; and evaluation for metabolic abnormalities with a 2-hour glucose tolerance test and fasting lipid panel.

Evidence summary

More than 50 million individuals in the United States have genital herpes. The diagnosis of genital herpes based on clinical history and physical examination is often inaccurate.¹ Clinical suspicion needs to be confirmed by laboratory testing because it has a direct impact on counseling and prognosis.²

Viral culture is still the gold standard test for the detection of HSV; however, the rate of positive cultures depends on the stage of the lesion, the quality of the specimen, and the transport conditions. A British study³ found the rate of virus recovery for early vesicles to be 52% to 93%. This dropped to 41% to 72% if midstage ulcers were present. Finally, the detection for late-stage crusted lesions was only 19% to 27%. Another disadvantage is that culture is labor-intensive. A positive culture takes an average of 3 days to grow, whereas a negative culture must incubate for 10 days.³

PCR techniques are more sensitive and results can be available in less than 4 hours.³ In 110 clinical samples from dermal or genital lesions of patients with suspected HSV infection, the sensitivity of PCR was 98% (positive likelihood ratio [LR+]=∞; negative likelihood ratio [LR–]=0.02) compared with 73% (LR+ = ∞; LR– = 0.27) for culture. The specificities of both were 100%.⁴ In London, 233 samples from patients at a genitourinary medicine clinic were tested with both viral culture and PCR. HSV was detected in 79 samples by culture and 132 samples by PCR. The detection by PCR was higher in early as well as late stages of infection and in both first and recurrent episodes.³ The reference standard for these studies was not an independent standard, but a positive result on both tests or modified versions of the PCR test. The use of a version of the test of interest (PCR) as part of the reference standard, while probably unavoidable in this situation, will tend inflate the sensitivity and specificity.

In another study, daily sampling of lesions in patients with known HSV infections detected HSV DNA on 15 of 17 days with PCR and only 3 of 17 days with culture.¹ This suggests that PCR is more effective in detecting early, as well as late, stages of infection. Currently PCR is more expensive, but it may become cheaper because of decreased labor expense when compared with culture.

Genital herpes may also be detected with enzyme immunoassay testing in as little as 5 hours. In a study⁵ using 275 samples from genital lesions, HSV was detected in 65% of the antigen tests and 53% of the viral cultures. The sensitivity of this method is equal to culture for early lesions, but much higher in late-stage lesions (58% vs 26%).⁵

Serologic tests are often used to detect HSV because they can differentiate between HSV-1 and HSV-2. There is an FDA-approved point-of-care test called POCkit that gives results from capillary blood or serum during an office visit. These tests are 80% to 98% sensitive and more than 96% specific. Unfortunately, they are not readily available in all countries.²

Other detection methods include the Tzanck smear, which is only 40% to 50% sensitive compared with culture, and the Pap smear, which is 60% to 70% sensitive.⁶ These tests should not be the sole method for the diagnosis of HSV. They cannot differentiate between HSV 1 and HSV 2; furthermore, the Tzanck prep will give a positive result if varicella zoster virus is present.⁶ If these tests are positive, confirmatory testing specific for HSV should be performed.

Recommendations from others

The Centers for Disease Control and Prevention⁷ recommends screening with a viral culture when a genital lesion is present, however, the sensitivity declines rapidly within a few days as the lesion begins to heal. To collect a sample the lesion must be unroofed using a Dacron swab, which is then placed in a viral transport medium and processed within 24 hours. Swabs containing calcium agglutinate are toxic to HSV.⁶ Type-specific antibodies develop during the first several weeks and can be detected with serologic tests; however, these may be falsely negative in the early stages of a primary infection.⁷

The US Preventative Services Task Force⁸ recommends against routine serologic screening for HSV in asymptomatic adolescents and adults. They also recommend against routine screening of asymptomatic pregnant women at any time during pregnancy as a way to decrease neonatal transmission.⁸

Evidence summary

More than 50 million individuals in the United States have genital herpes. The diagnosis of genital herpes based on clinical history and physical examination is often inaccurate.¹ Clinical suspicion needs to be confirmed by laboratory testing because it has a direct impact on counseling and prognosis.²

Viral culture is still the gold standard test for the detection of HSV; however, the rate of positive cultures depends on the stage of the lesion, the quality of the specimen, and the transport conditions. A British study³ found the rate of virus recovery for early vesicles to be 52% to 93%. This dropped to 41% to 72% if midstage ulcers were present. Finally, the detection for late-stage crusted lesions was only 19% to 27%. Another disadvantage is that culture is labor-intensive. A positive culture takes an average of 3 days to grow, whereas a negative culture must incubate for 10 days.³

PCR techniques are more sensitive and results can be available in less than 4 hours.³ In 110 clinical samples from dermal or genital lesions of patients with suspected HSV infection, the sensitivity of PCR was 98% (positive likelihood ratio [LR+]=∞; negative likelihood ratio [LR–]=0.02) compared with 73% (LR+ = ∞; LR– = 0.27) for culture. The specificities of both were 100%.⁴ In London, 233 samples from patients at a genitourinary medicine clinic were tested with both viral culture and PCR. HSV was detected in 79 samples by culture and 132 samples by PCR. The detection by PCR was higher in early as well as late stages of infection and in both first and recurrent episodes.³ The reference standard for these studies was not an independent standard, but a positive result on both tests or modified versions of the PCR test. The use of a version of the test of interest (PCR) as part of the reference standard, while probably unavoidable in this situation, will tend inflate the sensitivity and specificity.

In another study, daily sampling of lesions in patients with known HSV infections detected HSV DNA on 15 of 17 days with PCR and only 3 of 17 days with culture.¹ This suggests that PCR is more effective in detecting early, as well as late, stages of infection. Currently PCR is more expensive, but it may become cheaper because of decreased labor expense when compared with culture.

Genital herpes may also be detected with enzyme immunoassay testing in as little as 5 hours. In a study⁵ using 275 samples from genital lesions, HSV was detected in 65% of the antigen tests and 53% of the viral cultures. The sensitivity of this method is equal to culture for early lesions, but much higher in late-stage lesions (58% vs 26%).⁵

Serologic tests are often used to detect HSV because they can differentiate between HSV-1 and HSV-2. There is an FDA-approved point-of-care test called POCkit that gives results from capillary blood or serum during an office visit. These tests are 80% to 98% sensitive and more than 96% specific. Unfortunately, they are not readily available in all countries.²

Other detection methods include the Tzanck smear, which is only 40% to 50% sensitive compared with culture, and the Pap smear, which is 60% to 70% sensitive.⁶ These tests should not be the sole method for the diagnosis of HSV. They cannot differentiate between HSV 1 and HSV 2; furthermore, the Tzanck prep will give a positive result if varicella zoster virus is present.⁶ If these tests are positive, confirmatory testing specific for HSV should be performed.

Recommendations from others

The Centers for Disease Control and Prevention⁷ recommends screening with a viral culture when a genital lesion is present, however, the sensitivity declines rapidly within a few days as the lesion begins to heal. To collect a sample the lesion must be unroofed using a Dacron swab, which is then placed in a viral transport medium and processed within 24 hours. Swabs containing calcium agglutinate are toxic to HSV.⁶ Type-specific antibodies develop during the first several weeks and can be detected with serologic tests; however, these may be falsely negative in the early stages of a primary infection.⁷

The US Preventative Services Task Force⁸ recommends against routine serologic screening for HSV in asymptomatic adolescents and adults. They also recommend against routine screening of asymptomatic pregnant women at any time during pregnancy as a way to decrease neonatal transmission.⁸

Evidence summary

More than 50 million individuals in the United States have genital herpes. The diagnosis of genital herpes based on clinical history and physical examination is often inaccurate.¹ Clinical suspicion needs to be confirmed by laboratory testing because it has a direct impact on counseling and prognosis.²

Viral culture is still the gold standard test for the detection of HSV; however, the rate of positive cultures depends on the stage of the lesion, the quality of the specimen, and the transport conditions. A British study³ found the rate of virus recovery for early vesicles to be 52% to 93%. This dropped to 41% to 72% if midstage ulcers were present. Finally, the detection for late-stage crusted lesions was only 19% to 27%. Another disadvantage is that culture is labor-intensive. A positive culture takes an average of 3 days to grow, whereas a negative culture must incubate for 10 days.³

PCR techniques are more sensitive and results can be available in less than 4 hours.³ In 110 clinical samples from dermal or genital lesions of patients with suspected HSV infection, the sensitivity of PCR was 98% (positive likelihood ratio [LR+]=∞; negative likelihood ratio [LR–]=0.02) compared with 73% (LR+ = ∞; LR– = 0.27) for culture. The specificities of both were 100%.⁴ In London, 233 samples from patients at a genitourinary medicine clinic were tested with both viral culture and PCR. HSV was detected in 79 samples by culture and 132 samples by PCR. The detection by PCR was higher in early as well as late stages of infection and in both first and recurrent episodes.³ The reference standard for these studies was not an independent standard, but a positive result on both tests or modified versions of the PCR test. The use of a version of the test of interest (PCR) as part of the reference standard, while probably unavoidable in this situation, will tend inflate the sensitivity and specificity.

In another study, daily sampling of lesions in patients with known HSV infections detected HSV DNA on 15 of 17 days with PCR and only 3 of 17 days with culture.¹ This suggests that PCR is more effective in detecting early, as well as late, stages of infection. Currently PCR is more expensive, but it may become cheaper because of decreased labor expense when compared with culture.

Genital herpes may also be detected with enzyme immunoassay testing in as little as 5 hours. In a study⁵ using 275 samples from genital lesions, HSV was detected in 65% of the antigen tests and 53% of the viral cultures. The sensitivity of this method is equal to culture for early lesions, but much higher in late-stage lesions (58% vs 26%).⁵

Serologic tests are often used to detect HSV because they can differentiate between HSV-1 and HSV-2. There is an FDA-approved point-of-care test called POCkit that gives results from capillary blood or serum during an office visit. These tests are 80% to 98% sensitive and more than 96% specific. Unfortunately, they are not readily available in all countries.²

Other detection methods include the Tzanck smear, which is only 40% to 50% sensitive compared with culture, and the Pap smear, which is 60% to 70% sensitive.⁶ These tests should not be the sole method for the diagnosis of HSV. They cannot differentiate between HSV 1 and HSV 2; furthermore, the Tzanck prep will give a positive result if varicella zoster virus is present.⁶ If these tests are positive, confirmatory testing specific for HSV should be performed.

Recommendations from others

The Centers for Disease Control and Prevention⁷ recommends screening with a viral culture when a genital lesion is present, however, the sensitivity declines rapidly within a few days as the lesion begins to heal. To collect a sample the lesion must be unroofed using a Dacron swab, which is then placed in a viral transport medium and processed within 24 hours. Swabs containing calcium agglutinate are toxic to HSV.⁶ Type-specific antibodies develop during the first several weeks and can be detected with serologic tests; however, these may be falsely negative in the early stages of a primary infection.⁷

The US Preventative Services Task Force⁸ recommends against routine serologic screening for HSV in asymptomatic adolescents and adults. They also recommend against routine screening of asymptomatic pregnant women at any time during pregnancy as a way to decrease neonatal transmission.⁸

TABLE 1
Contraindications to empiric antibiotics for urinary tract infection (telephone treatment)

Evidence summary

An evidence-based review¹ found 5 high-quality studies on the diagnosis of acute uncomplicated UTI among women. (“Uncomplicated” was defined as normal urinary tract and no contributing medical problems, such as diabetes, neurogenic bladder, renal stones.) UTIs were defined as the presence of significant bacteriuria (≥10⁴ to 10⁵ colony-forming units) on culture. A patient presenting to a clinician with 1 or more UTI symptoms had approximately a 50% chance of having significant bacteriuria on culture.¹ The authors estimated the pretest probability of UTI as 5% from the incidence of asymptomatic bacteriuria among healthy women.^1,2 This produced a LR+ of 19 simply for presenting to a clinician with 1 or more UTI symptoms.¹ The summary LRs for clinical signs and symptoms in the prediction of UTI after presentation to the office are found in TABLE 2. A history of a vaginal discharge or irritation has a LR– of 0.3, decreasing the probability of UTI for a patient presenting to the office from approximately 50% to 20%, so further testing would be indicated.¹

No single sign or symptom accurately predicted UTI. However, the triad of dysuria with frequency but without vaginal symptoms increased the probability of significant bacteriuria on culture from 50% to 96% (LR+=24.6).¹ In contrast, a 1999 review of 51 studies calculated that if both the nitrites and leukocyte esterase are positive on urine dipstick testing, the LR+ is 4.2; if both are negative the LR– is 0.3.^1,3 Since the probability of UTI for patients with the symptom triad is so high, dipstick urinalysis is unlikely to alter management regardless of whether nitrites and leukocyte esterase were both positive or negative (posttest probability=98%–99% and 80%, respectively). If urine dipstick or other office-based tests are not needed to make the diagnosis of uncomplicated UTI for a patient with the classic triad of symptoms, then telephone treatment based on symptoms may be reasonable. Women who have recurrent UTIs (2 or more culture positive UTIs over the previous 12 months) can accurately self-diagnose subsequent UTIs based on symptoms (LR+=4.0).^4,5

A recent retrospective case series⁶ evaluated a telephone guideline for the empiric treatment of UTI for 4177 women in a California HMO. UTI criteria were ≤10 days of dysuria; frequency, urgency, pressure, or increased nocturia; or gross hematuria. Women were excluded if they had any one of a variety of contraindications (TABLE 1). Upper tract infection occurred in 21 patients (1.1%) within 60 days of telephone treatment, two thirds of which likely represented treatment failures. This is similar to rates in control groups of other studies. Fourteen women (1.5%) received care for sexually transmitted diseases or other gynecologic conditions, primarily bacterial vaginitis, within 60 days of telephone treatment. Of note, 6% of the cohort were elderly, diabetic, taking glucocorticoids or early in pregnancy and are typically excluded from other studies. This higher-risk group did not have an increased incidence of either sepsis or pyelonephritis.⁶ No increase in adverse outcomes was seen in another study of a telephone treatment protocol.⁷

Several studies^6-8 have noted that telephone treatment protocols increase the use of protocol-recommended antibiotics (eg, generally less expensive agents such as trimethoprim-sulfamethoxazole), which may help limit resistance to fluoroquinolones. However, specific data are not available.

McIssac et al⁹ reviewed a cohort of 231 women presenting to family physicians’ offices with uncomplicated cystitis symptoms. Empiric therapy resulted in approximately 40% of women unnecessarily receiving antibiotics. Treating only women with classic cystitis symptoms and pyuria would have decreased the unnecessary use of antibiotics to 26.2%, but fewer women with confirmed cystitis would have received immediate antibiotics (66.4% vs 91.8%). They derived a clinical decision rule designed to balance false positives and false negatives. It recommends immediate antibiotic treatment if women have ≥2 of 4 signs or symptoms: dysuria, leukocyte esterase (greater than trace), positive nitrites, or blood (greater than trace) on dipstick (LR+=2.29). Otherwise the rule recommends a culture to guide antibiotic therapy. This decision rule would have reduced unnecessary antibiotic use by 27.5% while ensuring that more women with confirmed UTIs received immediate antibiotics (81.3%).

In 1999, Saint et al⁸ estimated savings of $367,000 for 147,000 women enrolled over 1 year after widespread guideline implementation. Two cost-effectiveness studies^10,11 of office treatment concluded that empiric treatment without additional testing is the least costly option in this setting. However, a recent, comprehensive cost-effectiveness study¹¹ concluded that if a patient presents to an office, the marginal cost of performing a pelvic examination and urine culture for women with a negative dipstick was relatively low ($4 to $32 per symptom day avoided).

TABLE 2
Diagnosis of urinary tract infection

Recommendations from others

A 2002 Institute for Clinical Systems Improvement guideline¹² advised offering telephone treatment of uncomplicated UTI for low-risk patients if preferred by both provider and patient.

TABLE 1
Contraindications to empiric antibiotics for urinary tract infection (telephone treatment)

Evidence summary

An evidence-based review¹ found 5 high-quality studies on the diagnosis of acute uncomplicated UTI among women. (“Uncomplicated” was defined as normal urinary tract and no contributing medical problems, such as diabetes, neurogenic bladder, renal stones.) UTIs were defined as the presence of significant bacteriuria (≥10⁴ to 10⁵ colony-forming units) on culture. A patient presenting to a clinician with 1 or more UTI symptoms had approximately a 50% chance of having significant bacteriuria on culture.¹ The authors estimated the pretest probability of UTI as 5% from the incidence of asymptomatic bacteriuria among healthy women.^1,2 This produced a LR+ of 19 simply for presenting to a clinician with 1 or more UTI symptoms.¹ The summary LRs for clinical signs and symptoms in the prediction of UTI after presentation to the office are found in TABLE 2. A history of a vaginal discharge or irritation has a LR– of 0.3, decreasing the probability of UTI for a patient presenting to the office from approximately 50% to 20%, so further testing would be indicated.¹

No single sign or symptom accurately predicted UTI. However, the triad of dysuria with frequency but without vaginal symptoms increased the probability of significant bacteriuria on culture from 50% to 96% (LR+=24.6).¹ In contrast, a 1999 review of 51 studies calculated that if both the nitrites and leukocyte esterase are positive on urine dipstick testing, the LR+ is 4.2; if both are negative the LR– is 0.3.^1,3 Since the probability of UTI for patients with the symptom triad is so high, dipstick urinalysis is unlikely to alter management regardless of whether nitrites and leukocyte esterase were both positive or negative (posttest probability=98%–99% and 80%, respectively). If urine dipstick or other office-based tests are not needed to make the diagnosis of uncomplicated UTI for a patient with the classic triad of symptoms, then telephone treatment based on symptoms may be reasonable. Women who have recurrent UTIs (2 or more culture positive UTIs over the previous 12 months) can accurately self-diagnose subsequent UTIs based on symptoms (LR+=4.0).^4,5

A recent retrospective case series⁶ evaluated a telephone guideline for the empiric treatment of UTI for 4177 women in a California HMO. UTI criteria were ≤10 days of dysuria; frequency, urgency, pressure, or increased nocturia; or gross hematuria. Women were excluded if they had any one of a variety of contraindications (TABLE 1). Upper tract infection occurred in 21 patients (1.1%) within 60 days of telephone treatment, two thirds of which likely represented treatment failures. This is similar to rates in control groups of other studies. Fourteen women (1.5%) received care for sexually transmitted diseases or other gynecologic conditions, primarily bacterial vaginitis, within 60 days of telephone treatment. Of note, 6% of the cohort were elderly, diabetic, taking glucocorticoids or early in pregnancy and are typically excluded from other studies. This higher-risk group did not have an increased incidence of either sepsis or pyelonephritis.⁶ No increase in adverse outcomes was seen in another study of a telephone treatment protocol.⁷

Several studies^6-8 have noted that telephone treatment protocols increase the use of protocol-recommended antibiotics (eg, generally less expensive agents such as trimethoprim-sulfamethoxazole), which may help limit resistance to fluoroquinolones. However, specific data are not available.

McIssac et al⁹ reviewed a cohort of 231 women presenting to family physicians’ offices with uncomplicated cystitis symptoms. Empiric therapy resulted in approximately 40% of women unnecessarily receiving antibiotics. Treating only women with classic cystitis symptoms and pyuria would have decreased the unnecessary use of antibiotics to 26.2%, but fewer women with confirmed cystitis would have received immediate antibiotics (66.4% vs 91.8%). They derived a clinical decision rule designed to balance false positives and false negatives. It recommends immediate antibiotic treatment if women have ≥2 of 4 signs or symptoms: dysuria, leukocyte esterase (greater than trace), positive nitrites, or blood (greater than trace) on dipstick (LR+=2.29). Otherwise the rule recommends a culture to guide antibiotic therapy. This decision rule would have reduced unnecessary antibiotic use by 27.5% while ensuring that more women with confirmed UTIs received immediate antibiotics (81.3%).

In 1999, Saint et al⁸ estimated savings of $367,000 for 147,000 women enrolled over 1 year after widespread guideline implementation. Two cost-effectiveness studies^10,11 of office treatment concluded that empiric treatment without additional testing is the least costly option in this setting. However, a recent, comprehensive cost-effectiveness study¹¹ concluded that if a patient presents to an office, the marginal cost of performing a pelvic examination and urine culture for women with a negative dipstick was relatively low ($4 to $32 per symptom day avoided).

TABLE 2
Diagnosis of urinary tract infection

Recommendations from others

A 2002 Institute for Clinical Systems Improvement guideline¹² advised offering telephone treatment of uncomplicated UTI for low-risk patients if preferred by both provider and patient.

TABLE 1
Contraindications to empiric antibiotics for urinary tract infection (telephone treatment)

Evidence summary

An evidence-based review¹ found 5 high-quality studies on the diagnosis of acute uncomplicated UTI among women. (“Uncomplicated” was defined as normal urinary tract and no contributing medical problems, such as diabetes, neurogenic bladder, renal stones.) UTIs were defined as the presence of significant bacteriuria (≥10⁴ to 10⁵ colony-forming units) on culture. A patient presenting to a clinician with 1 or more UTI symptoms had approximately a 50% chance of having significant bacteriuria on culture.¹ The authors estimated the pretest probability of UTI as 5% from the incidence of asymptomatic bacteriuria among healthy women.^1,2 This produced a LR+ of 19 simply for presenting to a clinician with 1 or more UTI symptoms.¹ The summary LRs for clinical signs and symptoms in the prediction of UTI after presentation to the office are found in TABLE 2. A history of a vaginal discharge or irritation has a LR– of 0.3, decreasing the probability of UTI for a patient presenting to the office from approximately 50% to 20%, so further testing would be indicated.¹

No single sign or symptom accurately predicted UTI. However, the triad of dysuria with frequency but without vaginal symptoms increased the probability of significant bacteriuria on culture from 50% to 96% (LR+=24.6).¹ In contrast, a 1999 review of 51 studies calculated that if both the nitrites and leukocyte esterase are positive on urine dipstick testing, the LR+ is 4.2; if both are negative the LR– is 0.3.^1,3 Since the probability of UTI for patients with the symptom triad is so high, dipstick urinalysis is unlikely to alter management regardless of whether nitrites and leukocyte esterase were both positive or negative (posttest probability=98%–99% and 80%, respectively). If urine dipstick or other office-based tests are not needed to make the diagnosis of uncomplicated UTI for a patient with the classic triad of symptoms, then telephone treatment based on symptoms may be reasonable. Women who have recurrent UTIs (2 or more culture positive UTIs over the previous 12 months) can accurately self-diagnose subsequent UTIs based on symptoms (LR+=4.0).^4,5

A recent retrospective case series⁶ evaluated a telephone guideline for the empiric treatment of UTI for 4177 women in a California HMO. UTI criteria were ≤10 days of dysuria; frequency, urgency, pressure, or increased nocturia; or gross hematuria. Women were excluded if they had any one of a variety of contraindications (TABLE 1). Upper tract infection occurred in 21 patients (1.1%) within 60 days of telephone treatment, two thirds of which likely represented treatment failures. This is similar to rates in control groups of other studies. Fourteen women (1.5%) received care for sexually transmitted diseases or other gynecologic conditions, primarily bacterial vaginitis, within 60 days of telephone treatment. Of note, 6% of the cohort were elderly, diabetic, taking glucocorticoids or early in pregnancy and are typically excluded from other studies. This higher-risk group did not have an increased incidence of either sepsis or pyelonephritis.⁶ No increase in adverse outcomes was seen in another study of a telephone treatment protocol.⁷

Several studies^6-8 have noted that telephone treatment protocols increase the use of protocol-recommended antibiotics (eg, generally less expensive agents such as trimethoprim-sulfamethoxazole), which may help limit resistance to fluoroquinolones. However, specific data are not available.

McIssac et al⁹ reviewed a cohort of 231 women presenting to family physicians’ offices with uncomplicated cystitis symptoms. Empiric therapy resulted in approximately 40% of women unnecessarily receiving antibiotics. Treating only women with classic cystitis symptoms and pyuria would have decreased the unnecessary use of antibiotics to 26.2%, but fewer women with confirmed cystitis would have received immediate antibiotics (66.4% vs 91.8%). They derived a clinical decision rule designed to balance false positives and false negatives. It recommends immediate antibiotic treatment if women have ≥2 of 4 signs or symptoms: dysuria, leukocyte esterase (greater than trace), positive nitrites, or blood (greater than trace) on dipstick (LR+=2.29). Otherwise the rule recommends a culture to guide antibiotic therapy. This decision rule would have reduced unnecessary antibiotic use by 27.5% while ensuring that more women with confirmed UTIs received immediate antibiotics (81.3%).

In 1999, Saint et al⁸ estimated savings of $367,000 for 147,000 women enrolled over 1 year after widespread guideline implementation. Two cost-effectiveness studies^10,11 of office treatment concluded that empiric treatment without additional testing is the least costly option in this setting. However, a recent, comprehensive cost-effectiveness study¹¹ concluded that if a patient presents to an office, the marginal cost of performing a pelvic examination and urine culture for women with a negative dipstick was relatively low ($4 to $32 per symptom day avoided).

TABLE 2
Diagnosis of urinary tract infection

Recommendations from others

A 2002 Institute for Clinical Systems Improvement guideline¹² advised offering telephone treatment of uncomplicated UTI for low-risk patients if preferred by both provider and patient.

Evidence summary

Three large cohort studies determined that cryptorchidism (FIGURE) is present at birth in approximately 3% of term infants (higher in preterm infants), with spontaneous descent occurring in two thirds of cases by age 3 to 6 months. One study¹ of 10,730 consecutive male term infants found cryptorchidism at birth in 2.7%, dropping to 1.22% by 6 months of age, but without further change at 1 year. A similar study² followed 6935 infant boys, finding cryptorchidism at birth in 3.7%, which decreased to 1% at 3 months and remained unchanged at 1 year. A third study³ found cryptorchidism at birth in 90 of 6414 (2.7%) infant boys. At follow-up, 45 of 90 had testicular descent at 1 month, 60 of 90 at 3 months, 67 of 90 at 9 months and at 1 year.

The 2 main indications for orchiopexy are potential avoidance of infertility and early detection and treatment of testicular cancer. A literature review⁴ of fertility after orchiopexy for undescended testis found inconclusive results. While epidemiological and pathological data (testicular biopsy, hormonal analysis, and sperm counts performed after orchiopexy) predict diminished fertility potential for men with unilaterally undescended testes, studies evaluating paternity find no difference from normal men. Biopsy studies of undescended testes at the time of orchiopexy show increased incidence of germ cell aplasia with older age at surgery (0.5%, 2%, 20%, and 45% at 6, 12, 24, and 48 months, respectively).⁴ A retrospective cohort study⁵ found 87% successful paternity after orchiopexy for 24 patients with unilateral undescended testis and 33% success for 9 with bilateral undescended testes but there was no normal control group. The boys were aged 1 to 14 years (mean, 7 years) at surgery, and there was no relationship between timing of orchiopexy and paternity success.⁵

The benefits of orchiopexy for testicular cancer are also unclear; expert opinion suggests that orchiopexy may allow earlier detection of testicular tumors.⁶ A cohort study⁷ of boys with cryptorchidism showed an increased risk of testicular cancer (relative risk=5.2). However, risk did not decrease after orchiopexy in early childhood. A retrospective cohort study⁸ of 137 men with cryptorchidism who developed testicular cancer found no difference in 5-year survival between those who had orchiopexy (at ages 2 to 42) and those who had not (61% vs 63%, respectively).

FIGURE
Cryptorchidism

Recommendations from others

The American Academy of Pediatrics policy section on urology says that spontaneous descent after 6 months is unlikely and recommends orchiopexy by 1 year of age.⁹

Evidence summary

Three large cohort studies determined that cryptorchidism (FIGURE) is present at birth in approximately 3% of term infants (higher in preterm infants), with spontaneous descent occurring in two thirds of cases by age 3 to 6 months. One study¹ of 10,730 consecutive male term infants found cryptorchidism at birth in 2.7%, dropping to 1.22% by 6 months of age, but without further change at 1 year. A similar study² followed 6935 infant boys, finding cryptorchidism at birth in 3.7%, which decreased to 1% at 3 months and remained unchanged at 1 year. A third study³ found cryptorchidism at birth in 90 of 6414 (2.7%) infant boys. At follow-up, 45 of 90 had testicular descent at 1 month, 60 of 90 at 3 months, 67 of 90 at 9 months and at 1 year.

The 2 main indications for orchiopexy are potential avoidance of infertility and early detection and treatment of testicular cancer. A literature review⁴ of fertility after orchiopexy for undescended testis found inconclusive results. While epidemiological and pathological data (testicular biopsy, hormonal analysis, and sperm counts performed after orchiopexy) predict diminished fertility potential for men with unilaterally undescended testes, studies evaluating paternity find no difference from normal men. Biopsy studies of undescended testes at the time of orchiopexy show increased incidence of germ cell aplasia with older age at surgery (0.5%, 2%, 20%, and 45% at 6, 12, 24, and 48 months, respectively).⁴ A retrospective cohort study⁵ found 87% successful paternity after orchiopexy for 24 patients with unilateral undescended testis and 33% success for 9 with bilateral undescended testes but there was no normal control group. The boys were aged 1 to 14 years (mean, 7 years) at surgery, and there was no relationship between timing of orchiopexy and paternity success.⁵

The benefits of orchiopexy for testicular cancer are also unclear; expert opinion suggests that orchiopexy may allow earlier detection of testicular tumors.⁶ A cohort study⁷ of boys with cryptorchidism showed an increased risk of testicular cancer (relative risk=5.2). However, risk did not decrease after orchiopexy in early childhood. A retrospective cohort study⁸ of 137 men with cryptorchidism who developed testicular cancer found no difference in 5-year survival between those who had orchiopexy (at ages 2 to 42) and those who had not (61% vs 63%, respectively).

FIGURE
Cryptorchidism

Recommendations from others

The American Academy of Pediatrics policy section on urology says that spontaneous descent after 6 months is unlikely and recommends orchiopexy by 1 year of age.⁹

Evidence summary

Three large cohort studies determined that cryptorchidism (FIGURE) is present at birth in approximately 3% of term infants (higher in preterm infants), with spontaneous descent occurring in two thirds of cases by age 3 to 6 months. One study¹ of 10,730 consecutive male term infants found cryptorchidism at birth in 2.7%, dropping to 1.22% by 6 months of age, but without further change at 1 year. A similar study² followed 6935 infant boys, finding cryptorchidism at birth in 3.7%, which decreased to 1% at 3 months and remained unchanged at 1 year. A third study³ found cryptorchidism at birth in 90 of 6414 (2.7%) infant boys. At follow-up, 45 of 90 had testicular descent at 1 month, 60 of 90 at 3 months, 67 of 90 at 9 months and at 1 year.

The 2 main indications for orchiopexy are potential avoidance of infertility and early detection and treatment of testicular cancer. A literature review⁴ of fertility after orchiopexy for undescended testis found inconclusive results. While epidemiological and pathological data (testicular biopsy, hormonal analysis, and sperm counts performed after orchiopexy) predict diminished fertility potential for men with unilaterally undescended testes, studies evaluating paternity find no difference from normal men. Biopsy studies of undescended testes at the time of orchiopexy show increased incidence of germ cell aplasia with older age at surgery (0.5%, 2%, 20%, and 45% at 6, 12, 24, and 48 months, respectively).⁴ A retrospective cohort study⁵ found 87% successful paternity after orchiopexy for 24 patients with unilateral undescended testis and 33% success for 9 with bilateral undescended testes but there was no normal control group. The boys were aged 1 to 14 years (mean, 7 years) at surgery, and there was no relationship between timing of orchiopexy and paternity success.⁵

The benefits of orchiopexy for testicular cancer are also unclear; expert opinion suggests that orchiopexy may allow earlier detection of testicular tumors.⁶ A cohort study⁷ of boys with cryptorchidism showed an increased risk of testicular cancer (relative risk=5.2). However, risk did not decrease after orchiopexy in early childhood. A retrospective cohort study⁸ of 137 men with cryptorchidism who developed testicular cancer found no difference in 5-year survival between those who had orchiopexy (at ages 2 to 42) and those who had not (61% vs 63%, respectively).

FIGURE
Cryptorchidism

Recommendations from others

The American Academy of Pediatrics policy section on urology says that spontaneous descent after 6 months is unlikely and recommends orchiopexy by 1 year of age.⁹

Evidence summary

A Cochrane review⁴ (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.

Another Cochrane review⁵ (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.

Two Cochrane reviews^6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).⁷ The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.

Similar cardiovascular adverse events were reported in the APPROVE trial.⁹ In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.¹⁰ This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).

Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).¹¹ A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.¹² This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.

TABLE 1
Prediction of serious gastrointestinal bleeding

Recommendations from others

The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.¹³ For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.

The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).^14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.

A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.¹⁶ It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.

TABLE 2
Risk factors for upper gastrointestinal adverse events

Evidence summary

A Cochrane review⁴ (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.

Another Cochrane review⁵ (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.

Two Cochrane reviews^6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).⁷ The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.

Similar cardiovascular adverse events were reported in the APPROVE trial.⁹ In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.¹⁰ This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).

Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).¹¹ A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.¹² This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.

TABLE 1
Prediction of serious gastrointestinal bleeding

Recommendations from others

The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.¹³ For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.

The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).^14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.

A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.¹⁶ It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.

TABLE 2
Risk factors for upper gastrointestinal adverse events

Evidence summary

A Cochrane review⁴ (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.

Another Cochrane review⁵ (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.

Two Cochrane reviews^6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).⁷ The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.

Similar cardiovascular adverse events were reported in the APPROVE trial.⁹ In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.¹⁰ This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).

Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).¹¹ A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.¹² This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.

TABLE 1
Prediction of serious gastrointestinal bleeding

Recommendations from others

The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.¹³ For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.

The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).^14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.

A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.¹⁶ It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.

TABLE 2
Risk factors for upper gastrointestinal adverse events

Evidence summary

Tinea cruris (“jock itch”) is a superficial dermatophyte infection of the groin and surrounding skin. Obese adult men are affected more than women, and it is rarely seen in children. Because excessive perspiration is the most common predisposing factor, patient education on proper hygiene makes intuitive sense for successful treatment, yet it has not been studied.¹Trichophyton rubrum is the most common source of tinea cruris, as well as tinea corporis (“ringworm”), in the United States.² Most studies involving patients with tinea cruris combine data with tinea corporis.

Although more than 25 RCTs document the safety and efficacy of antifungal treatments, few head-to-head trials are available. Several topical preparations are approved for the treatment of tinea cruris. Selection should be based on patient compliance (duration of treatment), overall cost, and tolerability. The 2 main classes of antifungals are allylamines and azoles.

Allylamines. Allylamines offer a shorter duration of therapy, lower relapse rates, and work independent of the cytochrome P450 system. Multiple RCTs have documented the efficacy and safety of the 2 available allylamine antifungals, terbinafine and naftifine, when compared with placebo and various azoles.

Terbinafine is available in several 1% formulations (emulsion-gel, cream, and solution/spray), all studied and dosed once daily for 1 week. One placebo controlled trial showed the 1% emulsion-gel version (Lamisil) was effective in 89% of the study population vs 23% of the placebo group (NNT=1.5); it was particularly suitable on hairy skin. Seven weeks post-treatment, 84% of the intent-to-treat population of the Lamisil group remained mycologically negative.³ Data combined from 2 other RCTs yielded 83% efficacy 3 weeks post-treatment when 66 patients were treated with terbinafine 1% cream, compared with 12% efficacy for 73 patients using the vehicle cream (NNT=1.4).⁴ Another placebo-controlled study of 66 patients demonstrated 100% microscopic cure of terbinafine 1% solution by week 2 and maintaining 90% cure at 4 weeks.⁵

In a multicenter, double-blind RCT funded by the manufacturers of terbinafine, bifonazole 1% cream for 3 weeks was compared with terbinafine 1% cream used daily for 1 week (followed by 2 weeks of its vehicle cream). Mycological and clinical cure rates were greater than 95% in both groups at 3 weeks. At the 8-week follow-up, no statistically significant differences were seen in KOH positivity rates (20.24% of patients in the bifonazole-treated group were KOH-positive vs 11.76% in the terbinafine group). Symptom relapse rates at 8 weeks were not available.⁶

In a 4-week study involving 104 patients, naftifine 1% cream (Naftin) was compared with econazole 1% cream (Spectazole) (both applied twice daily). At the end of the study, naftifine 1% cream had a higher (but not statistically significant) mycological and clinical cure rate of 78% compared with 68% with econazole 1% cream.⁷ Similar results (79% mycological cure) were seen in a placebo-controlled trial with 70 patients using once daily naftifine 1% cream after 2 weeks of treatment (NNT=2).⁸

Butenafine (Mentax), a benzylamine antifungal, was 88% to 93% mycologically effective in a noncomparative study, when used twice daily for 2 weeks.⁹ Similar results were found in a study of 76 patients with tinea cruris; after 2 weeks of daily application, 78% (modified intent-to-treat group) were mycologically cured. Mycological cure plus “cleared” or “excellent” clinical evaluation remained for 73% at day 42 vs 5% of the placebo group (NNT=1.47).¹⁰

Azoles. Azoles are less expensive than allylamines, but require longer treatment periods, theoretically compromising patient adherence to therapy. One of the more popular azoles is clotrimazole (Lotrimin, Mycelex), one of the oldest antifungal treatments. One RCT compared cure rates for 139 patients for clotrimazole 1% cream compared with ciclopirox olamine 1% cream when both were applied twice daily for 28 days. By the end of the 4-week period, 69% of the clotrimazole group was clinically and mycologically cured compared with 64% of the ciclopirox group.¹¹

Miconazole 2% cream (Micatin, Monistat) (used twice daily for 2 weeks by inmates in a Florida prison) demonstrated 75.5% clinical clearing (against tinea cruris, pedis, or corporis, or Candida cutaneous infections) when compared with placebo (NNT=1.57). Of the 99 patients evaluated, 48 were diagnosed with tinea cruris; however, results were not broken down into diagnostic category. The length of follow-up for these patients was not disclosed.¹²

Alternative therapy. Ajoene 0.6% gel (isolated from garlic), was as effective as terbinafine 1% cream (both applied twice daily for 2 weeks) in a RCT of 60 Venezuelan Army soldiers.¹³ Sixty days after treatment, 73% of the Ajoene-treated patients and 71% in the terbinafine group were asymptomatic. An open-pilot study of 14 patients with tinea cruris demonstrated 71% mycological cure with a honey, olive oil, and beeswax (1:1:1) mixture, applied 3 times daily up to 3 weeks, likely due to honey’s inhibitory effect on fungus and beeswax’s anti-inflammatory properties.¹⁴

Recommendations from others

The Sanford Guide to Antimicrobial Therapy (2005) recommends topical butenafine and terbinafine as primary agents of choice for tinea cruris due to their fungicidal activity.¹⁵ The American Academy of Family Physicians recommends any of the topical antifungal treatments as first-line treatment for tinea cruris.¹⁶ A systematic review on tinea pedis topical therapy acknowledges the higher cure rates by allylamines, compared with azoles, but concludes that azoles remain the most costeffective in the treatment of tinea pedis.¹⁷ No recent guidelines from the American Academy of Dermatology are available.

Evidence summary

Tinea cruris (“jock itch”) is a superficial dermatophyte infection of the groin and surrounding skin. Obese adult men are affected more than women, and it is rarely seen in children. Because excessive perspiration is the most common predisposing factor, patient education on proper hygiene makes intuitive sense for successful treatment, yet it has not been studied.¹Trichophyton rubrum is the most common source of tinea cruris, as well as tinea corporis (“ringworm”), in the United States.² Most studies involving patients with tinea cruris combine data with tinea corporis.

Although more than 25 RCTs document the safety and efficacy of antifungal treatments, few head-to-head trials are available. Several topical preparations are approved for the treatment of tinea cruris. Selection should be based on patient compliance (duration of treatment), overall cost, and tolerability. The 2 main classes of antifungals are allylamines and azoles.

Allylamines. Allylamines offer a shorter duration of therapy, lower relapse rates, and work independent of the cytochrome P450 system. Multiple RCTs have documented the efficacy and safety of the 2 available allylamine antifungals, terbinafine and naftifine, when compared with placebo and various azoles.

Terbinafine is available in several 1% formulations (emulsion-gel, cream, and solution/spray), all studied and dosed once daily for 1 week. One placebo controlled trial showed the 1% emulsion-gel version (Lamisil) was effective in 89% of the study population vs 23% of the placebo group (NNT=1.5); it was particularly suitable on hairy skin. Seven weeks post-treatment, 84% of the intent-to-treat population of the Lamisil group remained mycologically negative.³ Data combined from 2 other RCTs yielded 83% efficacy 3 weeks post-treatment when 66 patients were treated with terbinafine 1% cream, compared with 12% efficacy for 73 patients using the vehicle cream (NNT=1.4).⁴ Another placebo-controlled study of 66 patients demonstrated 100% microscopic cure of terbinafine 1% solution by week 2 and maintaining 90% cure at 4 weeks.⁵

In a multicenter, double-blind RCT funded by the manufacturers of terbinafine, bifonazole 1% cream for 3 weeks was compared with terbinafine 1% cream used daily for 1 week (followed by 2 weeks of its vehicle cream). Mycological and clinical cure rates were greater than 95% in both groups at 3 weeks. At the 8-week follow-up, no statistically significant differences were seen in KOH positivity rates (20.24% of patients in the bifonazole-treated group were KOH-positive vs 11.76% in the terbinafine group). Symptom relapse rates at 8 weeks were not available.⁶

In a 4-week study involving 104 patients, naftifine 1% cream (Naftin) was compared with econazole 1% cream (Spectazole) (both applied twice daily). At the end of the study, naftifine 1% cream had a higher (but not statistically significant) mycological and clinical cure rate of 78% compared with 68% with econazole 1% cream.⁷ Similar results (79% mycological cure) were seen in a placebo-controlled trial with 70 patients using once daily naftifine 1% cream after 2 weeks of treatment (NNT=2).⁸

Butenafine (Mentax), a benzylamine antifungal, was 88% to 93% mycologically effective in a noncomparative study, when used twice daily for 2 weeks.⁹ Similar results were found in a study of 76 patients with tinea cruris; after 2 weeks of daily application, 78% (modified intent-to-treat group) were mycologically cured. Mycological cure plus “cleared” or “excellent” clinical evaluation remained for 73% at day 42 vs 5% of the placebo group (NNT=1.47).¹⁰

Azoles. Azoles are less expensive than allylamines, but require longer treatment periods, theoretically compromising patient adherence to therapy. One of the more popular azoles is clotrimazole (Lotrimin, Mycelex), one of the oldest antifungal treatments. One RCT compared cure rates for 139 patients for clotrimazole 1% cream compared with ciclopirox olamine 1% cream when both were applied twice daily for 28 days. By the end of the 4-week period, 69% of the clotrimazole group was clinically and mycologically cured compared with 64% of the ciclopirox group.¹¹

Miconazole 2% cream (Micatin, Monistat) (used twice daily for 2 weeks by inmates in a Florida prison) demonstrated 75.5% clinical clearing (against tinea cruris, pedis, or corporis, or Candida cutaneous infections) when compared with placebo (NNT=1.57). Of the 99 patients evaluated, 48 were diagnosed with tinea cruris; however, results were not broken down into diagnostic category. The length of follow-up for these patients was not disclosed.¹²

Alternative therapy. Ajoene 0.6% gel (isolated from garlic), was as effective as terbinafine 1% cream (both applied twice daily for 2 weeks) in a RCT of 60 Venezuelan Army soldiers.¹³ Sixty days after treatment, 73% of the Ajoene-treated patients and 71% in the terbinafine group were asymptomatic. An open-pilot study of 14 patients with tinea cruris demonstrated 71% mycological cure with a honey, olive oil, and beeswax (1:1:1) mixture, applied 3 times daily up to 3 weeks, likely due to honey’s inhibitory effect on fungus and beeswax’s anti-inflammatory properties.¹⁴

Recommendations from others

The Sanford Guide to Antimicrobial Therapy (2005) recommends topical butenafine and terbinafine as primary agents of choice for tinea cruris due to their fungicidal activity.¹⁵ The American Academy of Family Physicians recommends any of the topical antifungal treatments as first-line treatment for tinea cruris.¹⁶ A systematic review on tinea pedis topical therapy acknowledges the higher cure rates by allylamines, compared with azoles, but concludes that azoles remain the most costeffective in the treatment of tinea pedis.¹⁷ No recent guidelines from the American Academy of Dermatology are available.

Evidence summary

Tinea cruris (“jock itch”) is a superficial dermatophyte infection of the groin and surrounding skin. Obese adult men are affected more than women, and it is rarely seen in children. Because excessive perspiration is the most common predisposing factor, patient education on proper hygiene makes intuitive sense for successful treatment, yet it has not been studied.¹Trichophyton rubrum is the most common source of tinea cruris, as well as tinea corporis (“ringworm”), in the United States.² Most studies involving patients with tinea cruris combine data with tinea corporis.

Although more than 25 RCTs document the safety and efficacy of antifungal treatments, few head-to-head trials are available. Several topical preparations are approved for the treatment of tinea cruris. Selection should be based on patient compliance (duration of treatment), overall cost, and tolerability. The 2 main classes of antifungals are allylamines and azoles.

Allylamines. Allylamines offer a shorter duration of therapy, lower relapse rates, and work independent of the cytochrome P450 system. Multiple RCTs have documented the efficacy and safety of the 2 available allylamine antifungals, terbinafine and naftifine, when compared with placebo and various azoles.

Terbinafine is available in several 1% formulations (emulsion-gel, cream, and solution/spray), all studied and dosed once daily for 1 week. One placebo controlled trial showed the 1% emulsion-gel version (Lamisil) was effective in 89% of the study population vs 23% of the placebo group (NNT=1.5); it was particularly suitable on hairy skin. Seven weeks post-treatment, 84% of the intent-to-treat population of the Lamisil group remained mycologically negative.³ Data combined from 2 other RCTs yielded 83% efficacy 3 weeks post-treatment when 66 patients were treated with terbinafine 1% cream, compared with 12% efficacy for 73 patients using the vehicle cream (NNT=1.4).⁴ Another placebo-controlled study of 66 patients demonstrated 100% microscopic cure of terbinafine 1% solution by week 2 and maintaining 90% cure at 4 weeks.⁵

In a multicenter, double-blind RCT funded by the manufacturers of terbinafine, bifonazole 1% cream for 3 weeks was compared with terbinafine 1% cream used daily for 1 week (followed by 2 weeks of its vehicle cream). Mycological and clinical cure rates were greater than 95% in both groups at 3 weeks. At the 8-week follow-up, no statistically significant differences were seen in KOH positivity rates (20.24% of patients in the bifonazole-treated group were KOH-positive vs 11.76% in the terbinafine group). Symptom relapse rates at 8 weeks were not available.⁶

In a 4-week study involving 104 patients, naftifine 1% cream (Naftin) was compared with econazole 1% cream (Spectazole) (both applied twice daily). At the end of the study, naftifine 1% cream had a higher (but not statistically significant) mycological and clinical cure rate of 78% compared with 68% with econazole 1% cream.⁷ Similar results (79% mycological cure) were seen in a placebo-controlled trial with 70 patients using once daily naftifine 1% cream after 2 weeks of treatment (NNT=2).⁸

Butenafine (Mentax), a benzylamine antifungal, was 88% to 93% mycologically effective in a noncomparative study, when used twice daily for 2 weeks.⁹ Similar results were found in a study of 76 patients with tinea cruris; after 2 weeks of daily application, 78% (modified intent-to-treat group) were mycologically cured. Mycological cure plus “cleared” or “excellent” clinical evaluation remained for 73% at day 42 vs 5% of the placebo group (NNT=1.47).¹⁰

Azoles. Azoles are less expensive than allylamines, but require longer treatment periods, theoretically compromising patient adherence to therapy. One of the more popular azoles is clotrimazole (Lotrimin, Mycelex), one of the oldest antifungal treatments. One RCT compared cure rates for 139 patients for clotrimazole 1% cream compared with ciclopirox olamine 1% cream when both were applied twice daily for 28 days. By the end of the 4-week period, 69% of the clotrimazole group was clinically and mycologically cured compared with 64% of the ciclopirox group.¹¹

Miconazole 2% cream (Micatin, Monistat) (used twice daily for 2 weeks by inmates in a Florida prison) demonstrated 75.5% clinical clearing (against tinea cruris, pedis, or corporis, or Candida cutaneous infections) when compared with placebo (NNT=1.57). Of the 99 patients evaluated, 48 were diagnosed with tinea cruris; however, results were not broken down into diagnostic category. The length of follow-up for these patients was not disclosed.¹²

Alternative therapy. Ajoene 0.6% gel (isolated from garlic), was as effective as terbinafine 1% cream (both applied twice daily for 2 weeks) in a RCT of 60 Venezuelan Army soldiers.¹³ Sixty days after treatment, 73% of the Ajoene-treated patients and 71% in the terbinafine group were asymptomatic. An open-pilot study of 14 patients with tinea cruris demonstrated 71% mycological cure with a honey, olive oil, and beeswax (1:1:1) mixture, applied 3 times daily up to 3 weeks, likely due to honey’s inhibitory effect on fungus and beeswax’s anti-inflammatory properties.¹⁴

Recommendations from others

The Sanford Guide to Antimicrobial Therapy (2005) recommends topical butenafine and terbinafine as primary agents of choice for tinea cruris due to their fungicidal activity.¹⁵ The American Academy of Family Physicians recommends any of the topical antifungal treatments as first-line treatment for tinea cruris.¹⁶ A systematic review on tinea pedis topical therapy acknowledges the higher cure rates by allylamines, compared with azoles, but concludes that azoles remain the most costeffective in the treatment of tinea pedis.¹⁷ No recent guidelines from the American Academy of Dermatology are available.

Evidence summary

Aggregated data from 2 randomized reflux esophagitis trials conducted in the United Kingdom were analyzed with respect to patient age. Comparison of symptom relief and esophageal lesion healing showed that elderly patients treated with omeprazole (Prilosec) fared better than those treated with either cimetidine (Tagamet) or ranitidine (Zantac).² The pooled data involved 555 patients with endoscopically proven reflux esophagitis, 154 of whom were over the age of 65. After 8 weeks, rates of esophageal healing among the elderly were 70% for those receiving omeprazole and 29% for those receiving H2RAs (41% difference; 95% confidence interval [CI], 26–55), while the rate of asymptomatic elderly patients was 79% for the omeprazole group and 51% for the H2RA group (28% difference; 95% CI, 12–44).³ Patients treated with omeprazole healed faster than those taking H2RAs, as shown by endoscopy, and more of them experienced symptom relief.

A multicenter, randomized, double-blind trial of GERD maintenance therapy started with an initial open phase in which elderly patients with GERD and documented esophagitis were treated and then had documented resolution of esophagitis by endoscopy after 6 months. The researchers then randomized 105 of these elderly patients to receive treatment with either low-dose (20 mg/d) pantoprazole or placebo for 6 months. Endoscopy was performed after 12 months for all patients, unless indicated sooner. Intention-to-treat analysis showed a disease-free rate of 79.6% (95% CI, 68.3–90.9) in the treatment group, compared with 30.4% (95% CI, 18.3–42.4) in the placebo group (number needed to treat [NNT]=2). Symptom reports concerning the same patients also suggest a marked drop in symptoms that correlated with healing.⁴

A prospective, nonequivalence, before-after study compared efficacy of, and complications from, laparoscopic surgery for symptomatic GERD between younger and older (≥65 years) patients. The investigators examined postoperative morbidity and mortality for 359 patients referred for laparoscopic surgery, either a partial or Nissen (full) fundoplication. They excluded those requiring more extensive surgery or repair of paraesophageal hernia. The 42 elderly patients had a higher mean American Society of Anesthesiologists score compared with the younger patients, reflecting higher preoperative comorbidity, but were similar with regard to weight and gender.

Before surgery, investigators performed 24-hour ambulatory pH monitoring. Preoperative exposure times to a pH below 4 (TpH <4) were similar for the younger and older patients (median 14.2% and 13.9%, respectively). Postoperative complication rates were similar for both groups. No deaths occurred. Minor postoperative complications involved 7% of the elderly patients and 6% of the younger group. The 24-hour pH monitoring scores showed improvement at 6 weeks after surgery for both groups, with the median TpH <4 at 1.1% (95% CL, 0.5) in the elderly vs a median of 1.8% (95% CL, 1.9) in the younger patients. At 1 year postoperatively, the values were also similar between the two groups; the median TpH <4 (95% CL) were 1.4% (1.5) in the elderly group and 1.2% (0.6) in the younger patient group.

The results of this study should be interpreted with caution, however. The study design is prone to bias, the patients had relatively low symptom scores at baseline, and sicker patients may have been excluded during the referral process.⁵

TABLE
Warning signs and symptoms of dyspepsia and GERD that suggest complicated disease or more serious underlying process¹

Recommendations from others

The Veterans Health Affairs/Department of Defense clinical practice guidelines recommend differentiating GERD (feelings of substernal burning associated with acid regurgitation) from dyspepsia (chronic or recurrent discomfort centered in the upper abdomen), of which GERD is a subset.⁶ The guidelines recommend gastroenterology consultation or upper endoscopy to rule out neoplastic or pre-neoplastic lesions if alarm symptoms (TABLE) suggesting complicated GERD are present.⁷

The Institute for Clinical Systems Improvement guidelines on dyspepsia and GERD recommend that all patients aged ≥50 years with symptoms of uncomplicated dyspepsia undergo upper endoscopy non-urgently because of the increased incidence of peptic ulcer disease, pre-neoplastic lesions, malignancy, and increased morbidity out of proportion to symptoms that are more common in an older patient population. The guidelines also recommend endoscopy for patients aged ≥50 years with uncomplicated GERD and the presence of symptoms for greater than 10 years because of the increased risk of pre-neoplastic and neoplastic lesions, including Barrett’s esophagus.⁸

Evidence summary

Aggregated data from 2 randomized reflux esophagitis trials conducted in the United Kingdom were analyzed with respect to patient age. Comparison of symptom relief and esophageal lesion healing showed that elderly patients treated with omeprazole (Prilosec) fared better than those treated with either cimetidine (Tagamet) or ranitidine (Zantac).² The pooled data involved 555 patients with endoscopically proven reflux esophagitis, 154 of whom were over the age of 65. After 8 weeks, rates of esophageal healing among the elderly were 70% for those receiving omeprazole and 29% for those receiving H2RAs (41% difference; 95% confidence interval [CI], 26–55), while the rate of asymptomatic elderly patients was 79% for the omeprazole group and 51% for the H2RA group (28% difference; 95% CI, 12–44).³ Patients treated with omeprazole healed faster than those taking H2RAs, as shown by endoscopy, and more of them experienced symptom relief.

A multicenter, randomized, double-blind trial of GERD maintenance therapy started with an initial open phase in which elderly patients with GERD and documented esophagitis were treated and then had documented resolution of esophagitis by endoscopy after 6 months. The researchers then randomized 105 of these elderly patients to receive treatment with either low-dose (20 mg/d) pantoprazole or placebo for 6 months. Endoscopy was performed after 12 months for all patients, unless indicated sooner. Intention-to-treat analysis showed a disease-free rate of 79.6% (95% CI, 68.3–90.9) in the treatment group, compared with 30.4% (95% CI, 18.3–42.4) in the placebo group (number needed to treat [NNT]=2). Symptom reports concerning the same patients also suggest a marked drop in symptoms that correlated with healing.⁴

A prospective, nonequivalence, before-after study compared efficacy of, and complications from, laparoscopic surgery for symptomatic GERD between younger and older (≥65 years) patients. The investigators examined postoperative morbidity and mortality for 359 patients referred for laparoscopic surgery, either a partial or Nissen (full) fundoplication. They excluded those requiring more extensive surgery or repair of paraesophageal hernia. The 42 elderly patients had a higher mean American Society of Anesthesiologists score compared with the younger patients, reflecting higher preoperative comorbidity, but were similar with regard to weight and gender.

Before surgery, investigators performed 24-hour ambulatory pH monitoring. Preoperative exposure times to a pH below 4 (TpH <4) were similar for the younger and older patients (median 14.2% and 13.9%, respectively). Postoperative complication rates were similar for both groups. No deaths occurred. Minor postoperative complications involved 7% of the elderly patients and 6% of the younger group. The 24-hour pH monitoring scores showed improvement at 6 weeks after surgery for both groups, with the median TpH <4 at 1.1% (95% CL, 0.5) in the elderly vs a median of 1.8% (95% CL, 1.9) in the younger patients. At 1 year postoperatively, the values were also similar between the two groups; the median TpH <4 (95% CL) were 1.4% (1.5) in the elderly group and 1.2% (0.6) in the younger patient group.

The results of this study should be interpreted with caution, however. The study design is prone to bias, the patients had relatively low symptom scores at baseline, and sicker patients may have been excluded during the referral process.⁵

TABLE
Warning signs and symptoms of dyspepsia and GERD that suggest complicated disease or more serious underlying process¹

Recommendations from others

The Veterans Health Affairs/Department of Defense clinical practice guidelines recommend differentiating GERD (feelings of substernal burning associated with acid regurgitation) from dyspepsia (chronic or recurrent discomfort centered in the upper abdomen), of which GERD is a subset.⁶ The guidelines recommend gastroenterology consultation or upper endoscopy to rule out neoplastic or pre-neoplastic lesions if alarm symptoms (TABLE) suggesting complicated GERD are present.⁷

The Institute for Clinical Systems Improvement guidelines on dyspepsia and GERD recommend that all patients aged ≥50 years with symptoms of uncomplicated dyspepsia undergo upper endoscopy non-urgently because of the increased incidence of peptic ulcer disease, pre-neoplastic lesions, malignancy, and increased morbidity out of proportion to symptoms that are more common in an older patient population. The guidelines also recommend endoscopy for patients aged ≥50 years with uncomplicated GERD and the presence of symptoms for greater than 10 years because of the increased risk of pre-neoplastic and neoplastic lesions, including Barrett’s esophagus.⁸

Evidence summary

Aggregated data from 2 randomized reflux esophagitis trials conducted in the United Kingdom were analyzed with respect to patient age. Comparison of symptom relief and esophageal lesion healing showed that elderly patients treated with omeprazole (Prilosec) fared better than those treated with either cimetidine (Tagamet) or ranitidine (Zantac).² The pooled data involved 555 patients with endoscopically proven reflux esophagitis, 154 of whom were over the age of 65. After 8 weeks, rates of esophageal healing among the elderly were 70% for those receiving omeprazole and 29% for those receiving H2RAs (41% difference; 95% confidence interval [CI], 26–55), while the rate of asymptomatic elderly patients was 79% for the omeprazole group and 51% for the H2RA group (28% difference; 95% CI, 12–44).³ Patients treated with omeprazole healed faster than those taking H2RAs, as shown by endoscopy, and more of them experienced symptom relief.

A multicenter, randomized, double-blind trial of GERD maintenance therapy started with an initial open phase in which elderly patients with GERD and documented esophagitis were treated and then had documented resolution of esophagitis by endoscopy after 6 months. The researchers then randomized 105 of these elderly patients to receive treatment with either low-dose (20 mg/d) pantoprazole or placebo for 6 months. Endoscopy was performed after 12 months for all patients, unless indicated sooner. Intention-to-treat analysis showed a disease-free rate of 79.6% (95% CI, 68.3–90.9) in the treatment group, compared with 30.4% (95% CI, 18.3–42.4) in the placebo group (number needed to treat [NNT]=2). Symptom reports concerning the same patients also suggest a marked drop in symptoms that correlated with healing.⁴

A prospective, nonequivalence, before-after study compared efficacy of, and complications from, laparoscopic surgery for symptomatic GERD between younger and older (≥65 years) patients. The investigators examined postoperative morbidity and mortality for 359 patients referred for laparoscopic surgery, either a partial or Nissen (full) fundoplication. They excluded those requiring more extensive surgery or repair of paraesophageal hernia. The 42 elderly patients had a higher mean American Society of Anesthesiologists score compared with the younger patients, reflecting higher preoperative comorbidity, but were similar with regard to weight and gender.

Before surgery, investigators performed 24-hour ambulatory pH monitoring. Preoperative exposure times to a pH below 4 (TpH <4) were similar for the younger and older patients (median 14.2% and 13.9%, respectively). Postoperative complication rates were similar for both groups. No deaths occurred. Minor postoperative complications involved 7% of the elderly patients and 6% of the younger group. The 24-hour pH monitoring scores showed improvement at 6 weeks after surgery for both groups, with the median TpH <4 at 1.1% (95% CL, 0.5) in the elderly vs a median of 1.8% (95% CL, 1.9) in the younger patients. At 1 year postoperatively, the values were also similar between the two groups; the median TpH <4 (95% CL) were 1.4% (1.5) in the elderly group and 1.2% (0.6) in the younger patient group.

The results of this study should be interpreted with caution, however. The study design is prone to bias, the patients had relatively low symptom scores at baseline, and sicker patients may have been excluded during the referral process.⁵

TABLE
Warning signs and symptoms of dyspepsia and GERD that suggest complicated disease or more serious underlying process¹

Recommendations from others

The Veterans Health Affairs/Department of Defense clinical practice guidelines recommend differentiating GERD (feelings of substernal burning associated with acid regurgitation) from dyspepsia (chronic or recurrent discomfort centered in the upper abdomen), of which GERD is a subset.⁶ The guidelines recommend gastroenterology consultation or upper endoscopy to rule out neoplastic or pre-neoplastic lesions if alarm symptoms (TABLE) suggesting complicated GERD are present.⁷

The Institute for Clinical Systems Improvement guidelines on dyspepsia and GERD recommend that all patients aged ≥50 years with symptoms of uncomplicated dyspepsia undergo upper endoscopy non-urgently because of the increased incidence of peptic ulcer disease, pre-neoplastic lesions, malignancy, and increased morbidity out of proportion to symptoms that are more common in an older patient population. The guidelines also recommend endoscopy for patients aged ≥50 years with uncomplicated GERD and the presence of symptoms for greater than 10 years because of the increased risk of pre-neoplastic and neoplastic lesions, including Barrett’s esophagus.⁸

Evidence summary

Barrett’s esophagus has been defined as “a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus.”¹ Intestinal metaplasia is a premalignant lesion for adenocarcinoma of the esophagus. Surveillance by serial endoscopy with biopsy has been recommended in an effort to find high-grade dysplasia or carcinoma in an early, asymptomatic, and potentially curable stage.^1-4 Approximately 75% of patients involved in a Barrett’s esophagus surveillance program will present with resectable tumors, compared with only 25% of those not receiving surveillance.⁴

A recent systematic review assessing screening tools for esophageal carcinoma found standard endoscopy to be superior (90%–100% sensitivity) to other less invasive methods such as questionnaire (60%–70%), and fecal occult blood testing (20%).⁴ Additional endoscopy tools such as brush and balloon cytology increased the cost of surveillance without any improvement in diagnostic yield.

The degree of dysplasia on esophageal biopsy in Barrett’s esophagus patients is currently the best indicator of risk of progression to esophageal carcinoma. The data reviewed by the ACG for the practice guideline was drawn from several prospective studies and one available registry. In sum, a total of 783 Barrett’s esophagus patients were followed for a mean of 2.9 to 7.3 years. Esophageal carcinoma developed in 2% of patients with no dysplasia, 7% of patients with low-grade dysplasia (LGD) and 22% of patients with high-grade dysplasia (HGD).¹ The ACG recommendations regarding frequency of esophagogastroduodenoscopy (EGD) were not based on an explicit critical appraisal of the literature. Recent cohort studies are consistent with recommendations for graded surveillance frequency. A randomized clinical trial to determine optimal endoscopic frequency and benefit has not been reported.

Several concerns have been raised regarding the utility of degree of dysplasia in determining optimal frequency of endoscopic surveillance. First, the progression of esophageal lesions over time is unpredictable. Skacel et al⁵ reported a series of 34 patients with LGD at initial pathologic examination. On subsequent surveillance endoscopy with repeat biopsy, 73% no longer demonstrated dysplasia. Such patients can be allowed to return to having surveillance every 3 years.

In addition to the non-linear progression of dysplasia, inter-rater reliability of the interpretation of pathology specimens varies substantially. Adequate reliability has been demonstrated among pathologists assigning results to 2 categories (either no dysplasia and LGD or HGD and carcinoma) (κ=0.7). Assignment to four distinct pathologic grades, however, was not reliable (κ=0.46, where 1.0 is complete agreement).¹ In order to make a diagnosis of HGD or carcinoma, interpretation must be independently confirmed by 2 expert pathologists.^1-3

Recommendations for frequent endoscopic surveillance are also weakened by the overall low rate of mortality from esophageal carcinoma noted in Barrett’s esophagus patients. A recent population based study demonstrated that there was no difference in overall mortality in those with a Barrett’s esophagus diagnosis compared with the general population.⁶ An increased risk of death from esophageal carcinoma was seen in patients with Barrett’s esophagus (4.7% seen in Barrett’s esophagus patients compared with 0.8% predicted in the general population; P<.05). The overall increased effect on mortality, however, was relatively small. Esophageal carcinoma accounted for less then 5% of deaths in Barrett’s esophagus patients reported during the study’s 6-year follow-up period.

Data from prospective studies published after 2002 may better predict prognosis for Barrett’s esophagus patients.^6-9 Even lower rates of progression to esophageal carcinoma (<0.5% a year or <1/220 patient-years) have been reported in these studies drawing from the general population rather than referred patients, likely stemming from differences in gender mix, patient age, and risk factors.

In addition to grade of dysplasia, the length of the dysplastic Barrett’s esophagus segment is emerging as a potentially predictive risk factor. While the ACG cautions that esophageal cancer has been reported in patients with so-called “short segment” Barrett’s esophagus (SSBE) (≤3 cm),¹ recent prospective studies have shown an increased risk of carcinoma development with long segment Barrett’s esophagus (LSBE).^7-9 Weston et al⁷ reported a 2.4% progression rate to HGD or esophageal carcinoma with SSBE and no dysplasia compared with 6.8% with LSBE (P=.002). If patients had LGD, the rate of progression to esophageal carcinoma with SSBE was 5.3% and jumped to 35% in patients with LSBE (P<.001). Conio et al⁸ reported that 4 of 5 cases of esophageal carcinoma noted through surveillance had LSBE. Hage et al⁹ reported a significantly increased risk of progression to HGD or esophageal carcinoma with long segment disease (P<.02).

While currently still considered investigational, DNA content flow cytometry may be a future tool used in risk stratification. Reid et al¹⁰ report a 5-year cumulative risk of esophageal carcinoma of 1.7% in Barrett’s esophagus patients with negative, low-grade or indefinite grades of dysplasia. Subsequent application of flow cytometry allowed for further stratification of these low-risk patients. Those with neither aneuploidy nor an increased 4N had a 5-year cumulative risk of cancer of 0% while the risk for those with abnormalities on cytometry increased to 28% (relative risk=19; P<.001).

TABLE
Grade of dysplasia and recommendations for Barrett’s esophagus surveillance as proposed by the ACG

Recommendations from others

The French Society of Digestive Endoscopy has published guidelines on monitoring Barrett’s esophagus.³ Their recommendations differ only slightly from the ACG in advocating a slightly increased frequency of EGD surveillance based on degree of dysplasia, and utilizing the length of the dysplastic segment in decision-making. Neither the American Academy of Family Physicians nor the US Preventive Services Task Force make any specific recommendations about Barrett’s esophagus surveillance.

Evidence summary

Barrett’s esophagus has been defined as “a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus.”¹ Intestinal metaplasia is a premalignant lesion for adenocarcinoma of the esophagus. Surveillance by serial endoscopy with biopsy has been recommended in an effort to find high-grade dysplasia or carcinoma in an early, asymptomatic, and potentially curable stage.^1-4 Approximately 75% of patients involved in a Barrett’s esophagus surveillance program will present with resectable tumors, compared with only 25% of those not receiving surveillance.⁴

A recent systematic review assessing screening tools for esophageal carcinoma found standard endoscopy to be superior (90%–100% sensitivity) to other less invasive methods such as questionnaire (60%–70%), and fecal occult blood testing (20%).⁴ Additional endoscopy tools such as brush and balloon cytology increased the cost of surveillance without any improvement in diagnostic yield.

The degree of dysplasia on esophageal biopsy in Barrett’s esophagus patients is currently the best indicator of risk of progression to esophageal carcinoma. The data reviewed by the ACG for the practice guideline was drawn from several prospective studies and one available registry. In sum, a total of 783 Barrett’s esophagus patients were followed for a mean of 2.9 to 7.3 years. Esophageal carcinoma developed in 2% of patients with no dysplasia, 7% of patients with low-grade dysplasia (LGD) and 22% of patients with high-grade dysplasia (HGD).¹ The ACG recommendations regarding frequency of esophagogastroduodenoscopy (EGD) were not based on an explicit critical appraisal of the literature. Recent cohort studies are consistent with recommendations for graded surveillance frequency. A randomized clinical trial to determine optimal endoscopic frequency and benefit has not been reported.

Several concerns have been raised regarding the utility of degree of dysplasia in determining optimal frequency of endoscopic surveillance. First, the progression of esophageal lesions over time is unpredictable. Skacel et al⁵ reported a series of 34 patients with LGD at initial pathologic examination. On subsequent surveillance endoscopy with repeat biopsy, 73% no longer demonstrated dysplasia. Such patients can be allowed to return to having surveillance every 3 years.

In addition to the non-linear progression of dysplasia, inter-rater reliability of the interpretation of pathology specimens varies substantially. Adequate reliability has been demonstrated among pathologists assigning results to 2 categories (either no dysplasia and LGD or HGD and carcinoma) (κ=0.7). Assignment to four distinct pathologic grades, however, was not reliable (κ=0.46, where 1.0 is complete agreement).¹ In order to make a diagnosis of HGD or carcinoma, interpretation must be independently confirmed by 2 expert pathologists.^1-3

Recommendations for frequent endoscopic surveillance are also weakened by the overall low rate of mortality from esophageal carcinoma noted in Barrett’s esophagus patients. A recent population based study demonstrated that there was no difference in overall mortality in those with a Barrett’s esophagus diagnosis compared with the general population.⁶ An increased risk of death from esophageal carcinoma was seen in patients with Barrett’s esophagus (4.7% seen in Barrett’s esophagus patients compared with 0.8% predicted in the general population; P<.05). The overall increased effect on mortality, however, was relatively small. Esophageal carcinoma accounted for less then 5% of deaths in Barrett’s esophagus patients reported during the study’s 6-year follow-up period.

Data from prospective studies published after 2002 may better predict prognosis for Barrett’s esophagus patients.^6-9 Even lower rates of progression to esophageal carcinoma (<0.5% a year or <1/220 patient-years) have been reported in these studies drawing from the general population rather than referred patients, likely stemming from differences in gender mix, patient age, and risk factors.

In addition to grade of dysplasia, the length of the dysplastic Barrett’s esophagus segment is emerging as a potentially predictive risk factor. While the ACG cautions that esophageal cancer has been reported in patients with so-called “short segment” Barrett’s esophagus (SSBE) (≤3 cm),¹ recent prospective studies have shown an increased risk of carcinoma development with long segment Barrett’s esophagus (LSBE).^7-9 Weston et al⁷ reported a 2.4% progression rate to HGD or esophageal carcinoma with SSBE and no dysplasia compared with 6.8% with LSBE (P=.002). If patients had LGD, the rate of progression to esophageal carcinoma with SSBE was 5.3% and jumped to 35% in patients with LSBE (P<.001). Conio et al⁸ reported that 4 of 5 cases of esophageal carcinoma noted through surveillance had LSBE. Hage et al⁹ reported a significantly increased risk of progression to HGD or esophageal carcinoma with long segment disease (P<.02).

While currently still considered investigational, DNA content flow cytometry may be a future tool used in risk stratification. Reid et al¹⁰ report a 5-year cumulative risk of esophageal carcinoma of 1.7% in Barrett’s esophagus patients with negative, low-grade or indefinite grades of dysplasia. Subsequent application of flow cytometry allowed for further stratification of these low-risk patients. Those with neither aneuploidy nor an increased 4N had a 5-year cumulative risk of cancer of 0% while the risk for those with abnormalities on cytometry increased to 28% (relative risk=19; P<.001).

TABLE
Grade of dysplasia and recommendations for Barrett’s esophagus surveillance as proposed by the ACG

Recommendations from others

The French Society of Digestive Endoscopy has published guidelines on monitoring Barrett’s esophagus.³ Their recommendations differ only slightly from the ACG in advocating a slightly increased frequency of EGD surveillance based on degree of dysplasia, and utilizing the length of the dysplastic segment in decision-making. Neither the American Academy of Family Physicians nor the US Preventive Services Task Force make any specific recommendations about Barrett’s esophagus surveillance.

Evidence summary

Barrett’s esophagus has been defined as “a change in the esophageal epithelium of any length that can be recognized at endoscopy and is confirmed to have intestinal metaplasia by biopsy of the tubular esophagus.”¹ Intestinal metaplasia is a premalignant lesion for adenocarcinoma of the esophagus. Surveillance by serial endoscopy with biopsy has been recommended in an effort to find high-grade dysplasia or carcinoma in an early, asymptomatic, and potentially curable stage.^1-4 Approximately 75% of patients involved in a Barrett’s esophagus surveillance program will present with resectable tumors, compared with only 25% of those not receiving surveillance.⁴

A recent systematic review assessing screening tools for esophageal carcinoma found standard endoscopy to be superior (90%–100% sensitivity) to other less invasive methods such as questionnaire (60%–70%), and fecal occult blood testing (20%).⁴ Additional endoscopy tools such as brush and balloon cytology increased the cost of surveillance without any improvement in diagnostic yield.

The degree of dysplasia on esophageal biopsy in Barrett’s esophagus patients is currently the best indicator of risk of progression to esophageal carcinoma. The data reviewed by the ACG for the practice guideline was drawn from several prospective studies and one available registry. In sum, a total of 783 Barrett’s esophagus patients were followed for a mean of 2.9 to 7.3 years. Esophageal carcinoma developed in 2% of patients with no dysplasia, 7% of patients with low-grade dysplasia (LGD) and 22% of patients with high-grade dysplasia (HGD).¹ The ACG recommendations regarding frequency of esophagogastroduodenoscopy (EGD) were not based on an explicit critical appraisal of the literature. Recent cohort studies are consistent with recommendations for graded surveillance frequency. A randomized clinical trial to determine optimal endoscopic frequency and benefit has not been reported.

Several concerns have been raised regarding the utility of degree of dysplasia in determining optimal frequency of endoscopic surveillance. First, the progression of esophageal lesions over time is unpredictable. Skacel et al⁵ reported a series of 34 patients with LGD at initial pathologic examination. On subsequent surveillance endoscopy with repeat biopsy, 73% no longer demonstrated dysplasia. Such patients can be allowed to return to having surveillance every 3 years.

In addition to the non-linear progression of dysplasia, inter-rater reliability of the interpretation of pathology specimens varies substantially. Adequate reliability has been demonstrated among pathologists assigning results to 2 categories (either no dysplasia and LGD or HGD and carcinoma) (κ=0.7). Assignment to four distinct pathologic grades, however, was not reliable (κ=0.46, where 1.0 is complete agreement).¹ In order to make a diagnosis of HGD or carcinoma, interpretation must be independently confirmed by 2 expert pathologists.^1-3

Recommendations for frequent endoscopic surveillance are also weakened by the overall low rate of mortality from esophageal carcinoma noted in Barrett’s esophagus patients. A recent population based study demonstrated that there was no difference in overall mortality in those with a Barrett’s esophagus diagnosis compared with the general population.⁶ An increased risk of death from esophageal carcinoma was seen in patients with Barrett’s esophagus (4.7% seen in Barrett’s esophagus patients compared with 0.8% predicted in the general population; P<.05). The overall increased effect on mortality, however, was relatively small. Esophageal carcinoma accounted for less then 5% of deaths in Barrett’s esophagus patients reported during the study’s 6-year follow-up period.

Data from prospective studies published after 2002 may better predict prognosis for Barrett’s esophagus patients.^6-9 Even lower rates of progression to esophageal carcinoma (<0.5% a year or <1/220 patient-years) have been reported in these studies drawing from the general population rather than referred patients, likely stemming from differences in gender mix, patient age, and risk factors.

In addition to grade of dysplasia, the length of the dysplastic Barrett’s esophagus segment is emerging as a potentially predictive risk factor. While the ACG cautions that esophageal cancer has been reported in patients with so-called “short segment” Barrett’s esophagus (SSBE) (≤3 cm),¹ recent prospective studies have shown an increased risk of carcinoma development with long segment Barrett’s esophagus (LSBE).^7-9 Weston et al⁷ reported a 2.4% progression rate to HGD or esophageal carcinoma with SSBE and no dysplasia compared with 6.8% with LSBE (P=.002). If patients had LGD, the rate of progression to esophageal carcinoma with SSBE was 5.3% and jumped to 35% in patients with LSBE (P<.001). Conio et al⁸ reported that 4 of 5 cases of esophageal carcinoma noted through surveillance had LSBE. Hage et al⁹ reported a significantly increased risk of progression to HGD or esophageal carcinoma with long segment disease (P<.02).

While currently still considered investigational, DNA content flow cytometry may be a future tool used in risk stratification. Reid et al¹⁰ report a 5-year cumulative risk of esophageal carcinoma of 1.7% in Barrett’s esophagus patients with negative, low-grade or indefinite grades of dysplasia. Subsequent application of flow cytometry allowed for further stratification of these low-risk patients. Those with neither aneuploidy nor an increased 4N had a 5-year cumulative risk of cancer of 0% while the risk for those with abnormalities on cytometry increased to 28% (relative risk=19; P<.001).

TABLE
Grade of dysplasia and recommendations for Barrett’s esophagus surveillance as proposed by the ACG

Recommendations from others

The French Society of Digestive Endoscopy has published guidelines on monitoring Barrett’s esophagus.³ Their recommendations differ only slightly from the ACG in advocating a slightly increased frequency of EGD surveillance based on degree of dysplasia, and utilizing the length of the dysplastic segment in decision-making. Neither the American Academy of Family Physicians nor the US Preventive Services Task Force make any specific recommendations about Barrett’s esophagus surveillance.