Clinical Inquiries

Evidence summary

A retrospective cohort study of health insurance claims compared the incidence of CHF among 5441 patients with diabetes who had taken TZDs (rosiglitazone, troglitazone, or pioglitazone) vs 28,103 who had not. Patients were allowed other oral agents and insulin, and they were followed for up to 6 years. The TZD group had more patients on insulin and with pre-existing comorbidities. Based on Kaplan-Meier estimates, which control for censored information, the incidence of new heart failure at 40 months was 8.2% in the TZD group and 5.3% in the non-TZD group (number needed to harm [NNH]=34.5). Using a multivariate analysis that controlled for the coadministration of insulin, the hazard ratio for TZD use was 1.76 (95% confidence interval [CI], 1.43–2.17).¹ The incidence of CHF was 3.24% in the troglitazone group (n=1665), 2.39% in the rosiglitazone group (n=1882), and 1.63% in the pioglitazone group (n=1347). The difference in these rates is not statistically significant. Of the 28,103 patients not on a TZD, 1.41% developed heart failure. Individual agents were not compared with placebo.

A manufacturer-sponsored study that combined data from 4 separate unpublished randomized controlled trials compared the incidence of CHF at 1 year for patients treated with pioglitazone (as monotherapy and in combination with other oral agents) with those treated only with other oral agents. Cardiac failure was noted in 12 of 1857 in the pioglitazone group vs 10 of 1856 subjects in the non-pioglitazone groups (not statistically significant). The paper did not comment on how the patients were recruited, how outcomes were measured, or why the 4 original studies were not published.²

Another manufacturer-sponsored retrospective cohort study of pioglitazone analyzed insurance claims data to compare the incidence of CHF among 1668 adult patients taking pioglitazone (and possibly other medications, but not insulin) vs 1668 adult patients taking insulin (and possibly other medications, but not a TZD). The 2 groups were matched in terms of comorbid conditions, but statistical analysis did not take disease severity into account. The incidence of CHF was 2% of pioglitazone users compared with 4% of patients using insulin (NNH for insulin=50). In addition, CHF-related hospitalizations were 0.7% for CHF in the pioglitazone group vs 2.5% in the insulin group (NNH for insulin=55). Both of these findings are statistically significant.³

Recommendations from others

The American Diabetes Association/American Heart Association recommends that patients be evaluated for heart disease or heart failure before starting TZD therapy and monitored for symptoms thereafter. Patients who are at risk for developing CHF, who already have New York Heart Association class I or II CHF, or who take insulin should begin TZD therapy with low doses that are titrated up gradually. The US Food and Drug Administration has not approved TZDs for patients with class III or IV CHF, as there are no studies in these populations.⁴

Evidence summary

A retrospective cohort study of health insurance claims compared the incidence of CHF among 5441 patients with diabetes who had taken TZDs (rosiglitazone, troglitazone, or pioglitazone) vs 28,103 who had not. Patients were allowed other oral agents and insulin, and they were followed for up to 6 years. The TZD group had more patients on insulin and with pre-existing comorbidities. Based on Kaplan-Meier estimates, which control for censored information, the incidence of new heart failure at 40 months was 8.2% in the TZD group and 5.3% in the non-TZD group (number needed to harm [NNH]=34.5). Using a multivariate analysis that controlled for the coadministration of insulin, the hazard ratio for TZD use was 1.76 (95% confidence interval [CI], 1.43–2.17).¹ The incidence of CHF was 3.24% in the troglitazone group (n=1665), 2.39% in the rosiglitazone group (n=1882), and 1.63% in the pioglitazone group (n=1347). The difference in these rates is not statistically significant. Of the 28,103 patients not on a TZD, 1.41% developed heart failure. Individual agents were not compared with placebo.

A manufacturer-sponsored study that combined data from 4 separate unpublished randomized controlled trials compared the incidence of CHF at 1 year for patients treated with pioglitazone (as monotherapy and in combination with other oral agents) with those treated only with other oral agents. Cardiac failure was noted in 12 of 1857 in the pioglitazone group vs 10 of 1856 subjects in the non-pioglitazone groups (not statistically significant). The paper did not comment on how the patients were recruited, how outcomes were measured, or why the 4 original studies were not published.²

Another manufacturer-sponsored retrospective cohort study of pioglitazone analyzed insurance claims data to compare the incidence of CHF among 1668 adult patients taking pioglitazone (and possibly other medications, but not insulin) vs 1668 adult patients taking insulin (and possibly other medications, but not a TZD). The 2 groups were matched in terms of comorbid conditions, but statistical analysis did not take disease severity into account. The incidence of CHF was 2% of pioglitazone users compared with 4% of patients using insulin (NNH for insulin=50). In addition, CHF-related hospitalizations were 0.7% for CHF in the pioglitazone group vs 2.5% in the insulin group (NNH for insulin=55). Both of these findings are statistically significant.³

Recommendations from others

The American Diabetes Association/American Heart Association recommends that patients be evaluated for heart disease or heart failure before starting TZD therapy and monitored for symptoms thereafter. Patients who are at risk for developing CHF, who already have New York Heart Association class I or II CHF, or who take insulin should begin TZD therapy with low doses that are titrated up gradually. The US Food and Drug Administration has not approved TZDs for patients with class III or IV CHF, as there are no studies in these populations.⁴

Evidence summary

A retrospective cohort study of health insurance claims compared the incidence of CHF among 5441 patients with diabetes who had taken TZDs (rosiglitazone, troglitazone, or pioglitazone) vs 28,103 who had not. Patients were allowed other oral agents and insulin, and they were followed for up to 6 years. The TZD group had more patients on insulin and with pre-existing comorbidities. Based on Kaplan-Meier estimates, which control for censored information, the incidence of new heart failure at 40 months was 8.2% in the TZD group and 5.3% in the non-TZD group (number needed to harm [NNH]=34.5). Using a multivariate analysis that controlled for the coadministration of insulin, the hazard ratio for TZD use was 1.76 (95% confidence interval [CI], 1.43–2.17).¹ The incidence of CHF was 3.24% in the troglitazone group (n=1665), 2.39% in the rosiglitazone group (n=1882), and 1.63% in the pioglitazone group (n=1347). The difference in these rates is not statistically significant. Of the 28,103 patients not on a TZD, 1.41% developed heart failure. Individual agents were not compared with placebo.

A manufacturer-sponsored study that combined data from 4 separate unpublished randomized controlled trials compared the incidence of CHF at 1 year for patients treated with pioglitazone (as monotherapy and in combination with other oral agents) with those treated only with other oral agents. Cardiac failure was noted in 12 of 1857 in the pioglitazone group vs 10 of 1856 subjects in the non-pioglitazone groups (not statistically significant). The paper did not comment on how the patients were recruited, how outcomes were measured, or why the 4 original studies were not published.²

Another manufacturer-sponsored retrospective cohort study of pioglitazone analyzed insurance claims data to compare the incidence of CHF among 1668 adult patients taking pioglitazone (and possibly other medications, but not insulin) vs 1668 adult patients taking insulin (and possibly other medications, but not a TZD). The 2 groups were matched in terms of comorbid conditions, but statistical analysis did not take disease severity into account. The incidence of CHF was 2% of pioglitazone users compared with 4% of patients using insulin (NNH for insulin=50). In addition, CHF-related hospitalizations were 0.7% for CHF in the pioglitazone group vs 2.5% in the insulin group (NNH for insulin=55). Both of these findings are statistically significant.³

Recommendations from others

The American Diabetes Association/American Heart Association recommends that patients be evaluated for heart disease or heart failure before starting TZD therapy and monitored for symptoms thereafter. Patients who are at risk for developing CHF, who already have New York Heart Association class I or II CHF, or who take insulin should begin TZD therapy with low doses that are titrated up gradually. The US Food and Drug Administration has not approved TZDs for patients with class III or IV CHF, as there are no studies in these populations.⁴

Evidence summary

The 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines malingering as “the intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives such as avoiding military duty, avoiding work, obtaining financial compensation, evading criminal prosecution, or obtaining drugs.”¹ Malingering is not considered a mental disorder because symptoms are intentionally produced for external incentives.

No physical exam maneuver can determine a patient's external incentives. Traditionally, a physician uses certain exam techniques to determine if symptoms are of functional, or nonorganic, origin. Both terms denote the absence of a structural or physiological source for the phenomena, and include malingering and mental disorders such as factitious disorder, conversion disorder, and somatoform disorders. Our literature search only found studies concerning the detection of nonorganic causes of back pain, paralysis, and sensory loss.

Several exam tests are commonly thought to detect nonorganic causes of low back pain. Gordon Waddell described 8 signs in 5 categories (TABLE 2) used to “identify [back pain] patients who require more detailed psychological assessment.”² A systematic review critiqued 60 studies of Waddell’s signs published between 1980 and 2000.³ The authors performed a thorough database search, including hand searches of key pain journals, meeting abstracts, and textbooks. The majority of the reviewed studies were small and of lower quality. The review found little evidence on test-retest or interrater reliability. There was consistent evidence that Waddell’s signs are associated with poorer treatment outcomes and generally consistent evidence that they are not associated with secondary gain and cannot discriminate organic from nonorganic problems.

A small, diagnostic case-control study of Mankopf’s test, which is based on the theory that pain increases heart rate, investigated 20 chronic low back pain patients considered nonorganic vs 20 pain-free controls using mechanical pain stimulus applied to subjects’ fingers.⁴ There was no significant difference in heart rate response between groups, and no significant effect of pain on heart rate in either group. The authors did not define their criteria for determining patients’ back pain as non-organic, nor did they include patients with low back pain caused by an identifiable pathology. There was no mention of blinding. This literature search found no published studies of McBride’s test, where the patient’s refusal to stand on the unaffected leg and flex the affected leg to the chest determines a feigned radiculopathy.

A few tests attempt to detect nonorganic causes of paralysis. In Hoover’s test, a patient is asked to alternately press down with the paralyzed leg and raise the unaffected leg to resistance, while the hand of the examiner cups the heel of the affected leg.⁵ A small, diagnostic case-control study using a computer-assisted strain gauge to measure movement effort during Hoover’s test involved 7 women with true paresis, 9 with nonorganic paresis, and 10 controls.⁶ The investigators diagnosed nonorganic paresis by history, neurological exam, and lack of positive neuroradiologic findings. The authors calculated a maximal involuntary to voluntary ratio for each patient’s extremities. The calculation discriminated between all 9 nonorganic patients and both the normal controls and patients with true paresis. The authors did not mention blinding in the study. No attempt was made to compare the strain gauge measurements with a clinician-performed Hoover’s test.

The Abductor sign, based on a similar theory that thigh abductors work in concert, was developed and studied by one individual.⁷ In this diagnostic case-control study, the single author tested 33 patients from his practice, 17 with organic paresis, and 16 with nonorganic paresis. The author differentiated organic from nonorganic paresis by history, physical exam, and various imaging studies with no independent assessment. He reported his test as 100% accurate. We did not find any published studies of the Arm Drop test, where feigned paralysis of an upper extremity is tested by holding the arm over the face of the supine patient and letting go.

The Midline Split test attempts to detect nonorganic causes of sensory loss. The fact that cutaneous nerves cross the midline is the basis for the idea that a sharp midline split denotes nonorganic sensory loss. In 1 diagnostic cohort study of 100 people presenting to a neurology department with complaints of decreased sensation on one side of the face, 80 patients were determined to have organic deficits such as multiple sclerosis or stroke. The author did not describe how these diseases were diagnosed. Of those with organic deficits, 7.5% showed midline splitting of sensory loss, falsely suggesting a nonorganic process. Only 20% of the patients with nonorganic sensory loss showed the expected midline split.⁸ The author apparently performed the sensory exam without blinding or independent confirmation.

TABLE 1
Summary of tests for the detection of malingering

TABLE 2
Waddell’s signs

Recommendations from others

The DSM-IV recommends suspicion of malingering for patients who present with 2 or more of the following: medicolegal issues, disagreement between objective and subjective stress or disability, noncompliance with evaluation or treatment, or antisocial personality disorder.¹

The American Medical Association published the Guides to the Evaluation of Permanent Impairment, which states, “Confirmation of malingering is extremely difficult and generally depends on intentional or inadvertent surveillance.”⁹

Evidence summary

The 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines malingering as “the intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives such as avoiding military duty, avoiding work, obtaining financial compensation, evading criminal prosecution, or obtaining drugs.”¹ Malingering is not considered a mental disorder because symptoms are intentionally produced for external incentives.

No physical exam maneuver can determine a patient's external incentives. Traditionally, a physician uses certain exam techniques to determine if symptoms are of functional, or nonorganic, origin. Both terms denote the absence of a structural or physiological source for the phenomena, and include malingering and mental disorders such as factitious disorder, conversion disorder, and somatoform disorders. Our literature search only found studies concerning the detection of nonorganic causes of back pain, paralysis, and sensory loss.

Several exam tests are commonly thought to detect nonorganic causes of low back pain. Gordon Waddell described 8 signs in 5 categories (TABLE 2) used to “identify [back pain] patients who require more detailed psychological assessment.”² A systematic review critiqued 60 studies of Waddell’s signs published between 1980 and 2000.³ The authors performed a thorough database search, including hand searches of key pain journals, meeting abstracts, and textbooks. The majority of the reviewed studies were small and of lower quality. The review found little evidence on test-retest or interrater reliability. There was consistent evidence that Waddell’s signs are associated with poorer treatment outcomes and generally consistent evidence that they are not associated with secondary gain and cannot discriminate organic from nonorganic problems.

A small, diagnostic case-control study of Mankopf’s test, which is based on the theory that pain increases heart rate, investigated 20 chronic low back pain patients considered nonorganic vs 20 pain-free controls using mechanical pain stimulus applied to subjects’ fingers.⁴ There was no significant difference in heart rate response between groups, and no significant effect of pain on heart rate in either group. The authors did not define their criteria for determining patients’ back pain as non-organic, nor did they include patients with low back pain caused by an identifiable pathology. There was no mention of blinding. This literature search found no published studies of McBride’s test, where the patient’s refusal to stand on the unaffected leg and flex the affected leg to the chest determines a feigned radiculopathy.

A few tests attempt to detect nonorganic causes of paralysis. In Hoover’s test, a patient is asked to alternately press down with the paralyzed leg and raise the unaffected leg to resistance, while the hand of the examiner cups the heel of the affected leg.⁵ A small, diagnostic case-control study using a computer-assisted strain gauge to measure movement effort during Hoover’s test involved 7 women with true paresis, 9 with nonorganic paresis, and 10 controls.⁶ The investigators diagnosed nonorganic paresis by history, neurological exam, and lack of positive neuroradiologic findings. The authors calculated a maximal involuntary to voluntary ratio for each patient’s extremities. The calculation discriminated between all 9 nonorganic patients and both the normal controls and patients with true paresis. The authors did not mention blinding in the study. No attempt was made to compare the strain gauge measurements with a clinician-performed Hoover’s test.

The Abductor sign, based on a similar theory that thigh abductors work in concert, was developed and studied by one individual.⁷ In this diagnostic case-control study, the single author tested 33 patients from his practice, 17 with organic paresis, and 16 with nonorganic paresis. The author differentiated organic from nonorganic paresis by history, physical exam, and various imaging studies with no independent assessment. He reported his test as 100% accurate. We did not find any published studies of the Arm Drop test, where feigned paralysis of an upper extremity is tested by holding the arm over the face of the supine patient and letting go.

The Midline Split test attempts to detect nonorganic causes of sensory loss. The fact that cutaneous nerves cross the midline is the basis for the idea that a sharp midline split denotes nonorganic sensory loss. In 1 diagnostic cohort study of 100 people presenting to a neurology department with complaints of decreased sensation on one side of the face, 80 patients were determined to have organic deficits such as multiple sclerosis or stroke. The author did not describe how these diseases were diagnosed. Of those with organic deficits, 7.5% showed midline splitting of sensory loss, falsely suggesting a nonorganic process. Only 20% of the patients with nonorganic sensory loss showed the expected midline split.⁸ The author apparently performed the sensory exam without blinding or independent confirmation.

TABLE 1
Summary of tests for the detection of malingering

TABLE 2
Waddell’s signs

Recommendations from others

The DSM-IV recommends suspicion of malingering for patients who present with 2 or more of the following: medicolegal issues, disagreement between objective and subjective stress or disability, noncompliance with evaluation or treatment, or antisocial personality disorder.¹

The American Medical Association published the Guides to the Evaluation of Permanent Impairment, which states, “Confirmation of malingering is extremely difficult and generally depends on intentional or inadvertent surveillance.”⁹

Evidence summary

The 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) defines malingering as “the intentional production of false or grossly exaggerated physical or psychological symptoms motivated by external incentives such as avoiding military duty, avoiding work, obtaining financial compensation, evading criminal prosecution, or obtaining drugs.”¹ Malingering is not considered a mental disorder because symptoms are intentionally produced for external incentives.

No physical exam maneuver can determine a patient's external incentives. Traditionally, a physician uses certain exam techniques to determine if symptoms are of functional, or nonorganic, origin. Both terms denote the absence of a structural or physiological source for the phenomena, and include malingering and mental disorders such as factitious disorder, conversion disorder, and somatoform disorders. Our literature search only found studies concerning the detection of nonorganic causes of back pain, paralysis, and sensory loss.

Several exam tests are commonly thought to detect nonorganic causes of low back pain. Gordon Waddell described 8 signs in 5 categories (TABLE 2) used to “identify [back pain] patients who require more detailed psychological assessment.”² A systematic review critiqued 60 studies of Waddell’s signs published between 1980 and 2000.³ The authors performed a thorough database search, including hand searches of key pain journals, meeting abstracts, and textbooks. The majority of the reviewed studies were small and of lower quality. The review found little evidence on test-retest or interrater reliability. There was consistent evidence that Waddell’s signs are associated with poorer treatment outcomes and generally consistent evidence that they are not associated with secondary gain and cannot discriminate organic from nonorganic problems.

A small, diagnostic case-control study of Mankopf’s test, which is based on the theory that pain increases heart rate, investigated 20 chronic low back pain patients considered nonorganic vs 20 pain-free controls using mechanical pain stimulus applied to subjects’ fingers.⁴ There was no significant difference in heart rate response between groups, and no significant effect of pain on heart rate in either group. The authors did not define their criteria for determining patients’ back pain as non-organic, nor did they include patients with low back pain caused by an identifiable pathology. There was no mention of blinding. This literature search found no published studies of McBride’s test, where the patient’s refusal to stand on the unaffected leg and flex the affected leg to the chest determines a feigned radiculopathy.

A few tests attempt to detect nonorganic causes of paralysis. In Hoover’s test, a patient is asked to alternately press down with the paralyzed leg and raise the unaffected leg to resistance, while the hand of the examiner cups the heel of the affected leg.⁵ A small, diagnostic case-control study using a computer-assisted strain gauge to measure movement effort during Hoover’s test involved 7 women with true paresis, 9 with nonorganic paresis, and 10 controls.⁶ The investigators diagnosed nonorganic paresis by history, neurological exam, and lack of positive neuroradiologic findings. The authors calculated a maximal involuntary to voluntary ratio for each patient’s extremities. The calculation discriminated between all 9 nonorganic patients and both the normal controls and patients with true paresis. The authors did not mention blinding in the study. No attempt was made to compare the strain gauge measurements with a clinician-performed Hoover’s test.

The Abductor sign, based on a similar theory that thigh abductors work in concert, was developed and studied by one individual.⁷ In this diagnostic case-control study, the single author tested 33 patients from his practice, 17 with organic paresis, and 16 with nonorganic paresis. The author differentiated organic from nonorganic paresis by history, physical exam, and various imaging studies with no independent assessment. He reported his test as 100% accurate. We did not find any published studies of the Arm Drop test, where feigned paralysis of an upper extremity is tested by holding the arm over the face of the supine patient and letting go.

The Midline Split test attempts to detect nonorganic causes of sensory loss. The fact that cutaneous nerves cross the midline is the basis for the idea that a sharp midline split denotes nonorganic sensory loss. In 1 diagnostic cohort study of 100 people presenting to a neurology department with complaints of decreased sensation on one side of the face, 80 patients were determined to have organic deficits such as multiple sclerosis or stroke. The author did not describe how these diseases were diagnosed. Of those with organic deficits, 7.5% showed midline splitting of sensory loss, falsely suggesting a nonorganic process. Only 20% of the patients with nonorganic sensory loss showed the expected midline split.⁸ The author apparently performed the sensory exam without blinding or independent confirmation.

TABLE 1
Summary of tests for the detection of malingering

TABLE 2
Waddell’s signs

Recommendations from others

The DSM-IV recommends suspicion of malingering for patients who present with 2 or more of the following: medicolegal issues, disagreement between objective and subjective stress or disability, noncompliance with evaluation or treatment, or antisocial personality disorder.¹

The American Medical Association published the Guides to the Evaluation of Permanent Impairment, which states, “Confirmation of malingering is extremely difficult and generally depends on intentional or inadvertent surveillance.”⁹

Evidence summary

A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.¹ This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).^2,3

At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis^4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).⁶ A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.⁷ The majority of patients used either form of treatment for 1 year.

Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.⁸ At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).

In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).⁹

The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.

Recommendations from others

In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.¹⁰ This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.

Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.

In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.

Evidence summary

A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.¹ This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).^2,3

At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis^4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).⁶ A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.⁷ The majority of patients used either form of treatment for 1 year.

Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.⁸ At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).

In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).⁹

The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.

Recommendations from others

In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.¹⁰ This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.

Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.

In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.

Evidence summary

A recent meta-analysis included 25 randomized controlled trials involving tacrolimus and pimecrolimus.¹ This review included trials of tacrolimus and pimecrolimus in comparison with placebo, topical corticosteroids of varying strengths, and each other. They reported on both safety and efficacy. Fifteen vehicle-controlled trials of pimecrolimus and tacrolimus were reviewed. Both medications proved to be significantly more effective than the vehicle alone. A total of 3 trials (732 patients) compared tacrolimus 0.1% with potent topical corticosteroids (hydrocortisone butyrate 0.1%, beta-methasone valerate 0.1%) and found it to be as effective as the topical steroids after 3 weeks of application (number needed to treat [NNT]=6).^2,3

At both the 0.03% and 0.1% strengths, tacrolimus was found to be more effective than mild topical corticosteroids (hydrocortisone acetate 1%) in 2 studies enrolling a total of 1183 children with moderate to severe atopic dermatitis^4,5 (NNT=5 for the tacrolimus 0.03%, and NNT= 3 for tacrolimus 0.1%).⁶ A randomized, double-blinded, multicenter trial compared the use of pimecrolimus 1% cream with 0.1% triamcinolone acetonide cream and 1% hydrocortisone acetate cream for 658 adults with moderate-to-severe atopic dermatitis.⁷ The majority of patients used either form of treatment for 1 year.

Although long-term safety and tolerability were similar, topical corticosteroids were more efficacious (NNT=13). Another study compared pimecrolimus 1% with betamethasone valerate 0.1% (a potent corticosteroid) in a study of 87 patients.⁸ At the end of 3 weeks, the pimecrolimus 1% cream was significantly less effective than betamethasone valerate 0.1% (NNT=4).

In a meta-analysis of 3 randomized studies of head-to-head comparison of pimecrolimus 1% and tacrolimus 0.03% or 0.1% among children and adults, tacrolimus ointment was more effective than pimecrolimus cream at the end of the study for adults (P<.0001), for children with moderate-to-severe disease (P=.04), in the combined analysis (P<.0001), and at week 1 for children with mild disease (P=.04). No significant difference was seen in the incidence of adverse effects, although more pimecrolimus-treated patients withdrew from the studies because of a lack of efficacy (P≤.03) or adverse events (P=.002; pediatric mild).⁹

The authors of the first meta-analysis concluded that pimecrolimus 1% was more effective compared with placebo, less effective than potent topical corticosteroids, and had yet to be studied in comparison with low-potency topical corticosteroids. Tacrolimus 0.1% was more effective than placebo, more effective than mild corticosteroids, and as effective as potent topical corticosteroids. It was noted that both these agents caused more burning of the skin than topical corticosteroids—pimecrolimus 1% compared with betamethasone valerate 0.1% (number needed to harm [NNH]=50); tacrolimus 0.1% compared with betamethasone valerate 0.1% and hydrocortisone butyrate 0.1% (NNH=3); and tacrolimus 0.03% compared with the mild corticosteroid hydrocortisone acetate 1% (NNH=10). However, there was no significant difference in the rate of skin infections.

Recommendations from others

In 2003, a work group of dermatologists appointed by the president of the American Academy of Dermatology published a technical report on the guidelines of care for atopic dermatitis.¹⁰ This group evaluated the effectiveness of several topical treatments for the treatment of atopic dermatitis. They noted that coal tar and its derivatives may reduce the severity of atopic dermatitis symptoms, but there are significant barriers to compliance. The severity of pruritus associated with atopic dermatitis may be reduced with shortterm use of topical doxepin.

Evidence supports the use of emollients in combination with other topical corticosteroid treatments to reduce the severity of atopic dermatitis. However, emollients need frequent application, which may be associated with poor compliance. The work group also concluded that both tacrolimus and pimecrolimus are effective and safe in reducing the severity of atopic dermatitis symptoms for both children and adults up to 1 year of treatment.

In March 2005, the FDA posted a Public Health Advisory and Alerts for Healthcare Professionals regarding the potential cancer risk from the use tacrolimus and pimecrolimus products when applied to the skin to treat atopic dermatitis. These creams will carry a “black box” warning regarding this potential risk. They recommended use only as a second-line therapy, at minimal amounts necessary, and for short periods of time, not continuously. They also recommended against their use for children aged <2 years and for people with diminished immune systems.

Evidence summary

Diabetic nephropathy is the leading cause of end-stage renal disease, and it occurs in 20% to 40% of patients with diabetes. Optimal glycemic (glycosylated hemoglobin [HbA_1c] level <7%) and hypertension control (<130/80 mm Hg) can prevent or slow the progression of diabetic nephropathy.^1-3

An average of 3 antihypertensive medications are needed to achieve currently recommended blood pressure goals in those with diabetes.² In hypertensive and normotensive patients with type 2 diabetes and microalbuminuria, ACE inhibitors have been well studied and found to reduce the risk of mortality, major cardiovascular events, and slow the progression to overt nephropathy, in patients with diabetes and at least 1 other risk factor.⁴ In patients with type 2 diabetes and hypertension, macroalbuminuria, and serum creatinine >1.5 mg/dL, ARBs are effective in slowing the progression of diabetic nephropathy.⁵

Some patients, however, are intolerant to ACE inhibitors and ARBs. When patients are intolerant to these medications, diuretics, NDCAs, or beta-blockers are recommended agents for the treatment of hypertension.

According to a systematic review, NDCAs cause a greater reduction in proteinuria compared with DCAs (dihydropyridine calcium antagonists, such as nifedipine and amlodipine), although there was no significant differences in lowering blood pressure.⁶ Mean change in proteinuria was +2% for DCAs and –30% for NDCAs (95% confidence interval [CI], 10%–54%; P=.01). In another RCT, amlodipine was no more effective than placebo in reducing proteinuria, while irbesartan effectively reduced end-stage renal disease (number needed to treat [NNT]=25 over 2.6 years).⁵

In the UKPDS-Hypertension in Diabetes study (a multicenter randomized study in patients with type 2 diabetes that evaluated the effects of different levels of blood pressure control on diabetic complications), researchers found that patients assigned to the tight-control group (blood pressure goal <150/85 mm Hg) had 37% risk reduction in microvascular endpoints (nephropathy and advanced retinopathy).⁷ There was no difference in study endpoints between the ACE inhibitor captopril and the beta-blocker atenolol. Selective beta-blockers like carvedilol appear to have fewer adverse metabolic effects, although the clinical significance of this difference is unclear.⁸ In insulin-dependent patients and patients with hypoglycemic episodes, peripheral vascular disease, and bronchospastic disease, beta-blockers should be used with caution.

The NESTOR study—a multinational, multicenter, double-blind, randomized controlled, 2-parallel-groups study over 1 year—found that indapamide SR (a thiazide-type diuretic) treatment is as efficacious as enalapril in reducing proteinuria and lowering blood pressure.⁹

A meta-analysis of RCTs in patients with non-diabetic renal disease and RCTs or time-controlled studies with nonrandomized crossover design in patients with diabetic nephropathy revealed that dietary protein restriction effectively slows the progression of both diabetic and non-diabetic renal disease.¹⁰ In small studies, weight loss, use of lipid-lowering agents, and smoking cessation all revealed reduction in proteinuria.^11,12

Recommendations from others

From the American Diabetes Association’s “Standards of Medical Care in Diabetes”¹² (position statement): to reduce the risk or slow the progression of nephropathy, optimize glucose and blood pressure control.

• Patients with diabetes should be treated to a blood pressure <130/80 mm Hg
• For patients with diabetes and albuminuria or nephropathy who are intolerant to ACE inhibitors or ARBs, NDCAs, diuretics, or beta blockers are recommended for treating hypertension. NDCA use may reduce albuminuria in patients with diabetes, including during pregnancy.

Evidence summary

Diabetic nephropathy is the leading cause of end-stage renal disease, and it occurs in 20% to 40% of patients with diabetes. Optimal glycemic (glycosylated hemoglobin [HbA_1c] level <7%) and hypertension control (<130/80 mm Hg) can prevent or slow the progression of diabetic nephropathy.^1-3

An average of 3 antihypertensive medications are needed to achieve currently recommended blood pressure goals in those with diabetes.² In hypertensive and normotensive patients with type 2 diabetes and microalbuminuria, ACE inhibitors have been well studied and found to reduce the risk of mortality, major cardiovascular events, and slow the progression to overt nephropathy, in patients with diabetes and at least 1 other risk factor.⁴ In patients with type 2 diabetes and hypertension, macroalbuminuria, and serum creatinine >1.5 mg/dL, ARBs are effective in slowing the progression of diabetic nephropathy.⁵

Some patients, however, are intolerant to ACE inhibitors and ARBs. When patients are intolerant to these medications, diuretics, NDCAs, or beta-blockers are recommended agents for the treatment of hypertension.

According to a systematic review, NDCAs cause a greater reduction in proteinuria compared with DCAs (dihydropyridine calcium antagonists, such as nifedipine and amlodipine), although there was no significant differences in lowering blood pressure.⁶ Mean change in proteinuria was +2% for DCAs and –30% for NDCAs (95% confidence interval [CI], 10%–54%; P=.01). In another RCT, amlodipine was no more effective than placebo in reducing proteinuria, while irbesartan effectively reduced end-stage renal disease (number needed to treat [NNT]=25 over 2.6 years).⁵

In the UKPDS-Hypertension in Diabetes study (a multicenter randomized study in patients with type 2 diabetes that evaluated the effects of different levels of blood pressure control on diabetic complications), researchers found that patients assigned to the tight-control group (blood pressure goal <150/85 mm Hg) had 37% risk reduction in microvascular endpoints (nephropathy and advanced retinopathy).⁷ There was no difference in study endpoints between the ACE inhibitor captopril and the beta-blocker atenolol. Selective beta-blockers like carvedilol appear to have fewer adverse metabolic effects, although the clinical significance of this difference is unclear.⁸ In insulin-dependent patients and patients with hypoglycemic episodes, peripheral vascular disease, and bronchospastic disease, beta-blockers should be used with caution.

The NESTOR study—a multinational, multicenter, double-blind, randomized controlled, 2-parallel-groups study over 1 year—found that indapamide SR (a thiazide-type diuretic) treatment is as efficacious as enalapril in reducing proteinuria and lowering blood pressure.⁹

A meta-analysis of RCTs in patients with non-diabetic renal disease and RCTs or time-controlled studies with nonrandomized crossover design in patients with diabetic nephropathy revealed that dietary protein restriction effectively slows the progression of both diabetic and non-diabetic renal disease.¹⁰ In small studies, weight loss, use of lipid-lowering agents, and smoking cessation all revealed reduction in proteinuria.^11,12

Recommendations from others

From the American Diabetes Association’s “Standards of Medical Care in Diabetes”¹² (position statement): to reduce the risk or slow the progression of nephropathy, optimize glucose and blood pressure control.

• Patients with diabetes should be treated to a blood pressure <130/80 mm Hg
• For patients with diabetes and albuminuria or nephropathy who are intolerant to ACE inhibitors or ARBs, NDCAs, diuretics, or beta blockers are recommended for treating hypertension. NDCA use may reduce albuminuria in patients with diabetes, including during pregnancy.

Evidence summary

Diabetic nephropathy is the leading cause of end-stage renal disease, and it occurs in 20% to 40% of patients with diabetes. Optimal glycemic (glycosylated hemoglobin [HbA_1c] level <7%) and hypertension control (<130/80 mm Hg) can prevent or slow the progression of diabetic nephropathy.^1-3

An average of 3 antihypertensive medications are needed to achieve currently recommended blood pressure goals in those with diabetes.² In hypertensive and normotensive patients with type 2 diabetes and microalbuminuria, ACE inhibitors have been well studied and found to reduce the risk of mortality, major cardiovascular events, and slow the progression to overt nephropathy, in patients with diabetes and at least 1 other risk factor.⁴ In patients with type 2 diabetes and hypertension, macroalbuminuria, and serum creatinine >1.5 mg/dL, ARBs are effective in slowing the progression of diabetic nephropathy.⁵

Some patients, however, are intolerant to ACE inhibitors and ARBs. When patients are intolerant to these medications, diuretics, NDCAs, or beta-blockers are recommended agents for the treatment of hypertension.

According to a systematic review, NDCAs cause a greater reduction in proteinuria compared with DCAs (dihydropyridine calcium antagonists, such as nifedipine and amlodipine), although there was no significant differences in lowering blood pressure.⁶ Mean change in proteinuria was +2% for DCAs and –30% for NDCAs (95% confidence interval [CI], 10%–54%; P=.01). In another RCT, amlodipine was no more effective than placebo in reducing proteinuria, while irbesartan effectively reduced end-stage renal disease (number needed to treat [NNT]=25 over 2.6 years).⁵

In the UKPDS-Hypertension in Diabetes study (a multicenter randomized study in patients with type 2 diabetes that evaluated the effects of different levels of blood pressure control on diabetic complications), researchers found that patients assigned to the tight-control group (blood pressure goal <150/85 mm Hg) had 37% risk reduction in microvascular endpoints (nephropathy and advanced retinopathy).⁷ There was no difference in study endpoints between the ACE inhibitor captopril and the beta-blocker atenolol. Selective beta-blockers like carvedilol appear to have fewer adverse metabolic effects, although the clinical significance of this difference is unclear.⁸ In insulin-dependent patients and patients with hypoglycemic episodes, peripheral vascular disease, and bronchospastic disease, beta-blockers should be used with caution.

The NESTOR study—a multinational, multicenter, double-blind, randomized controlled, 2-parallel-groups study over 1 year—found that indapamide SR (a thiazide-type diuretic) treatment is as efficacious as enalapril in reducing proteinuria and lowering blood pressure.⁹

A meta-analysis of RCTs in patients with non-diabetic renal disease and RCTs or time-controlled studies with nonrandomized crossover design in patients with diabetic nephropathy revealed that dietary protein restriction effectively slows the progression of both diabetic and non-diabetic renal disease.¹⁰ In small studies, weight loss, use of lipid-lowering agents, and smoking cessation all revealed reduction in proteinuria.^11,12

Recommendations from others

From the American Diabetes Association’s “Standards of Medical Care in Diabetes”¹² (position statement): to reduce the risk or slow the progression of nephropathy, optimize glucose and blood pressure control.

• Patients with diabetes should be treated to a blood pressure <130/80 mm Hg
• For patients with diabetes and albuminuria or nephropathy who are intolerant to ACE inhibitors or ARBs, NDCAs, diuretics, or beta blockers are recommended for treating hypertension. NDCA use may reduce albuminuria in patients with diabetes, including during pregnancy.

Evidence summary

Because of the nature of major surgery, there are practical and ethical barriers to true randomized controlled trials (RCTs) comparing bariatric surgery with placebo or to no intervention. However, multiple RCTs have compared the weight-reducing effects of different bariatric surgical techniques against each other.¹ All studies included patients who had a BMI >40 kg/m², or a BMI >35 kg/m² with at least 1 comorbidity, such as cardiovascular disease, sleep apnea, uncontrolled type 2 diabetes, or weight-induced physical problems interfering with performance of daily life activities. It is these study inclusion criteria that, by default, have become widely accepted indications for bariatric surgery. Weight loss in all RCTs was substantial, ranging from 50 to 100 kg over 6 months to 1 year. Comorbid factors associated with obesity showed either resolution or improvement after surgery in 91% of patients.

Patients with a BMI >40 have substantially more serious health consequences and a reduced life expectancy. Obesity significantly impairs quality of life, and the risk of morbidity and mortality increases with the degree of obesity.² Those who are extremely obese often do not have sustained benefit from more conservative treatment. The benefits of nonsurgical treatment are significantly limited by the failure to maintain reduced body weight.

A large literature of controlled and uncontrolled cohort studies show that surgery has produced the longest period of sustained weight loss.³ A recent meta-analysis proved bariatric surgery not only efficacious for weight loss, but showed that a substantial majority of patients with diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea experienced complete resolution or significant improvement of their comorbid condition after surgery.⁴

The possibility of significant adverse effects remains. The postoperative mortality rate for bariatric surgery is approximately 0.2%. Reoperation is required for up to 25% of patients within 5 years. Other complications are wound infection, staple failure, vitamin deficiency, diarrhea, and hemorrhage.³ The long-term health effects of bariatric surgery are not well known.

Recommendations from others

The NIH statement “Gastrointestinal Surgery for Severe Obesity” concluded that the benefits outweigh the risks and that surgical treatment is reasonable in those who strongly desire substantial weight loss and have life-threatening comorbid conditions.²

Clinical guidelines developed by the National Heart, Lung, and Blood Institute Expert Panel on the identification, evaluation, and treatment of obesity for adults recommend that bariatric surgery be an option for carefully selected patients with clinically severe obesity (BMI >40 or >35 with comorbid conditions) when less invasive methods of weight loss have failed and the patient is at high risk for obesity-associated morbidity and mortality.¹

The American Gastroenterological Association (AGA) medical position statement on obesity finds surgical therapy to be the most effective approach for achieving long-term weight loss. The AGA recommends surgery for patients with a BMI >40, or those with BMI >35 and 1 or more severe obesity-related medical complication (eg, hypertension, heart failure, or sleep apnea) if they have been unable to achieve or maintain weight loss with conventional therapy, have acceptable operative risks, and are able to comply with long-term treatment and follow-up.⁵

The American College of Preventive Medicine, in its policy statement on weight management counseling, recommends limiting surgical therapy for obesity to severely obese patients, defined as BMI >40.⁶

Evidence summary

Because of the nature of major surgery, there are practical and ethical barriers to true randomized controlled trials (RCTs) comparing bariatric surgery with placebo or to no intervention. However, multiple RCTs have compared the weight-reducing effects of different bariatric surgical techniques against each other.¹ All studies included patients who had a BMI >40 kg/m², or a BMI >35 kg/m² with at least 1 comorbidity, such as cardiovascular disease, sleep apnea, uncontrolled type 2 diabetes, or weight-induced physical problems interfering with performance of daily life activities. It is these study inclusion criteria that, by default, have become widely accepted indications for bariatric surgery. Weight loss in all RCTs was substantial, ranging from 50 to 100 kg over 6 months to 1 year. Comorbid factors associated with obesity showed either resolution or improvement after surgery in 91% of patients.

Patients with a BMI >40 have substantially more serious health consequences and a reduced life expectancy. Obesity significantly impairs quality of life, and the risk of morbidity and mortality increases with the degree of obesity.² Those who are extremely obese often do not have sustained benefit from more conservative treatment. The benefits of nonsurgical treatment are significantly limited by the failure to maintain reduced body weight.

A large literature of controlled and uncontrolled cohort studies show that surgery has produced the longest period of sustained weight loss.³ A recent meta-analysis proved bariatric surgery not only efficacious for weight loss, but showed that a substantial majority of patients with diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea experienced complete resolution or significant improvement of their comorbid condition after surgery.⁴

The possibility of significant adverse effects remains. The postoperative mortality rate for bariatric surgery is approximately 0.2%. Reoperation is required for up to 25% of patients within 5 years. Other complications are wound infection, staple failure, vitamin deficiency, diarrhea, and hemorrhage.³ The long-term health effects of bariatric surgery are not well known.

Recommendations from others

The NIH statement “Gastrointestinal Surgery for Severe Obesity” concluded that the benefits outweigh the risks and that surgical treatment is reasonable in those who strongly desire substantial weight loss and have life-threatening comorbid conditions.²

Clinical guidelines developed by the National Heart, Lung, and Blood Institute Expert Panel on the identification, evaluation, and treatment of obesity for adults recommend that bariatric surgery be an option for carefully selected patients with clinically severe obesity (BMI >40 or >35 with comorbid conditions) when less invasive methods of weight loss have failed and the patient is at high risk for obesity-associated morbidity and mortality.¹

The American Gastroenterological Association (AGA) medical position statement on obesity finds surgical therapy to be the most effective approach for achieving long-term weight loss. The AGA recommends surgery for patients with a BMI >40, or those with BMI >35 and 1 or more severe obesity-related medical complication (eg, hypertension, heart failure, or sleep apnea) if they have been unable to achieve or maintain weight loss with conventional therapy, have acceptable operative risks, and are able to comply with long-term treatment and follow-up.⁵

The American College of Preventive Medicine, in its policy statement on weight management counseling, recommends limiting surgical therapy for obesity to severely obese patients, defined as BMI >40.⁶

Evidence summary

Because of the nature of major surgery, there are practical and ethical barriers to true randomized controlled trials (RCTs) comparing bariatric surgery with placebo or to no intervention. However, multiple RCTs have compared the weight-reducing effects of different bariatric surgical techniques against each other.¹ All studies included patients who had a BMI >40 kg/m², or a BMI >35 kg/m² with at least 1 comorbidity, such as cardiovascular disease, sleep apnea, uncontrolled type 2 diabetes, or weight-induced physical problems interfering with performance of daily life activities. It is these study inclusion criteria that, by default, have become widely accepted indications for bariatric surgery. Weight loss in all RCTs was substantial, ranging from 50 to 100 kg over 6 months to 1 year. Comorbid factors associated with obesity showed either resolution or improvement after surgery in 91% of patients.

Patients with a BMI >40 have substantially more serious health consequences and a reduced life expectancy. Obesity significantly impairs quality of life, and the risk of morbidity and mortality increases with the degree of obesity.² Those who are extremely obese often do not have sustained benefit from more conservative treatment. The benefits of nonsurgical treatment are significantly limited by the failure to maintain reduced body weight.

A large literature of controlled and uncontrolled cohort studies show that surgery has produced the longest period of sustained weight loss.³ A recent meta-analysis proved bariatric surgery not only efficacious for weight loss, but showed that a substantial majority of patients with diabetes, hyperlipidemia, hypertension, and obstructive sleep apnea experienced complete resolution or significant improvement of their comorbid condition after surgery.⁴

The possibility of significant adverse effects remains. The postoperative mortality rate for bariatric surgery is approximately 0.2%. Reoperation is required for up to 25% of patients within 5 years. Other complications are wound infection, staple failure, vitamin deficiency, diarrhea, and hemorrhage.³ The long-term health effects of bariatric surgery are not well known.

Recommendations from others

The NIH statement “Gastrointestinal Surgery for Severe Obesity” concluded that the benefits outweigh the risks and that surgical treatment is reasonable in those who strongly desire substantial weight loss and have life-threatening comorbid conditions.²

Clinical guidelines developed by the National Heart, Lung, and Blood Institute Expert Panel on the identification, evaluation, and treatment of obesity for adults recommend that bariatric surgery be an option for carefully selected patients with clinically severe obesity (BMI >40 or >35 with comorbid conditions) when less invasive methods of weight loss have failed and the patient is at high risk for obesity-associated morbidity and mortality.¹

The American Gastroenterological Association (AGA) medical position statement on obesity finds surgical therapy to be the most effective approach for achieving long-term weight loss. The AGA recommends surgery for patients with a BMI >40, or those with BMI >35 and 1 or more severe obesity-related medical complication (eg, hypertension, heart failure, or sleep apnea) if they have been unable to achieve or maintain weight loss with conventional therapy, have acceptable operative risks, and are able to comply with long-term treatment and follow-up.⁵

The American College of Preventive Medicine, in its policy statement on weight management counseling, recommends limiting surgical therapy for obesity to severely obese patients, defined as BMI >40.⁶

Evidence summary

Onset of diabetes in childhood with ketoacidosis and insulin dependency has traditionally been sufficient to diagnose type 1 diabetes, while onset in older, obese patients with primary insulin resistance suggested type 2 diabetes. Unfortunately, features of type 1 and type 2 diabetes may be present in the same patient, making differentiation difficult. No diagnostic studies in the literature were identified that definitively demonstrate how to separate type 1 from type 2 diabetes.

A patient’s age may suggest, but does not reliably distinguish, diabetes types. A study of 569 new-onset type 1 and type 2 diabetic children and adolescents showed that older age was only weakly associated with type 2 diagnosis (odds ratio [OR]= 1.4 for each 1-year increment in age; 95% confidence interval [CI], 1.3–1.6).² In fact, newly diagnosed 12-year-old children have an equal incidence of type 1 as type 2 diabetes. Likewise, adults with type 2 phenotype (no initial insulin requirement) can present with positive autoantibodies typically found in younger type 1 patients. Older patients who fit this profile have been classified as type 1.5 diabetes or latent autoimmune disease in adults (LADA).³

A history of diabetic ketoacidosis (DKA) also does not reliably distinguish between types 1 and 2. A retrospective chart review gathered data on adults over 18 years of age who were admitted for DKA in a urban US hospital. Many patients with DKA were subsequently diagnosed with type 2 diabetes. Rates of type 2 diabetes in patients with DKA varied by race: 47% of Hispanics, 44% of African Americans, and 17% of Caucasians had type 2 diabetes.⁴

The overlapping presence of autoantibodies in both types of diabetes limits their use (TABLE). Autoantibodies do predict an earlier need for insulin. One prevalence study of 101 type 2 adult patients found 20% were positive for glutamic acid decarboxylase autoantibody (GADAb), which was positively associated with insulin dependence at 4 years postdiagnosis (OR=5.8; 95% CI, 1.8–18.9).⁵ Eighty percent of patients with autoantibodies required insulin compared with 41% of patients without autoantibodies. Another study in young adults with type 2 or unclassified diabetes from Sweden found 93% of patients who were GADAb+ required insulin at 3 years, compared with 51% who were GADAb–(OR=18.8; 95% CI, 1.8–191).⁶

One motivation to study autoantibody testing is a potential benefit in preserving pancreatic function. Kobayashi proposed treating those with autoantibody-positive diabetes (presumed type 1 or type 1.5) with insulin immediately, while initiating oral medications in those who test negative (presumed type 2 diabetes). This approach lacks significant patient-oriented outcome data, but his small RCT of 55 patients was encouraging. With a 3-year follow-up rate of 89%, early insulin use in GADAb+ patients preserved C-peptide levels and possibly prolonged pancreatic beta cell survival.⁷ Insulin dependency, defined as needing insulin for survival, occurred in 47% of controls (who received oral sulfonylureas) and only 13% of patients receiving insulin (number needed to treat [NNT]= 4; P=.043).⁷ The theoretical benefit is that if beta cell exhaustion can be delayed, endogenous insulin production could be maintained to assist prevention of damaging postprandial glucose spikes.

Although daily variation in serum insulin levels limits its use, C-peptide levels show more promise. Random C-peptide levels were superior to fasting or glucagon stimulated levels in 1093 patients, who were followed for 3 years to confirm insulin requirements. Using a receiver operating characteristic (ROC) curve, the area under the curve for random C-peptide levels to distinguish diabetes types was 0.98 (95% CI, 0.97–0.99).⁸ For patients under the optimal cutoff of 0.5 nmol/L, the positive predictive value was 96% for diagnosing type 1 and the likelihood ratio was 22.5.

Finally, the ratio of adiponectin to leptin hormone may show diagnostic merit. Adipocytes secrete adiponectin which acts as an insulin sensitizer, antiatherogenic and anti-inflammatory agent. Obesity and type 2 phenotype correlate with lower levels of adiponectin, but are associated with higher levels of leptin hormone, another molecule secreted by adipocytes. A recent case-control study of children aged 6 to 21 years analyzed adiponectin and leptin hormone levels in patients with classical type 1 and 2 diabetes, as determined by 2 pediatric endocrinologists; interestingly, 29% of the type 1 patients were autoantibody negative.⁹ After plotting a ROC curve, they found the area under the curve was 0.97 (95% CI, 0.93–1.00). At an adiponectin-to-leptin ratio cutoff less than 0.7, they found the sensitivity to diagnose type 2 was 88% (95% CI, 64–99%), the specificity was 90% (95% CI, 77–97), and the likelihood ratio for a positive test was 8.8.⁹

TABLE 1
Antibody markers and diabetes type

Recommendations from others

The National Academy of Clinical Biochemistry and the American Association of Clinical Endocrinologists recommend against routine testing of insulin, C-peptide, autoantibodies and genetic markers.^1,10 Guidelines from the American Diabetes Association admit that many diabetic individuals do not easily fit into a distinct diagnostic category; however, they only provide criteria for the general diagnosis of diabetes, not specific criteria to distinguish type 1 from type 2.¹¹

Acknowledgments

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

Evidence summary

Onset of diabetes in childhood with ketoacidosis and insulin dependency has traditionally been sufficient to diagnose type 1 diabetes, while onset in older, obese patients with primary insulin resistance suggested type 2 diabetes. Unfortunately, features of type 1 and type 2 diabetes may be present in the same patient, making differentiation difficult. No diagnostic studies in the literature were identified that definitively demonstrate how to separate type 1 from type 2 diabetes.

A patient’s age may suggest, but does not reliably distinguish, diabetes types. A study of 569 new-onset type 1 and type 2 diabetic children and adolescents showed that older age was only weakly associated with type 2 diagnosis (odds ratio [OR]= 1.4 for each 1-year increment in age; 95% confidence interval [CI], 1.3–1.6).² In fact, newly diagnosed 12-year-old children have an equal incidence of type 1 as type 2 diabetes. Likewise, adults with type 2 phenotype (no initial insulin requirement) can present with positive autoantibodies typically found in younger type 1 patients. Older patients who fit this profile have been classified as type 1.5 diabetes or latent autoimmune disease in adults (LADA).³

A history of diabetic ketoacidosis (DKA) also does not reliably distinguish between types 1 and 2. A retrospective chart review gathered data on adults over 18 years of age who were admitted for DKA in a urban US hospital. Many patients with DKA were subsequently diagnosed with type 2 diabetes. Rates of type 2 diabetes in patients with DKA varied by race: 47% of Hispanics, 44% of African Americans, and 17% of Caucasians had type 2 diabetes.⁴

The overlapping presence of autoantibodies in both types of diabetes limits their use (TABLE). Autoantibodies do predict an earlier need for insulin. One prevalence study of 101 type 2 adult patients found 20% were positive for glutamic acid decarboxylase autoantibody (GADAb), which was positively associated with insulin dependence at 4 years postdiagnosis (OR=5.8; 95% CI, 1.8–18.9).⁵ Eighty percent of patients with autoantibodies required insulin compared with 41% of patients without autoantibodies. Another study in young adults with type 2 or unclassified diabetes from Sweden found 93% of patients who were GADAb+ required insulin at 3 years, compared with 51% who were GADAb–(OR=18.8; 95% CI, 1.8–191).⁶

One motivation to study autoantibody testing is a potential benefit in preserving pancreatic function. Kobayashi proposed treating those with autoantibody-positive diabetes (presumed type 1 or type 1.5) with insulin immediately, while initiating oral medications in those who test negative (presumed type 2 diabetes). This approach lacks significant patient-oriented outcome data, but his small RCT of 55 patients was encouraging. With a 3-year follow-up rate of 89%, early insulin use in GADAb+ patients preserved C-peptide levels and possibly prolonged pancreatic beta cell survival.⁷ Insulin dependency, defined as needing insulin for survival, occurred in 47% of controls (who received oral sulfonylureas) and only 13% of patients receiving insulin (number needed to treat [NNT]= 4; P=.043).⁷ The theoretical benefit is that if beta cell exhaustion can be delayed, endogenous insulin production could be maintained to assist prevention of damaging postprandial glucose spikes.

Although daily variation in serum insulin levels limits its use, C-peptide levels show more promise. Random C-peptide levels were superior to fasting or glucagon stimulated levels in 1093 patients, who were followed for 3 years to confirm insulin requirements. Using a receiver operating characteristic (ROC) curve, the area under the curve for random C-peptide levels to distinguish diabetes types was 0.98 (95% CI, 0.97–0.99).⁸ For patients under the optimal cutoff of 0.5 nmol/L, the positive predictive value was 96% for diagnosing type 1 and the likelihood ratio was 22.5.

Finally, the ratio of adiponectin to leptin hormone may show diagnostic merit. Adipocytes secrete adiponectin which acts as an insulin sensitizer, antiatherogenic and anti-inflammatory agent. Obesity and type 2 phenotype correlate with lower levels of adiponectin, but are associated with higher levels of leptin hormone, another molecule secreted by adipocytes. A recent case-control study of children aged 6 to 21 years analyzed adiponectin and leptin hormone levels in patients with classical type 1 and 2 diabetes, as determined by 2 pediatric endocrinologists; interestingly, 29% of the type 1 patients were autoantibody negative.⁹ After plotting a ROC curve, they found the area under the curve was 0.97 (95% CI, 0.93–1.00). At an adiponectin-to-leptin ratio cutoff less than 0.7, they found the sensitivity to diagnose type 2 was 88% (95% CI, 64–99%), the specificity was 90% (95% CI, 77–97), and the likelihood ratio for a positive test was 8.8.⁹

TABLE 1
Antibody markers and diabetes type

Recommendations from others

The National Academy of Clinical Biochemistry and the American Association of Clinical Endocrinologists recommend against routine testing of insulin, C-peptide, autoantibodies and genetic markers.^1,10 Guidelines from the American Diabetes Association admit that many diabetic individuals do not easily fit into a distinct diagnostic category; however, they only provide criteria for the general diagnosis of diabetes, not specific criteria to distinguish type 1 from type 2.¹¹

Acknowledgments

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

Evidence summary

Onset of diabetes in childhood with ketoacidosis and insulin dependency has traditionally been sufficient to diagnose type 1 diabetes, while onset in older, obese patients with primary insulin resistance suggested type 2 diabetes. Unfortunately, features of type 1 and type 2 diabetes may be present in the same patient, making differentiation difficult. No diagnostic studies in the literature were identified that definitively demonstrate how to separate type 1 from type 2 diabetes.

A patient’s age may suggest, but does not reliably distinguish, diabetes types. A study of 569 new-onset type 1 and type 2 diabetic children and adolescents showed that older age was only weakly associated with type 2 diagnosis (odds ratio [OR]= 1.4 for each 1-year increment in age; 95% confidence interval [CI], 1.3–1.6).² In fact, newly diagnosed 12-year-old children have an equal incidence of type 1 as type 2 diabetes. Likewise, adults with type 2 phenotype (no initial insulin requirement) can present with positive autoantibodies typically found in younger type 1 patients. Older patients who fit this profile have been classified as type 1.5 diabetes or latent autoimmune disease in adults (LADA).³

A history of diabetic ketoacidosis (DKA) also does not reliably distinguish between types 1 and 2. A retrospective chart review gathered data on adults over 18 years of age who were admitted for DKA in a urban US hospital. Many patients with DKA were subsequently diagnosed with type 2 diabetes. Rates of type 2 diabetes in patients with DKA varied by race: 47% of Hispanics, 44% of African Americans, and 17% of Caucasians had type 2 diabetes.⁴

The overlapping presence of autoantibodies in both types of diabetes limits their use (TABLE). Autoantibodies do predict an earlier need for insulin. One prevalence study of 101 type 2 adult patients found 20% were positive for glutamic acid decarboxylase autoantibody (GADAb), which was positively associated with insulin dependence at 4 years postdiagnosis (OR=5.8; 95% CI, 1.8–18.9).⁵ Eighty percent of patients with autoantibodies required insulin compared with 41% of patients without autoantibodies. Another study in young adults with type 2 or unclassified diabetes from Sweden found 93% of patients who were GADAb+ required insulin at 3 years, compared with 51% who were GADAb–(OR=18.8; 95% CI, 1.8–191).⁶

One motivation to study autoantibody testing is a potential benefit in preserving pancreatic function. Kobayashi proposed treating those with autoantibody-positive diabetes (presumed type 1 or type 1.5) with insulin immediately, while initiating oral medications in those who test negative (presumed type 2 diabetes). This approach lacks significant patient-oriented outcome data, but his small RCT of 55 patients was encouraging. With a 3-year follow-up rate of 89%, early insulin use in GADAb+ patients preserved C-peptide levels and possibly prolonged pancreatic beta cell survival.⁷ Insulin dependency, defined as needing insulin for survival, occurred in 47% of controls (who received oral sulfonylureas) and only 13% of patients receiving insulin (number needed to treat [NNT]= 4; P=.043).⁷ The theoretical benefit is that if beta cell exhaustion can be delayed, endogenous insulin production could be maintained to assist prevention of damaging postprandial glucose spikes.

Although daily variation in serum insulin levels limits its use, C-peptide levels show more promise. Random C-peptide levels were superior to fasting or glucagon stimulated levels in 1093 patients, who were followed for 3 years to confirm insulin requirements. Using a receiver operating characteristic (ROC) curve, the area under the curve for random C-peptide levels to distinguish diabetes types was 0.98 (95% CI, 0.97–0.99).⁸ For patients under the optimal cutoff of 0.5 nmol/L, the positive predictive value was 96% for diagnosing type 1 and the likelihood ratio was 22.5.

Finally, the ratio of adiponectin to leptin hormone may show diagnostic merit. Adipocytes secrete adiponectin which acts as an insulin sensitizer, antiatherogenic and anti-inflammatory agent. Obesity and type 2 phenotype correlate with lower levels of adiponectin, but are associated with higher levels of leptin hormone, another molecule secreted by adipocytes. A recent case-control study of children aged 6 to 21 years analyzed adiponectin and leptin hormone levels in patients with classical type 1 and 2 diabetes, as determined by 2 pediatric endocrinologists; interestingly, 29% of the type 1 patients were autoantibody negative.⁹ After plotting a ROC curve, they found the area under the curve was 0.97 (95% CI, 0.93–1.00). At an adiponectin-to-leptin ratio cutoff less than 0.7, they found the sensitivity to diagnose type 2 was 88% (95% CI, 64–99%), the specificity was 90% (95% CI, 77–97), and the likelihood ratio for a positive test was 8.8.⁹

TABLE 1
Antibody markers and diabetes type

Recommendations from others

The National Academy of Clinical Biochemistry and the American Association of Clinical Endocrinologists recommend against routine testing of insulin, C-peptide, autoantibodies and genetic markers.^1,10 Guidelines from the American Diabetes Association admit that many diabetic individuals do not easily fit into a distinct diagnostic category; however, they only provide criteria for the general diagnosis of diabetes, not specific criteria to distinguish type 1 from type 2.¹¹

Acknowledgments

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

Evidence summary

A systematic review of the literature on PPE identified 310 studies of athletes age <36 years. The authors searched multiple electronic databases and reviewed the bibliographies of retrieved articles but did not perform hand searches of journals or contact authors directly. The review did not find any prospective cohort or randomized trials addressing the effectiveness of clinical PPE. The 5 studies that assessed the format of the PPE concluded that it is not adequately standardized, does not consistently address the American Heart Association (AHA) recommendations for cardiovascular screening and exam, and is administered by a variety of health care professionals, some without proper training.¹

Sudden cardiac death is defined as a nontraumatic, nonviolent, unexpected event resulting from sudden cardiac arrest within 6 hours of a previously witnessed state of normal health.² Such events occur in about 1 in 200,000 high school athletes per academic year (about 16 deaths in the US annually). Detection of cardiovascular abnormalities that may cause morbidity or mortality is difficult. A case series reviewed 158 sudden deaths that occurred in trained athletes in the US from 1985 to 1995. The athletes were identified from news accounts, the National Center for Catastrophic Sports Injury Registry, and informal communications and reports. The authors interviewed families, witnesses, and coaches, and they analyzed postmortem information. Of the 115 athletes who had a standard preparticipation medical evaluation, only 4 (3%) were suspected of having cardiovascular disease. The cardiovascular abnormality responsible for sudden death was prospectively identified in only 1 athlete.³

PPE does not accurately identify student athletes with exercise-induced bronchospasm (EIB). Of the studies on EIB, the best was a prospective cross-sectional study of 352 adolescents from 3 suburban Washington state schools. The students completed a 14-item EIB questionnaire, had a physical exam, and underwent a 7-minute exercise challenge spirometry. Complete data were available for 256 of the students. EIB was diagnosed by spirometry in 9.4% of the athletes. No student had EIB detected solely by physical exam. Using a cutoff of 2 positive questions, the questionnaire had a sensitivity of 71% and a specificity of 47%, with a negative and positive predictive value of 6% and 12%, respectively. This study concluded that EIB occurs frequently in adolescent athletes, but screening by physical exam and medical history does not accurately detect it.⁴

PPEs are not able to predict which student athletes will experience an orthopedic injury, and no controlled studies have been done to determine whether PPE prevents or reduces the severity of orthopedic injuries. A study surveyed 1204 student athletes (aged 13–20 years) from Richmond County, Georgia, who had a standardized PPE before participating in sports. The questionnaire was administered via mail or telephone and inquired about injuries sustained after the PPE. The response rate to the survey was 56%. The study found that a history of knee or ankle injury and abnormal findings on exam in male athletes slightly increased the likelihood of repeated injury of the same joint. However, the sensitivities of history or physical exam for ankle or knee injuries were all <25%.⁵

Recommendations from others

The AHA recommends a national standard for PPE and that screening should be mandatory for all high school and college athletes before participation in organized sports, with screening repeated every 2 years, and an interim history obtained during the intervening years. Specific items are given in the TABLE.⁶

In 2004, the American Academy of Family Physicians, along with the American Academy of Pediatrics, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine, published recommendations for PPEs. They suggested a detailed history (consisting of a 16-point questionnaire incorporating AHA recommendations for cardiovascular screening), limited medical exam, and a detailed musculoskeletal exam evaluating strength, flexibility, and stability of major joints.⁷

TABLE
AHA recommendations for preparticipation exams

Evidence summary

A systematic review of the literature on PPE identified 310 studies of athletes age <36 years. The authors searched multiple electronic databases and reviewed the bibliographies of retrieved articles but did not perform hand searches of journals or contact authors directly. The review did not find any prospective cohort or randomized trials addressing the effectiveness of clinical PPE. The 5 studies that assessed the format of the PPE concluded that it is not adequately standardized, does not consistently address the American Heart Association (AHA) recommendations for cardiovascular screening and exam, and is administered by a variety of health care professionals, some without proper training.¹

Sudden cardiac death is defined as a nontraumatic, nonviolent, unexpected event resulting from sudden cardiac arrest within 6 hours of a previously witnessed state of normal health.² Such events occur in about 1 in 200,000 high school athletes per academic year (about 16 deaths in the US annually). Detection of cardiovascular abnormalities that may cause morbidity or mortality is difficult. A case series reviewed 158 sudden deaths that occurred in trained athletes in the US from 1985 to 1995. The athletes were identified from news accounts, the National Center for Catastrophic Sports Injury Registry, and informal communications and reports. The authors interviewed families, witnesses, and coaches, and they analyzed postmortem information. Of the 115 athletes who had a standard preparticipation medical evaluation, only 4 (3%) were suspected of having cardiovascular disease. The cardiovascular abnormality responsible for sudden death was prospectively identified in only 1 athlete.³

PPE does not accurately identify student athletes with exercise-induced bronchospasm (EIB). Of the studies on EIB, the best was a prospective cross-sectional study of 352 adolescents from 3 suburban Washington state schools. The students completed a 14-item EIB questionnaire, had a physical exam, and underwent a 7-minute exercise challenge spirometry. Complete data were available for 256 of the students. EIB was diagnosed by spirometry in 9.4% of the athletes. No student had EIB detected solely by physical exam. Using a cutoff of 2 positive questions, the questionnaire had a sensitivity of 71% and a specificity of 47%, with a negative and positive predictive value of 6% and 12%, respectively. This study concluded that EIB occurs frequently in adolescent athletes, but screening by physical exam and medical history does not accurately detect it.⁴

PPEs are not able to predict which student athletes will experience an orthopedic injury, and no controlled studies have been done to determine whether PPE prevents or reduces the severity of orthopedic injuries. A study surveyed 1204 student athletes (aged 13–20 years) from Richmond County, Georgia, who had a standardized PPE before participating in sports. The questionnaire was administered via mail or telephone and inquired about injuries sustained after the PPE. The response rate to the survey was 56%. The study found that a history of knee or ankle injury and abnormal findings on exam in male athletes slightly increased the likelihood of repeated injury of the same joint. However, the sensitivities of history or physical exam for ankle or knee injuries were all <25%.⁵

Recommendations from others

The AHA recommends a national standard for PPE and that screening should be mandatory for all high school and college athletes before participation in organized sports, with screening repeated every 2 years, and an interim history obtained during the intervening years. Specific items are given in the TABLE.⁶

In 2004, the American Academy of Family Physicians, along with the American Academy of Pediatrics, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine, published recommendations for PPEs. They suggested a detailed history (consisting of a 16-point questionnaire incorporating AHA recommendations for cardiovascular screening), limited medical exam, and a detailed musculoskeletal exam evaluating strength, flexibility, and stability of major joints.⁷

TABLE
AHA recommendations for preparticipation exams

Evidence summary

A systematic review of the literature on PPE identified 310 studies of athletes age <36 years. The authors searched multiple electronic databases and reviewed the bibliographies of retrieved articles but did not perform hand searches of journals or contact authors directly. The review did not find any prospective cohort or randomized trials addressing the effectiveness of clinical PPE. The 5 studies that assessed the format of the PPE concluded that it is not adequately standardized, does not consistently address the American Heart Association (AHA) recommendations for cardiovascular screening and exam, and is administered by a variety of health care professionals, some without proper training.¹

Sudden cardiac death is defined as a nontraumatic, nonviolent, unexpected event resulting from sudden cardiac arrest within 6 hours of a previously witnessed state of normal health.² Such events occur in about 1 in 200,000 high school athletes per academic year (about 16 deaths in the US annually). Detection of cardiovascular abnormalities that may cause morbidity or mortality is difficult. A case series reviewed 158 sudden deaths that occurred in trained athletes in the US from 1985 to 1995. The athletes were identified from news accounts, the National Center for Catastrophic Sports Injury Registry, and informal communications and reports. The authors interviewed families, witnesses, and coaches, and they analyzed postmortem information. Of the 115 athletes who had a standard preparticipation medical evaluation, only 4 (3%) were suspected of having cardiovascular disease. The cardiovascular abnormality responsible for sudden death was prospectively identified in only 1 athlete.³

PPE does not accurately identify student athletes with exercise-induced bronchospasm (EIB). Of the studies on EIB, the best was a prospective cross-sectional study of 352 adolescents from 3 suburban Washington state schools. The students completed a 14-item EIB questionnaire, had a physical exam, and underwent a 7-minute exercise challenge spirometry. Complete data were available for 256 of the students. EIB was diagnosed by spirometry in 9.4% of the athletes. No student had EIB detected solely by physical exam. Using a cutoff of 2 positive questions, the questionnaire had a sensitivity of 71% and a specificity of 47%, with a negative and positive predictive value of 6% and 12%, respectively. This study concluded that EIB occurs frequently in adolescent athletes, but screening by physical exam and medical history does not accurately detect it.⁴

PPEs are not able to predict which student athletes will experience an orthopedic injury, and no controlled studies have been done to determine whether PPE prevents or reduces the severity of orthopedic injuries. A study surveyed 1204 student athletes (aged 13–20 years) from Richmond County, Georgia, who had a standardized PPE before participating in sports. The questionnaire was administered via mail or telephone and inquired about injuries sustained after the PPE. The response rate to the survey was 56%. The study found that a history of knee or ankle injury and abnormal findings on exam in male athletes slightly increased the likelihood of repeated injury of the same joint. However, the sensitivities of history or physical exam for ankle or knee injuries were all <25%.⁵

Recommendations from others

The AHA recommends a national standard for PPE and that screening should be mandatory for all high school and college athletes before participation in organized sports, with screening repeated every 2 years, and an interim history obtained during the intervening years. Specific items are given in the TABLE.⁶

In 2004, the American Academy of Family Physicians, along with the American Academy of Pediatrics, American College of Sports Medicine, American Medical Society for Sports Medicine, American Orthopedic Society for Sports Medicine, and the American Osteopathic Academy of Sports Medicine, published recommendations for PPEs. They suggested a detailed history (consisting of a 16-point questionnaire incorporating AHA recommendations for cardiovascular screening), limited medical exam, and a detailed musculoskeletal exam evaluating strength, flexibility, and stability of major joints.⁷

TABLE
AHA recommendations for preparticipation exams

Evidence summary

Approximately 4 million people in the United States suffer with Alzheimer’s disease. The prevalence rises with age and is approximately 47% among those aged 85 years and older.⁷

Amyloid plaques are thought to be responsible for clinical changes associated with Alzheimer’s dementia. Research has indicated that amyloid precursors may be more prevalent in a cholesterol-rich environment. This led to the theory that treating hypercholesterolemia may decrease the prevalence of Alzheimer’s disease.⁸

The PROSPER trial, which was designed to test the effect of pravastatin (Pravachol) on coronary heart disease and stroke, randomized 5804 study participants into 1 group assigned to take pravastatin and another group assigned to take placebo. An additional study endpoint was pravastatin’s effect on cognitive function as measured by 4 different tests, including the Mini-Mental Status Exam (MMSE). Overall cognitive function declined at the same rate in treatment and placebo groups. There was no significant difference between the 2 groups over 3 years using 4 different methods of assessment. In particular, the MMSE scores differed by only 0.06 points (95% confidence interval [CI], 0.04–0.16; P=.26).

The largest RCT of a statin agent, the Heart Protection Study, enrolled more than 20,000 people and randomized them to simvastatin (Zocor) or placebo. After a median of 5 years of follow-up, there was no difference in cognitive scores or the rate of diagnosis of dementia between the 2 groups.²

A systematic review concluded that no good evidence recommended statins for reducing the risk of Alzheimer’s dementia.³ Notably, the review did find a body of inconclusive evidence that lowering serum cholesterol may retard disease pathogenesis. An observational study of 56,790 charts included in the computer databases of 3 hospitals found that the prevalence of probable Alzheimer’s dementia in the cohort taking statins was 60% to 73% (P<.001) lower than in the total patient population or in patients taking antihypertensive or cardiovascular medications.⁴

Also included in the review was a nested case-control study of 1364 patients that found an adjusted relative risk for dementia of 0.29 (95% CI, 0.013–0.063; P=.002) among those taking statins.⁵ This study did not distinguish between Alzheimer’s dementia and other forms of dementia. These studies do not demonstrate a causal relationship between statins and Alzheimer’s dementia.

The best way to determine if there is a true effect of statins on Alzheimer’s dementia is to conduct a clinical trial. Two ongoing clinical trials are designed specifically to determine if the use of statins delay the onset or slow the progression of Alzheimer’s dementia.^9,10 To date, these trials have not published interim findings.

Recommendations from others

No organization has issued recommendations for the use of statins to delay the onset or slow the progression of Alzheimer’s dementia.

Evidence summary

Approximately 4 million people in the United States suffer with Alzheimer’s disease. The prevalence rises with age and is approximately 47% among those aged 85 years and older.⁷

Amyloid plaques are thought to be responsible for clinical changes associated with Alzheimer’s dementia. Research has indicated that amyloid precursors may be more prevalent in a cholesterol-rich environment. This led to the theory that treating hypercholesterolemia may decrease the prevalence of Alzheimer’s disease.⁸

The PROSPER trial, which was designed to test the effect of pravastatin (Pravachol) on coronary heart disease and stroke, randomized 5804 study participants into 1 group assigned to take pravastatin and another group assigned to take placebo. An additional study endpoint was pravastatin’s effect on cognitive function as measured by 4 different tests, including the Mini-Mental Status Exam (MMSE). Overall cognitive function declined at the same rate in treatment and placebo groups. There was no significant difference between the 2 groups over 3 years using 4 different methods of assessment. In particular, the MMSE scores differed by only 0.06 points (95% confidence interval [CI], 0.04–0.16; P=.26).

The largest RCT of a statin agent, the Heart Protection Study, enrolled more than 20,000 people and randomized them to simvastatin (Zocor) or placebo. After a median of 5 years of follow-up, there was no difference in cognitive scores or the rate of diagnosis of dementia between the 2 groups.²

A systematic review concluded that no good evidence recommended statins for reducing the risk of Alzheimer’s dementia.³ Notably, the review did find a body of inconclusive evidence that lowering serum cholesterol may retard disease pathogenesis. An observational study of 56,790 charts included in the computer databases of 3 hospitals found that the prevalence of probable Alzheimer’s dementia in the cohort taking statins was 60% to 73% (P<.001) lower than in the total patient population or in patients taking antihypertensive or cardiovascular medications.⁴

Also included in the review was a nested case-control study of 1364 patients that found an adjusted relative risk for dementia of 0.29 (95% CI, 0.013–0.063; P=.002) among those taking statins.⁵ This study did not distinguish between Alzheimer’s dementia and other forms of dementia. These studies do not demonstrate a causal relationship between statins and Alzheimer’s dementia.

The best way to determine if there is a true effect of statins on Alzheimer’s dementia is to conduct a clinical trial. Two ongoing clinical trials are designed specifically to determine if the use of statins delay the onset or slow the progression of Alzheimer’s dementia.^9,10 To date, these trials have not published interim findings.

Recommendations from others

No organization has issued recommendations for the use of statins to delay the onset or slow the progression of Alzheimer’s dementia.

Evidence summary

Approximately 4 million people in the United States suffer with Alzheimer’s disease. The prevalence rises with age and is approximately 47% among those aged 85 years and older.⁷

Amyloid plaques are thought to be responsible for clinical changes associated with Alzheimer’s dementia. Research has indicated that amyloid precursors may be more prevalent in a cholesterol-rich environment. This led to the theory that treating hypercholesterolemia may decrease the prevalence of Alzheimer’s disease.⁸

The PROSPER trial, which was designed to test the effect of pravastatin (Pravachol) on coronary heart disease and stroke, randomized 5804 study participants into 1 group assigned to take pravastatin and another group assigned to take placebo. An additional study endpoint was pravastatin’s effect on cognitive function as measured by 4 different tests, including the Mini-Mental Status Exam (MMSE). Overall cognitive function declined at the same rate in treatment and placebo groups. There was no significant difference between the 2 groups over 3 years using 4 different methods of assessment. In particular, the MMSE scores differed by only 0.06 points (95% confidence interval [CI], 0.04–0.16; P=.26).

The largest RCT of a statin agent, the Heart Protection Study, enrolled more than 20,000 people and randomized them to simvastatin (Zocor) or placebo. After a median of 5 years of follow-up, there was no difference in cognitive scores or the rate of diagnosis of dementia between the 2 groups.²

A systematic review concluded that no good evidence recommended statins for reducing the risk of Alzheimer’s dementia.³ Notably, the review did find a body of inconclusive evidence that lowering serum cholesterol may retard disease pathogenesis. An observational study of 56,790 charts included in the computer databases of 3 hospitals found that the prevalence of probable Alzheimer’s dementia in the cohort taking statins was 60% to 73% (P<.001) lower than in the total patient population or in patients taking antihypertensive or cardiovascular medications.⁴

Also included in the review was a nested case-control study of 1364 patients that found an adjusted relative risk for dementia of 0.29 (95% CI, 0.013–0.063; P=.002) among those taking statins.⁵ This study did not distinguish between Alzheimer’s dementia and other forms of dementia. These studies do not demonstrate a causal relationship between statins and Alzheimer’s dementia.

The best way to determine if there is a true effect of statins on Alzheimer’s dementia is to conduct a clinical trial. Two ongoing clinical trials are designed specifically to determine if the use of statins delay the onset or slow the progression of Alzheimer’s dementia.^9,10 To date, these trials have not published interim findings.

Recommendations from others

No organization has issued recommendations for the use of statins to delay the onset or slow the progression of Alzheimer’s dementia.

Evidence summary

Infection with hepatitis A virus (HAV) is a reportable illness in all 50 states, and it continues to be one of the most reported vaccine-preventable illnesses. The persistence of extensive community-wide outbreaks indicates that hepatitis A remains a major public health problem.

The costs associated with HAV are substantial: 11% to 22% of individuals with HAV are hospitalized, and adults who become ill lose an average of 27 days of work. The average cost of hepatitis A ranges from $1817 to $2459 per case for adults and $433 to $1492 for children. In 1989, the estimated annual direct and indirect costs of HAV in the United States were more then $300 million (in 1997 dollars).¹

Hepatitis A can produce either asymptomatic or symptomatic infection in humans after an average incubation period of 28 days. The illness is usually marked by a sudden onset of symptoms including fever, malaise, nausea, anorexia, abdominal discomfort, jaundice, and dark urine. The illness usually lasts less than 2 months. Though not usually life threatening, an estimated 100 deaths annually are attributed to acute liver failure due to hepatitis A. Patients with chronic liver disease may be at higher risk of developing fulminant hepatitis A.^2,3 The likelihood of symptomatic disease is directly related to age, with 70% of adults developing jaundice and most infections in children aged <6 years having no symptoms.

HAV is transmitted primarily from fecal-oral route by either person-to-person contact or ingestion of fecally contaminated food or water. Although rare, it is possible for transmission by blood or blood products collected from donors during the viremic phase of their infection. Although HAV has been detected in saliva, transmission by saliva has not been demonstrated. Under the right conditions HAV can be stable in the environment for months. Heating foods to >185° F for 1 minute or disinfecting surfaces with 1:100 dilution of bleach in tap water is necessary to inactivate HAV.¹

Vaccination against HAV is recommended for those at high risk for contracting the illness or for any person wishing to obtain immunity. Prospective studies indicate that persons traveling in areas with high rates of HAV are themselves at 44 times increased risk.⁴ Among men who have sex with men, numerous cohort studies reveal increased rates of infection due to anal-oral sexual practices and higher number of sexual partners.^5-7 Intravenous drug users and non-IV illicit drug users are both at increased risk of HAV infection.^8-10 In the United States, children living in states with increased HAV incidence rates are also considered to be at high risk.¹ Less strong evidence exists for vaccinating those with occupational hazards (for example, working in a research setting with nonhuman primates) or persons with clotting factor disorders.^11,12

A corollary question is who does not routinely need hepatitis A vaccine. In general, food service workers, sewerage workers, healthcare workers, children aged <2 years, day-care attendees, and residents of institutions for the developmentally disabled do not need routine immunization

The currently licensed inactivated hepatitis A vaccines are highly immunogenic and clinically effective in children 2 to 18 years and in adults. In a double-blind, controlled, randomized study of 1000 children in New York revealed clinical efficacy of 100%.¹³ A second study of 40,000 children in Thailand had a clinical efficacy of 94%.¹³ Numerous other studies have supported findings of near 100% immuno-genicity in all age groups and clinical efficacy in all age groups.¹

Evidence summary

Infection with hepatitis A virus (HAV) is a reportable illness in all 50 states, and it continues to be one of the most reported vaccine-preventable illnesses. The persistence of extensive community-wide outbreaks indicates that hepatitis A remains a major public health problem.

The costs associated with HAV are substantial: 11% to 22% of individuals with HAV are hospitalized, and adults who become ill lose an average of 27 days of work. The average cost of hepatitis A ranges from $1817 to $2459 per case for adults and $433 to $1492 for children. In 1989, the estimated annual direct and indirect costs of HAV in the United States were more then $300 million (in 1997 dollars).¹

Hepatitis A can produce either asymptomatic or symptomatic infection in humans after an average incubation period of 28 days. The illness is usually marked by a sudden onset of symptoms including fever, malaise, nausea, anorexia, abdominal discomfort, jaundice, and dark urine. The illness usually lasts less than 2 months. Though not usually life threatening, an estimated 100 deaths annually are attributed to acute liver failure due to hepatitis A. Patients with chronic liver disease may be at higher risk of developing fulminant hepatitis A.^2,3 The likelihood of symptomatic disease is directly related to age, with 70% of adults developing jaundice and most infections in children aged <6 years having no symptoms.

HAV is transmitted primarily from fecal-oral route by either person-to-person contact or ingestion of fecally contaminated food or water. Although rare, it is possible for transmission by blood or blood products collected from donors during the viremic phase of their infection. Although HAV has been detected in saliva, transmission by saliva has not been demonstrated. Under the right conditions HAV can be stable in the environment for months. Heating foods to >185° F for 1 minute or disinfecting surfaces with 1:100 dilution of bleach in tap water is necessary to inactivate HAV.¹

Vaccination against HAV is recommended for those at high risk for contracting the illness or for any person wishing to obtain immunity. Prospective studies indicate that persons traveling in areas with high rates of HAV are themselves at 44 times increased risk.⁴ Among men who have sex with men, numerous cohort studies reveal increased rates of infection due to anal-oral sexual practices and higher number of sexual partners.^5-7 Intravenous drug users and non-IV illicit drug users are both at increased risk of HAV infection.^8-10 In the United States, children living in states with increased HAV incidence rates are also considered to be at high risk.¹ Less strong evidence exists for vaccinating those with occupational hazards (for example, working in a research setting with nonhuman primates) or persons with clotting factor disorders.^11,12

A corollary question is who does not routinely need hepatitis A vaccine. In general, food service workers, sewerage workers, healthcare workers, children aged <2 years, day-care attendees, and residents of institutions for the developmentally disabled do not need routine immunization

The currently licensed inactivated hepatitis A vaccines are highly immunogenic and clinically effective in children 2 to 18 years and in adults. In a double-blind, controlled, randomized study of 1000 children in New York revealed clinical efficacy of 100%.¹³ A second study of 40,000 children in Thailand had a clinical efficacy of 94%.¹³ Numerous other studies have supported findings of near 100% immuno-genicity in all age groups and clinical efficacy in all age groups.¹

Evidence summary

Infection with hepatitis A virus (HAV) is a reportable illness in all 50 states, and it continues to be one of the most reported vaccine-preventable illnesses. The persistence of extensive community-wide outbreaks indicates that hepatitis A remains a major public health problem.

The costs associated with HAV are substantial: 11% to 22% of individuals with HAV are hospitalized, and adults who become ill lose an average of 27 days of work. The average cost of hepatitis A ranges from $1817 to $2459 per case for adults and $433 to $1492 for children. In 1989, the estimated annual direct and indirect costs of HAV in the United States were more then $300 million (in 1997 dollars).¹

Hepatitis A can produce either asymptomatic or symptomatic infection in humans after an average incubation period of 28 days. The illness is usually marked by a sudden onset of symptoms including fever, malaise, nausea, anorexia, abdominal discomfort, jaundice, and dark urine. The illness usually lasts less than 2 months. Though not usually life threatening, an estimated 100 deaths annually are attributed to acute liver failure due to hepatitis A. Patients with chronic liver disease may be at higher risk of developing fulminant hepatitis A.^2,3 The likelihood of symptomatic disease is directly related to age, with 70% of adults developing jaundice and most infections in children aged <6 years having no symptoms.

HAV is transmitted primarily from fecal-oral route by either person-to-person contact or ingestion of fecally contaminated food or water. Although rare, it is possible for transmission by blood or blood products collected from donors during the viremic phase of their infection. Although HAV has been detected in saliva, transmission by saliva has not been demonstrated. Under the right conditions HAV can be stable in the environment for months. Heating foods to >185° F for 1 minute or disinfecting surfaces with 1:100 dilution of bleach in tap water is necessary to inactivate HAV.¹

Vaccination against HAV is recommended for those at high risk for contracting the illness or for any person wishing to obtain immunity. Prospective studies indicate that persons traveling in areas with high rates of HAV are themselves at 44 times increased risk.⁴ Among men who have sex with men, numerous cohort studies reveal increased rates of infection due to anal-oral sexual practices and higher number of sexual partners.^5-7 Intravenous drug users and non-IV illicit drug users are both at increased risk of HAV infection.^8-10 In the United States, children living in states with increased HAV incidence rates are also considered to be at high risk.¹ Less strong evidence exists for vaccinating those with occupational hazards (for example, working in a research setting with nonhuman primates) or persons with clotting factor disorders.^11,12

A corollary question is who does not routinely need hepatitis A vaccine. In general, food service workers, sewerage workers, healthcare workers, children aged <2 years, day-care attendees, and residents of institutions for the developmentally disabled do not need routine immunization

The currently licensed inactivated hepatitis A vaccines are highly immunogenic and clinically effective in children 2 to 18 years and in adults. In a double-blind, controlled, randomized study of 1000 children in New York revealed clinical efficacy of 100%.¹³ A second study of 40,000 children in Thailand had a clinical efficacy of 94%.¹³ Numerous other studies have supported findings of near 100% immuno-genicity in all age groups and clinical efficacy in all age groups.¹

Evidence summary

Public misperceptions and provider uncertainty about contraindications create missed opportunities for immunization.^1-3 The Centers for Disease Control and Prevention (CDC) defines contraindications as conditions that increase the risk of a serious reaction to vaccination. Precautions are conditions that might increase the risk of a serious reaction, or that diminish vaccine efficiency.⁴ Recommendations about contraindications and precautions for vaccine administration are partially based on studies of adverse effects (see the TABLE for common situations). Complete information on the contraindications and precautions for all common vaccinations can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm#tab5.⁴

Data on vaccination risks are limited by a relative lack of experimental studies. Initial recommendations of the Advisory Council on Immunization Practices have been based on the findings of a 14-member Institute of Medicine (IOM) expert committee and are updated regularly.^5-7 The IOM committee reported that because vaccine-related adverse events occur infrequently, available randomized controlled trials were too small to detect differences in incidence.⁶ Much of the data come from adverse effect surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS), to which health care providers report possible adverse effects of vaccinations.

Updated contraindications by ACIP to the initial IOM recommendations have also been based on observational reports and studies.⁴ A recent Cochrane review on acellular pertussis vaccines concluded that the acellular vaccine had fewer adverse effects than the whole-cell version, but did not support any changes in contraindications or precautions.⁸

TABLE
Contraindications and precautions for vaccine administration

Recommendations from others

The ACIP recommendations serve as national standards and have been adopted by American Academy of Pediatrics and the American Academy of Family Physicians and are included in most standard reference texts.^4,9

Evidence summary

Public misperceptions and provider uncertainty about contraindications create missed opportunities for immunization.^1-3 The Centers for Disease Control and Prevention (CDC) defines contraindications as conditions that increase the risk of a serious reaction to vaccination. Precautions are conditions that might increase the risk of a serious reaction, or that diminish vaccine efficiency.⁴ Recommendations about contraindications and precautions for vaccine administration are partially based on studies of adverse effects (see the TABLE for common situations). Complete information on the contraindications and precautions for all common vaccinations can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm#tab5.⁴

Data on vaccination risks are limited by a relative lack of experimental studies. Initial recommendations of the Advisory Council on Immunization Practices have been based on the findings of a 14-member Institute of Medicine (IOM) expert committee and are updated regularly.^5-7 The IOM committee reported that because vaccine-related adverse events occur infrequently, available randomized controlled trials were too small to detect differences in incidence.⁶ Much of the data come from adverse effect surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS), to which health care providers report possible adverse effects of vaccinations.

Updated contraindications by ACIP to the initial IOM recommendations have also been based on observational reports and studies.⁴ A recent Cochrane review on acellular pertussis vaccines concluded that the acellular vaccine had fewer adverse effects than the whole-cell version, but did not support any changes in contraindications or precautions.⁸

TABLE
Contraindications and precautions for vaccine administration

Recommendations from others

The ACIP recommendations serve as national standards and have been adopted by American Academy of Pediatrics and the American Academy of Family Physicians and are included in most standard reference texts.^4,9

Evidence summary

Public misperceptions and provider uncertainty about contraindications create missed opportunities for immunization.^1-3 The Centers for Disease Control and Prevention (CDC) defines contraindications as conditions that increase the risk of a serious reaction to vaccination. Precautions are conditions that might increase the risk of a serious reaction, or that diminish vaccine efficiency.⁴ Recommendations about contraindications and precautions for vaccine administration are partially based on studies of adverse effects (see the TABLE for common situations). Complete information on the contraindications and precautions for all common vaccinations can be accessed at www.cdc.gov/mmwr/preview/mmwrhtml/rr5102a1.htm#tab5.⁴

Data on vaccination risks are limited by a relative lack of experimental studies. Initial recommendations of the Advisory Council on Immunization Practices have been based on the findings of a 14-member Institute of Medicine (IOM) expert committee and are updated regularly.^5-7 The IOM committee reported that because vaccine-related adverse events occur infrequently, available randomized controlled trials were too small to detect differences in incidence.⁶ Much of the data come from adverse effect surveillance systems, such as the Vaccine Adverse Event Reporting System (VAERS), to which health care providers report possible adverse effects of vaccinations.

Updated contraindications by ACIP to the initial IOM recommendations have also been based on observational reports and studies.⁴ A recent Cochrane review on acellular pertussis vaccines concluded that the acellular vaccine had fewer adverse effects than the whole-cell version, but did not support any changes in contraindications or precautions.⁸

TABLE
Contraindications and precautions for vaccine administration

Recommendations from others

The ACIP recommendations serve as national standards and have been adopted by American Academy of Pediatrics and the American Academy of Family Physicians and are included in most standard reference texts.^4,9