Jon O. Neher, MD

Evidence summary

A prospective RCT found that medical therapy, radioablation with iodine-131 (¹³¹I), and surgery produced similar control of Graves’ hyperthyroidism in 179 patients.¹ Investigators stratified patients by age, assigning younger patients (20-34 years; N=60) to antithyroid medication (methimazole and a β-blocker) for 18 months or subtotal thyroidectomy and older patients (35-55 years; N=119) to 18 months of antithyroid medication, subtotal thyroidectomy, or ¹³¹I radioablation.

After 6 weeks, all therapies produced serum triiodothyronine levels of less than 2.5 nmol/L (data extracted from table; no comparison statistic given). Patients were followed for 48 to 121 months (average follow-up time not given). Investigators found no significant differences in sick leave (72 vs 83 days for medical treatment compared with radioablation; no comparison statistic given) or patient satisfaction (95% for both medical treatment and radioablation; no comparison statistic given).

Medication (initially methimazole) was changed in 16% of patients because of adverse effects. More than a third of patients relapsed after medications were stopped (time to relapse 1-57 months); 21% relapsed after a single ¹³¹I treatment (time to relapse 5-16 months).

In another study, radioablation outperforms medication
A retrospective case series found that radioablation resolved hyperthyroidism more often than medical therapy among 194 consecutive Saudi Arabian patients (mean age 32 years) diagnosed with Graves’ disease and followed for an average of 50 months.² One dose of radioiodine (13-15 mCi) cured hyperthyroidism in 83% of patients, whereas 18 months of medical therapy produced remission lasting at least 6 months past the end of therapy in only 26% of patients (no comparison statistic given).

The presence of TAO at diagnosis increased the likelihood of radioablation failure (odds ratio for failure to respond to single dose of radioiodine=6.4; 95% confidence interval [CI], 1.51-24.4; P<.01). A major weakness of the study was that the investigators didn’t describe the medication therapy clearly.

More patients develop TAO after radioablation than medical therapy
An RCT found that radioablation is more commonly associated with development of TAO than medical therapy.³ When investigators randomized 313 patients to receive ¹³¹I radioablation or medical therapy for 18 months and followed them for as long as 4 years, more patients receiving radioablation developed TAO (38% compared with 18% for medical therapy, using intention-to-treat analysis; P<.001; number needed to harm [NNH]=5). Twenty-five percent of patients initially receiving medical therapy later underwent radioablation, but these patients didn’t develop TAO at a higher rate.

An earlier meta-analysis of 2 RCTs (N=189) also found an increased risk of TAO with radioablation compared with medical therapy.⁴ Patients receiving radioablation were more likely to develop TAO (18% vs 4%; relative risk [RR]=4.2; 95% CI, 2.0-8.8; NNH=7) and more likely to develop severe TAO (10% vs 1.6%; RR=4.4; 95% CI, 1.3-15; NNH=12). Adjunctive use of steroids with radioablation didn’t alter the risk of new TAO. However, steroid prophylaxis in patients with preexisting TAO significantly reduced the risk of progression after radioablation (RR=0.03; 95% CI, 0.00-0.24). The authors of the meta-analysis didn’t evaluate the quality of the RCTs.

Despite low neoplasia risk, radioablation isn’t for young children
Expert guidelines state that the goal of radioablation is to induce lifelong hypothyroidism, which is managed with thyroid hormone replacement.⁵ The risk of neoplasia after radioablation is believed to be low with appropriate dosing. However, based on “theoretical concerns,” experts don’t recommend using radioiodine in children younger than 5 years and advise limited use in children 5 to 10 years of age.⁵

Medication adverse effects include rashes, transient agranulocytosis
A Cochrane review with 7 RCTs (N=620) describing withdrawal rates for patients receiving medication for Graves’ disease found that 9% to 16% of patients discontinued treatment because of adverse effects.⁶ Rashes were the most common adverse effect (6%-10% of patients), but as many as 3% of patients developed transient agranulocytosis. In addition, patients on medication need frequent blood tests to monitor for thyroid activity and potential toxicity.

Recommendations

The guidelines of the American Thyroid Association and the American Association of Clinical Endocrinologists state that overt Graves’ hyperthyroidism may be treated with any of the following: ¹³¹I radioablation, antithyroid medication, or thyroidectomy.³ Patient characteristics (pregnancy, mild disease, goiter compression symptoms) should help determine the appropriate option in any given case.

Evidence summary

A prospective RCT found that medical therapy, radioablation with iodine-131 (¹³¹I), and surgery produced similar control of Graves’ hyperthyroidism in 179 patients.¹ Investigators stratified patients by age, assigning younger patients (20-34 years; N=60) to antithyroid medication (methimazole and a β-blocker) for 18 months or subtotal thyroidectomy and older patients (35-55 years; N=119) to 18 months of antithyroid medication, subtotal thyroidectomy, or ¹³¹I radioablation.

After 6 weeks, all therapies produced serum triiodothyronine levels of less than 2.5 nmol/L (data extracted from table; no comparison statistic given). Patients were followed for 48 to 121 months (average follow-up time not given). Investigators found no significant differences in sick leave (72 vs 83 days for medical treatment compared with radioablation; no comparison statistic given) or patient satisfaction (95% for both medical treatment and radioablation; no comparison statistic given).

Medication (initially methimazole) was changed in 16% of patients because of adverse effects. More than a third of patients relapsed after medications were stopped (time to relapse 1-57 months); 21% relapsed after a single ¹³¹I treatment (time to relapse 5-16 months).

In another study, radioablation outperforms medication
A retrospective case series found that radioablation resolved hyperthyroidism more often than medical therapy among 194 consecutive Saudi Arabian patients (mean age 32 years) diagnosed with Graves’ disease and followed for an average of 50 months.² One dose of radioiodine (13-15 mCi) cured hyperthyroidism in 83% of patients, whereas 18 months of medical therapy produced remission lasting at least 6 months past the end of therapy in only 26% of patients (no comparison statistic given).

The presence of TAO at diagnosis increased the likelihood of radioablation failure (odds ratio for failure to respond to single dose of radioiodine=6.4; 95% confidence interval [CI], 1.51-24.4; P<.01). A major weakness of the study was that the investigators didn’t describe the medication therapy clearly.

More patients develop TAO after radioablation than medical therapy
An RCT found that radioablation is more commonly associated with development of TAO than medical therapy.³ When investigators randomized 313 patients to receive ¹³¹I radioablation or medical therapy for 18 months and followed them for as long as 4 years, more patients receiving radioablation developed TAO (38% compared with 18% for medical therapy, using intention-to-treat analysis; P<.001; number needed to harm [NNH]=5). Twenty-five percent of patients initially receiving medical therapy later underwent radioablation, but these patients didn’t develop TAO at a higher rate.

An earlier meta-analysis of 2 RCTs (N=189) also found an increased risk of TAO with radioablation compared with medical therapy.⁴ Patients receiving radioablation were more likely to develop TAO (18% vs 4%; relative risk [RR]=4.2; 95% CI, 2.0-8.8; NNH=7) and more likely to develop severe TAO (10% vs 1.6%; RR=4.4; 95% CI, 1.3-15; NNH=12). Adjunctive use of steroids with radioablation didn’t alter the risk of new TAO. However, steroid prophylaxis in patients with preexisting TAO significantly reduced the risk of progression after radioablation (RR=0.03; 95% CI, 0.00-0.24). The authors of the meta-analysis didn’t evaluate the quality of the RCTs.

Despite low neoplasia risk, radioablation isn’t for young children
Expert guidelines state that the goal of radioablation is to induce lifelong hypothyroidism, which is managed with thyroid hormone replacement.⁵ The risk of neoplasia after radioablation is believed to be low with appropriate dosing. However, based on “theoretical concerns,” experts don’t recommend using radioiodine in children younger than 5 years and advise limited use in children 5 to 10 years of age.⁵

Medication adverse effects include rashes, transient agranulocytosis
A Cochrane review with 7 RCTs (N=620) describing withdrawal rates for patients receiving medication for Graves’ disease found that 9% to 16% of patients discontinued treatment because of adverse effects.⁶ Rashes were the most common adverse effect (6%-10% of patients), but as many as 3% of patients developed transient agranulocytosis. In addition, patients on medication need frequent blood tests to monitor for thyroid activity and potential toxicity.

Recommendations

The guidelines of the American Thyroid Association and the American Association of Clinical Endocrinologists state that overt Graves’ hyperthyroidism may be treated with any of the following: ¹³¹I radioablation, antithyroid medication, or thyroidectomy.³ Patient characteristics (pregnancy, mild disease, goiter compression symptoms) should help determine the appropriate option in any given case.

Evidence summary

A prospective RCT found that medical therapy, radioablation with iodine-131 (¹³¹I), and surgery produced similar control of Graves’ hyperthyroidism in 179 patients.¹ Investigators stratified patients by age, assigning younger patients (20-34 years; N=60) to antithyroid medication (methimazole and a β-blocker) for 18 months or subtotal thyroidectomy and older patients (35-55 years; N=119) to 18 months of antithyroid medication, subtotal thyroidectomy, or ¹³¹I radioablation.

After 6 weeks, all therapies produced serum triiodothyronine levels of less than 2.5 nmol/L (data extracted from table; no comparison statistic given). Patients were followed for 48 to 121 months (average follow-up time not given). Investigators found no significant differences in sick leave (72 vs 83 days for medical treatment compared with radioablation; no comparison statistic given) or patient satisfaction (95% for both medical treatment and radioablation; no comparison statistic given).

Medication (initially methimazole) was changed in 16% of patients because of adverse effects. More than a third of patients relapsed after medications were stopped (time to relapse 1-57 months); 21% relapsed after a single ¹³¹I treatment (time to relapse 5-16 months).

In another study, radioablation outperforms medication
A retrospective case series found that radioablation resolved hyperthyroidism more often than medical therapy among 194 consecutive Saudi Arabian patients (mean age 32 years) diagnosed with Graves’ disease and followed for an average of 50 months.² One dose of radioiodine (13-15 mCi) cured hyperthyroidism in 83% of patients, whereas 18 months of medical therapy produced remission lasting at least 6 months past the end of therapy in only 26% of patients (no comparison statistic given).

The presence of TAO at diagnosis increased the likelihood of radioablation failure (odds ratio for failure to respond to single dose of radioiodine=6.4; 95% confidence interval [CI], 1.51-24.4; P<.01). A major weakness of the study was that the investigators didn’t describe the medication therapy clearly.

More patients develop TAO after radioablation than medical therapy
An RCT found that radioablation is more commonly associated with development of TAO than medical therapy.³ When investigators randomized 313 patients to receive ¹³¹I radioablation or medical therapy for 18 months and followed them for as long as 4 years, more patients receiving radioablation developed TAO (38% compared with 18% for medical therapy, using intention-to-treat analysis; P<.001; number needed to harm [NNH]=5). Twenty-five percent of patients initially receiving medical therapy later underwent radioablation, but these patients didn’t develop TAO at a higher rate.

An earlier meta-analysis of 2 RCTs (N=189) also found an increased risk of TAO with radioablation compared with medical therapy.⁴ Patients receiving radioablation were more likely to develop TAO (18% vs 4%; relative risk [RR]=4.2; 95% CI, 2.0-8.8; NNH=7) and more likely to develop severe TAO (10% vs 1.6%; RR=4.4; 95% CI, 1.3-15; NNH=12). Adjunctive use of steroids with radioablation didn’t alter the risk of new TAO. However, steroid prophylaxis in patients with preexisting TAO significantly reduced the risk of progression after radioablation (RR=0.03; 95% CI, 0.00-0.24). The authors of the meta-analysis didn’t evaluate the quality of the RCTs.

Despite low neoplasia risk, radioablation isn’t for young children
Expert guidelines state that the goal of radioablation is to induce lifelong hypothyroidism, which is managed with thyroid hormone replacement.⁵ The risk of neoplasia after radioablation is believed to be low with appropriate dosing. However, based on “theoretical concerns,” experts don’t recommend using radioiodine in children younger than 5 years and advise limited use in children 5 to 10 years of age.⁵

Medication adverse effects include rashes, transient agranulocytosis
A Cochrane review with 7 RCTs (N=620) describing withdrawal rates for patients receiving medication for Graves’ disease found that 9% to 16% of patients discontinued treatment because of adverse effects.⁶ Rashes were the most common adverse effect (6%-10% of patients), but as many as 3% of patients developed transient agranulocytosis. In addition, patients on medication need frequent blood tests to monitor for thyroid activity and potential toxicity.

Recommendations

The guidelines of the American Thyroid Association and the American Association of Clinical Endocrinologists state that overt Graves’ hyperthyroidism may be treated with any of the following: ¹³¹I radioablation, antithyroid medication, or thyroidectomy.³ Patient characteristics (pregnancy, mild disease, goiter compression symptoms) should help determine the appropriate option in any given case.

Evidence summary

A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).¹ All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.

DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).

This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.

But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.² When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).

Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).

Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.³ ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).

The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).

Recommendations

The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.⁴ (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.

The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.⁵ For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.

Evidence summary

A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).¹ All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.

DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).

This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.

But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.² When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).

Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).

Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.³ ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).

The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).

Recommendations

The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.⁴ (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.

The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.⁵ For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.

Evidence summary

A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).¹ All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.

DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).

This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.

But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.² When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).

Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).

Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.³ ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).

The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).

Recommendations

The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.⁴ (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.

The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.⁵ For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.

Evidence summary

A prospective cohort study of 220 patients from an outpatient dermatology center in Amsterdam investigated the natural course of chronic urticaria and angioedema.¹ Researchers categorized patients according to subtypes: idiopathic urticaria-angioedema, idiopathic urticaria, idiopathic angioedema, physical and idiopathic urticaria, and physical urticaria only.

The duration of symptoms at enrollment wasn’t reported. Therapy wasn’t controlled and was composed of oral antihistamines, steroids, and other drugs.

One year after enrollment, 35% of patients had complete resolution of symptoms. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause.

A study finds 1-year control or improvement in chronic urticaria
Another prospective cohort study from an outpatient dermatology center in Brazil evaluated 125 patients with chronic urticaria-angioedema.² Participants were predominantly adults 20 to 40 years of age, with a mean duration of symptoms of 45 months.

Most patients had idiopathic disease (78%), but some had parasitic and skin infections, medication sensitivities, thyroid disease, and other problems that could contribute to skin hyperreactivity. Therapeutic interventions for underlying conditions or angioedema-urticaria weren’t controlled or reported.

One year after presentation, 58.4% of patients had symptoms “under control,” 31.7% were improved, and 8.9% were unchanged. One patient’s symptoms worsened.

Urticaria is less severe in patients older than 30 years
A prospective cohort study followed 62 patients with urticaria caused by cold from a tertiary referral center in Greece.³ The mean age at presentation was 42 years and the mean duration of symptoms was 10 years. The study followed patients for a mean of 9 years. Therapeutic interventions weren’t controlled or reported

Overall, 29% of patients experienced resolution of symptoms, 41.9% noted improvement, and 29% experienced worsening of symptoms. The mean time to resolution was 5.6 years. The study also found that chronic urticaria was less severe if patients developed the condition after 30 years of age.

Worst prognosis found in patients with cold-related urticaria
A retrospective cohort study identified 544 cases of chronic urticaria and angioedema in 22 years of records from a tertiary referral center in the Netherlands.⁴ The mean age at presentation was 35 years; patients had been symptomatic an average of 5 years. All patients were sent a questionnaire to fill out; 372 questionnaires were returned.

At 5 years after presentation, symptoms resolved in 29% of patients; at 10 years, the number of resolved cases increased to 44%. Patients with cold-related urticaria had the worst prognosis.

Zafirlukast has no effect
An RCT with a study group of 137 patients (mean age 41 years) compared the effectiveness of zafirlukast vs placebo for treating chronic urticaria symptoms. Zafirlukast showed no significant benefit over placebo; symptoms resolved or improved in 41.3% of all patients after 12 weeks.⁵

Recommendations

Habif’s Clinical Dermatology states that chronic urticaria:

• may last for months or years
• may be subject to lengthy and often un-rewarding evaluation
• resolves spontaneously in most cases.⁶

Evidence summary

A prospective cohort study of 220 patients from an outpatient dermatology center in Amsterdam investigated the natural course of chronic urticaria and angioedema.¹ Researchers categorized patients according to subtypes: idiopathic urticaria-angioedema, idiopathic urticaria, idiopathic angioedema, physical and idiopathic urticaria, and physical urticaria only.

The duration of symptoms at enrollment wasn’t reported. Therapy wasn’t controlled and was composed of oral antihistamines, steroids, and other drugs.

One year after enrollment, 35% of patients had complete resolution of symptoms. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause.

A study finds 1-year control or improvement in chronic urticaria
Another prospective cohort study from an outpatient dermatology center in Brazil evaluated 125 patients with chronic urticaria-angioedema.² Participants were predominantly adults 20 to 40 years of age, with a mean duration of symptoms of 45 months.

Most patients had idiopathic disease (78%), but some had parasitic and skin infections, medication sensitivities, thyroid disease, and other problems that could contribute to skin hyperreactivity. Therapeutic interventions for underlying conditions or angioedema-urticaria weren’t controlled or reported.

One year after presentation, 58.4% of patients had symptoms “under control,” 31.7% were improved, and 8.9% were unchanged. One patient’s symptoms worsened.

Urticaria is less severe in patients older than 30 years
A prospective cohort study followed 62 patients with urticaria caused by cold from a tertiary referral center in Greece.³ The mean age at presentation was 42 years and the mean duration of symptoms was 10 years. The study followed patients for a mean of 9 years. Therapeutic interventions weren’t controlled or reported

Overall, 29% of patients experienced resolution of symptoms, 41.9% noted improvement, and 29% experienced worsening of symptoms. The mean time to resolution was 5.6 years. The study also found that chronic urticaria was less severe if patients developed the condition after 30 years of age.

Worst prognosis found in patients with cold-related urticaria
A retrospective cohort study identified 544 cases of chronic urticaria and angioedema in 22 years of records from a tertiary referral center in the Netherlands.⁴ The mean age at presentation was 35 years; patients had been symptomatic an average of 5 years. All patients were sent a questionnaire to fill out; 372 questionnaires were returned.

At 5 years after presentation, symptoms resolved in 29% of patients; at 10 years, the number of resolved cases increased to 44%. Patients with cold-related urticaria had the worst prognosis.

Zafirlukast has no effect
An RCT with a study group of 137 patients (mean age 41 years) compared the effectiveness of zafirlukast vs placebo for treating chronic urticaria symptoms. Zafirlukast showed no significant benefit over placebo; symptoms resolved or improved in 41.3% of all patients after 12 weeks.⁵

Recommendations

Habif’s Clinical Dermatology states that chronic urticaria:

• may last for months or years
• may be subject to lengthy and often un-rewarding evaluation
• resolves spontaneously in most cases.⁶

Evidence summary

A prospective cohort study of 220 patients from an outpatient dermatology center in Amsterdam investigated the natural course of chronic urticaria and angioedema.¹ Researchers categorized patients according to subtypes: idiopathic urticaria-angioedema, idiopathic urticaria, idiopathic angioedema, physical and idiopathic urticaria, and physical urticaria only.

The duration of symptoms at enrollment wasn’t reported. Therapy wasn’t controlled and was composed of oral antihistamines, steroids, and other drugs.

One year after enrollment, 35% of patients had complete resolution of symptoms. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause.

A study finds 1-year control or improvement in chronic urticaria
Another prospective cohort study from an outpatient dermatology center in Brazil evaluated 125 patients with chronic urticaria-angioedema.² Participants were predominantly adults 20 to 40 years of age, with a mean duration of symptoms of 45 months.

Most patients had idiopathic disease (78%), but some had parasitic and skin infections, medication sensitivities, thyroid disease, and other problems that could contribute to skin hyperreactivity. Therapeutic interventions for underlying conditions or angioedema-urticaria weren’t controlled or reported.

One year after presentation, 58.4% of patients had symptoms “under control,” 31.7% were improved, and 8.9% were unchanged. One patient’s symptoms worsened.

Urticaria is less severe in patients older than 30 years
A prospective cohort study followed 62 patients with urticaria caused by cold from a tertiary referral center in Greece.³ The mean age at presentation was 42 years and the mean duration of symptoms was 10 years. The study followed patients for a mean of 9 years. Therapeutic interventions weren’t controlled or reported

Overall, 29% of patients experienced resolution of symptoms, 41.9% noted improvement, and 29% experienced worsening of symptoms. The mean time to resolution was 5.6 years. The study also found that chronic urticaria was less severe if patients developed the condition after 30 years of age.

Worst prognosis found in patients with cold-related urticaria
A retrospective cohort study identified 544 cases of chronic urticaria and angioedema in 22 years of records from a tertiary referral center in the Netherlands.⁴ The mean age at presentation was 35 years; patients had been symptomatic an average of 5 years. All patients were sent a questionnaire to fill out; 372 questionnaires were returned.

At 5 years after presentation, symptoms resolved in 29% of patients; at 10 years, the number of resolved cases increased to 44%. Patients with cold-related urticaria had the worst prognosis.

Zafirlukast has no effect
An RCT with a study group of 137 patients (mean age 41 years) compared the effectiveness of zafirlukast vs placebo for treating chronic urticaria symptoms. Zafirlukast showed no significant benefit over placebo; symptoms resolved or improved in 41.3% of all patients after 12 weeks.⁵

Recommendations

Habif’s Clinical Dermatology states that chronic urticaria:

• may last for months or years
• may be subject to lengthy and often un-rewarding evaluation
• resolves spontaneously in most cases.⁶

Evidence summary

Two prospective cohort studies evaluated the effect on glycemic control of a single glucocorticoid injection into the knee of patients with controlled type 2 diabetes (glycosylated hemoglobin A1c <7.0%). The first enrolled 9 patients with symptomatic osteoarthritis of the knee unresponsive to 3 months of nonsteroidal anti-inflammatory drugs (NSAIDs).¹ All received a 50-mg injection of methylprednisolone acetate after maximal aspiration of any joint fluid. No changes were made to the diabetes care regimen, including medication, diet, or exercise prescriptions.

With self-monitoring 6 times a day during the week after the injection, 7 patients showed an increase over baseline blood glucose levels of more than 2 standard deviations; values typically rose above 300 mg/dL. Peak blood sugar elevation occurred 5 to 84 hours after injection; the hyperglycemic effect lasted for 2 or 3 days.

In a second cohort study, 6 patients received a knee injection of 1 mL Celestone Chronodose (3 mg betamethasone acetate and 3 mg betamethasone sodium phosphate, comparable in anti-inflammatory and glucocorticoid potency to 32 mg methylprednisolone acetate).² Patients monitored their blood glucose 6 times a day for 1 week; investigators measured fructosamine levels (a measure of intermediate-term glucose control) at baseline and again 2 weeks after injection.

The injection produced hyperglycemia in all participants, with peak blood glucose levels ranging from 251 to 430 mg/dL and time to peak glucose usually less than 6 hours. Fructosamine levels didn’t change significantly.

No change in glucose after a single shoulder injection
Two studies evaluated the effect of a single shoulder injection. One prospective cohort study included 18 patients with diabetes (type not specified, mean A1c=7.6%).³ All had shoulder pain unresponsive to NSAIDs for more than a month, had not changed diabetes medications within the preceding 2 weeks, and had not had steroid therapy within the preceding 3 months.

All patients received a single injection containing 35 mg methylprednisolone acetate into the anterior glenohumeral joint. They monitored their blood glucose levels 6 times a day for 1 week and had a fructosamine level drawn before injection and 2 weeks afterward. The injection produced no significant change in mean blood glucose or fructosamine levels.

But repeated shoulder injections raise postprandial glucose
In contrast, another prospective cohort study followed 11 patients (8 with diabetes) who received 3 injections of 3.75 mg cortivazol (comparable to 50 mg methylprednisolone acetate) at 3-day intervals into 1 shoulder joint.⁴ Investigators checked fasting and postprandial glucose levels before the first injection and on post-treatment days 1, 7, and 21.

The shoulder injections elevated post-prandial glucose levels (from 170±60 mg/dL at baseline to 258±100 mg/dL on day 1 and 252±87 mg/dL on day 7; P<.05 for both comparisons). Mean fasting glucose levels didn’t change, however.

Recommendations

The American Academy of Orthopedic Surgeons treatment guidelines for osteoarthritis of the knee don’t discuss possible adverse effects from steroid injections.⁵ The American Diabetes Association makes no recommendations regarding steroid injections in patients with diabetes.

Evidence summary

Two prospective cohort studies evaluated the effect on glycemic control of a single glucocorticoid injection into the knee of patients with controlled type 2 diabetes (glycosylated hemoglobin A1c <7.0%). The first enrolled 9 patients with symptomatic osteoarthritis of the knee unresponsive to 3 months of nonsteroidal anti-inflammatory drugs (NSAIDs).¹ All received a 50-mg injection of methylprednisolone acetate after maximal aspiration of any joint fluid. No changes were made to the diabetes care regimen, including medication, diet, or exercise prescriptions.

With self-monitoring 6 times a day during the week after the injection, 7 patients showed an increase over baseline blood glucose levels of more than 2 standard deviations; values typically rose above 300 mg/dL. Peak blood sugar elevation occurred 5 to 84 hours after injection; the hyperglycemic effect lasted for 2 or 3 days.

In a second cohort study, 6 patients received a knee injection of 1 mL Celestone Chronodose (3 mg betamethasone acetate and 3 mg betamethasone sodium phosphate, comparable in anti-inflammatory and glucocorticoid potency to 32 mg methylprednisolone acetate).² Patients monitored their blood glucose 6 times a day for 1 week; investigators measured fructosamine levels (a measure of intermediate-term glucose control) at baseline and again 2 weeks after injection.

The injection produced hyperglycemia in all participants, with peak blood glucose levels ranging from 251 to 430 mg/dL and time to peak glucose usually less than 6 hours. Fructosamine levels didn’t change significantly.

No change in glucose after a single shoulder injection
Two studies evaluated the effect of a single shoulder injection. One prospective cohort study included 18 patients with diabetes (type not specified, mean A1c=7.6%).³ All had shoulder pain unresponsive to NSAIDs for more than a month, had not changed diabetes medications within the preceding 2 weeks, and had not had steroid therapy within the preceding 3 months.

All patients received a single injection containing 35 mg methylprednisolone acetate into the anterior glenohumeral joint. They monitored their blood glucose levels 6 times a day for 1 week and had a fructosamine level drawn before injection and 2 weeks afterward. The injection produced no significant change in mean blood glucose or fructosamine levels.

But repeated shoulder injections raise postprandial glucose
In contrast, another prospective cohort study followed 11 patients (8 with diabetes) who received 3 injections of 3.75 mg cortivazol (comparable to 50 mg methylprednisolone acetate) at 3-day intervals into 1 shoulder joint.⁴ Investigators checked fasting and postprandial glucose levels before the first injection and on post-treatment days 1, 7, and 21.

The shoulder injections elevated post-prandial glucose levels (from 170±60 mg/dL at baseline to 258±100 mg/dL on day 1 and 252±87 mg/dL on day 7; P<.05 for both comparisons). Mean fasting glucose levels didn’t change, however.

Recommendations

The American Academy of Orthopedic Surgeons treatment guidelines for osteoarthritis of the knee don’t discuss possible adverse effects from steroid injections.⁵ The American Diabetes Association makes no recommendations regarding steroid injections in patients with diabetes.

Evidence summary

Two prospective cohort studies evaluated the effect on glycemic control of a single glucocorticoid injection into the knee of patients with controlled type 2 diabetes (glycosylated hemoglobin A1c <7.0%). The first enrolled 9 patients with symptomatic osteoarthritis of the knee unresponsive to 3 months of nonsteroidal anti-inflammatory drugs (NSAIDs).¹ All received a 50-mg injection of methylprednisolone acetate after maximal aspiration of any joint fluid. No changes were made to the diabetes care regimen, including medication, diet, or exercise prescriptions.

With self-monitoring 6 times a day during the week after the injection, 7 patients showed an increase over baseline blood glucose levels of more than 2 standard deviations; values typically rose above 300 mg/dL. Peak blood sugar elevation occurred 5 to 84 hours after injection; the hyperglycemic effect lasted for 2 or 3 days.

In a second cohort study, 6 patients received a knee injection of 1 mL Celestone Chronodose (3 mg betamethasone acetate and 3 mg betamethasone sodium phosphate, comparable in anti-inflammatory and glucocorticoid potency to 32 mg methylprednisolone acetate).² Patients monitored their blood glucose 6 times a day for 1 week; investigators measured fructosamine levels (a measure of intermediate-term glucose control) at baseline and again 2 weeks after injection.

The injection produced hyperglycemia in all participants, with peak blood glucose levels ranging from 251 to 430 mg/dL and time to peak glucose usually less than 6 hours. Fructosamine levels didn’t change significantly.

No change in glucose after a single shoulder injection
Two studies evaluated the effect of a single shoulder injection. One prospective cohort study included 18 patients with diabetes (type not specified, mean A1c=7.6%).³ All had shoulder pain unresponsive to NSAIDs for more than a month, had not changed diabetes medications within the preceding 2 weeks, and had not had steroid therapy within the preceding 3 months.

All patients received a single injection containing 35 mg methylprednisolone acetate into the anterior glenohumeral joint. They monitored their blood glucose levels 6 times a day for 1 week and had a fructosamine level drawn before injection and 2 weeks afterward. The injection produced no significant change in mean blood glucose or fructosamine levels.

But repeated shoulder injections raise postprandial glucose
In contrast, another prospective cohort study followed 11 patients (8 with diabetes) who received 3 injections of 3.75 mg cortivazol (comparable to 50 mg methylprednisolone acetate) at 3-day intervals into 1 shoulder joint.⁴ Investigators checked fasting and postprandial glucose levels before the first injection and on post-treatment days 1, 7, and 21.

The shoulder injections elevated post-prandial glucose levels (from 170±60 mg/dL at baseline to 258±100 mg/dL on day 1 and 252±87 mg/dL on day 7; P<.05 for both comparisons). Mean fasting glucose levels didn’t change, however.

Recommendations

The American Academy of Orthopedic Surgeons treatment guidelines for osteoarthritis of the knee don’t discuss possible adverse effects from steroid injections.⁵ The American Diabetes Association makes no recommendations regarding steroid injections in patients with diabetes.

Evidence summary

The American Academy of Allergy, Asthma and Immunology (AAAAI) states that a double-blind, placebo-controlled OFC is the best test for diagnosing infants clinically suspected of having food allergies (that is, who develop gastrointestinal symptoms after eating a specific food). However, performing an OFC in an infant is often difficult and potentially dangerous, especially if a severe allergy is suspected; testing also may eliminate nutritious foods, such as milk and eggs, from the infant’s diet.¹ For these reasons, physicians have sought simpler alternatives to the OFC.

Comparisons of serum and skin testing with OFCs produce variable, weak results
Two large cohort studies compared OFCs with serum and skin testing in infants, children, and teenagers. Overall, serum and skin testing didn’t produce robust results and the results varied with the antigen (TABLE).

TABLE
How allergy tests in infants and children compare with an oral food challenge

In 1 study, researchers compared specific serum IgE levels with OFC results for 4 foods—milk, eggs, wheat, and soy—in 501 consecutive pediatric patients referred to an allergy ward based on clinical or parental suspicion of food allergy. Children ranged in age from 1 month to 16 years (median age 13 months); results for infants were not provided separately. Eighty-eight percent of the children were atopic. Investigators measured serum IgE (using the Pharmacia CAP-system fluorescence enzyme immunoassay) before administering the OFCs.

Of 992 OFCs performed, 445 (45%) were positive (defined as producing urticaria, angioedema, wheezing, vomiting, diarrhea, abdominal pain, shock, or exacerbation of eczema). Most OFCs (73%) were double-blind placebo-controlled, but investigators performed open OFCs in infants and in children with a history of immediate allergic reactions. Investigators retrospectively analyzed serum-specific IgE levels for the 4 food antigens and compared them with the results of the OFCs. Positive likelihood ratios (LR+) for IgE testing ranged from 1.3 to 2.0 for the 4 antigens; negative likelihood ratios (LR–) ranged from 0.31 to 0.59.²

The second cohort study compared APT and SPT with OFCs for the same 4 food antigens (milk, eggs, wheat, soy) in 437 children. The study population comprised consecutive referrals to a pediatric immunology department based on either parental suspicion of a food allergy or a positive IgE test. The children ranged in age from 3 months to 14 years (median age 13 months); results for infants weren’t provided separately. Ninety percent of the children were atopic. Investigators performed APTs and SPTs for the 4 food antigens on all children and OFCs only for foods that were clinically suspect (total OFCs=873).

As in the previous study, investigators performed open OFCs (23%) in infants and children with a history of immediate reaction. A positive APT was defined by erythema with infiltration or papules, and a positive SPT by a wheal ≥3 mm. For the SPT, the LR+ ranged from 1.9 to 2.8 for the 4 antigens, and the LR–ranged from 0.13 (for egg) to 0.84. For the APT, the LR+ ranged from 1.6 to 6.2 (for milk), whereas the LR– was of little value, ranging from 0.68 to 0.90.³

For milk and eggs, the larger the wheal, the more sensitive the skin test
The size of the wheal may increase the sensitivity of the SPT in some situations. A cohort study similar to the ones described previously compared SPT with OFCs in children with possible food allergies and found that a large SPT wheal was highly correlated with OFC-confirmed allergy to milk and eggs.⁴

Investigators recruited 385 children—3 months to 14 years of age (median age 22 months), results for infants not provided separately—from consecutive referrals to a pediatric immunology department. Most children (87%) were atopic. Investigators performed SPTs, followed by OFCs for milk, egg, wheat, and soy allergens. Overall, 312 (43%) of the OFCs were positive. Wheals measuring ≥13 mm for eggs and ≥12.5 mm for milk correlated well with OFC results (95% positive predictive value). Wheal sizes for wheat and soy were poorly predictive, however.⁴

No validation yet for new techniques to improve accuracy and safety
New techniques to improve the accuracy and safety of allergy testing have yet to be validated clinically. One cohort study of 58 children that used fresh fruit or vegetable preparations for SPT instead of commonly used commercial extracts found added sensitivity.⁵ Another cohort study of 142 children allowed suspect foods to contact only the labial mucosa in order to reduce the risk of systemic reactions (1 case of anaphylaxis occurred nevertheless).⁶

Recommendations

The AAAAI guidelines state that history and physical examination help determine that food is causing symptoms and that an OFC is diagnostic of food allergy (but risks and benefits must be considered, including the possibility of severe adverse reaction).¹ The guidelines note that other available tests, including food-specific IgE and skin tests, are not specific enough for screening but may be used when a particular food allergy is clinically suspected.

Evidence summary

The American Academy of Allergy, Asthma and Immunology (AAAAI) states that a double-blind, placebo-controlled OFC is the best test for diagnosing infants clinically suspected of having food allergies (that is, who develop gastrointestinal symptoms after eating a specific food). However, performing an OFC in an infant is often difficult and potentially dangerous, especially if a severe allergy is suspected; testing also may eliminate nutritious foods, such as milk and eggs, from the infant’s diet.¹ For these reasons, physicians have sought simpler alternatives to the OFC.

Comparisons of serum and skin testing with OFCs produce variable, weak results
Two large cohort studies compared OFCs with serum and skin testing in infants, children, and teenagers. Overall, serum and skin testing didn’t produce robust results and the results varied with the antigen (TABLE).

TABLE
How allergy tests in infants and children compare with an oral food challenge

In 1 study, researchers compared specific serum IgE levels with OFC results for 4 foods—milk, eggs, wheat, and soy—in 501 consecutive pediatric patients referred to an allergy ward based on clinical or parental suspicion of food allergy. Children ranged in age from 1 month to 16 years (median age 13 months); results for infants were not provided separately. Eighty-eight percent of the children were atopic. Investigators measured serum IgE (using the Pharmacia CAP-system fluorescence enzyme immunoassay) before administering the OFCs.

Of 992 OFCs performed, 445 (45%) were positive (defined as producing urticaria, angioedema, wheezing, vomiting, diarrhea, abdominal pain, shock, or exacerbation of eczema). Most OFCs (73%) were double-blind placebo-controlled, but investigators performed open OFCs in infants and in children with a history of immediate allergic reactions. Investigators retrospectively analyzed serum-specific IgE levels for the 4 food antigens and compared them with the results of the OFCs. Positive likelihood ratios (LR+) for IgE testing ranged from 1.3 to 2.0 for the 4 antigens; negative likelihood ratios (LR–) ranged from 0.31 to 0.59.²

The second cohort study compared APT and SPT with OFCs for the same 4 food antigens (milk, eggs, wheat, soy) in 437 children. The study population comprised consecutive referrals to a pediatric immunology department based on either parental suspicion of a food allergy or a positive IgE test. The children ranged in age from 3 months to 14 years (median age 13 months); results for infants weren’t provided separately. Ninety percent of the children were atopic. Investigators performed APTs and SPTs for the 4 food antigens on all children and OFCs only for foods that were clinically suspect (total OFCs=873).

As in the previous study, investigators performed open OFCs (23%) in infants and children with a history of immediate reaction. A positive APT was defined by erythema with infiltration or papules, and a positive SPT by a wheal ≥3 mm. For the SPT, the LR+ ranged from 1.9 to 2.8 for the 4 antigens, and the LR–ranged from 0.13 (for egg) to 0.84. For the APT, the LR+ ranged from 1.6 to 6.2 (for milk), whereas the LR– was of little value, ranging from 0.68 to 0.90.³

For milk and eggs, the larger the wheal, the more sensitive the skin test
The size of the wheal may increase the sensitivity of the SPT in some situations. A cohort study similar to the ones described previously compared SPT with OFCs in children with possible food allergies and found that a large SPT wheal was highly correlated with OFC-confirmed allergy to milk and eggs.⁴

Investigators recruited 385 children—3 months to 14 years of age (median age 22 months), results for infants not provided separately—from consecutive referrals to a pediatric immunology department. Most children (87%) were atopic. Investigators performed SPTs, followed by OFCs for milk, egg, wheat, and soy allergens. Overall, 312 (43%) of the OFCs were positive. Wheals measuring ≥13 mm for eggs and ≥12.5 mm for milk correlated well with OFC results (95% positive predictive value). Wheal sizes for wheat and soy were poorly predictive, however.⁴

No validation yet for new techniques to improve accuracy and safety
New techniques to improve the accuracy and safety of allergy testing have yet to be validated clinically. One cohort study of 58 children that used fresh fruit or vegetable preparations for SPT instead of commonly used commercial extracts found added sensitivity.⁵ Another cohort study of 142 children allowed suspect foods to contact only the labial mucosa in order to reduce the risk of systemic reactions (1 case of anaphylaxis occurred nevertheless).⁶

Recommendations

The AAAAI guidelines state that history and physical examination help determine that food is causing symptoms and that an OFC is diagnostic of food allergy (but risks and benefits must be considered, including the possibility of severe adverse reaction).¹ The guidelines note that other available tests, including food-specific IgE and skin tests, are not specific enough for screening but may be used when a particular food allergy is clinically suspected.

Evidence summary

The American Academy of Allergy, Asthma and Immunology (AAAAI) states that a double-blind, placebo-controlled OFC is the best test for diagnosing infants clinically suspected of having food allergies (that is, who develop gastrointestinal symptoms after eating a specific food). However, performing an OFC in an infant is often difficult and potentially dangerous, especially if a severe allergy is suspected; testing also may eliminate nutritious foods, such as milk and eggs, from the infant’s diet.¹ For these reasons, physicians have sought simpler alternatives to the OFC.

Comparisons of serum and skin testing with OFCs produce variable, weak results
Two large cohort studies compared OFCs with serum and skin testing in infants, children, and teenagers. Overall, serum and skin testing didn’t produce robust results and the results varied with the antigen (TABLE).

TABLE
How allergy tests in infants and children compare with an oral food challenge

In 1 study, researchers compared specific serum IgE levels with OFC results for 4 foods—milk, eggs, wheat, and soy—in 501 consecutive pediatric patients referred to an allergy ward based on clinical or parental suspicion of food allergy. Children ranged in age from 1 month to 16 years (median age 13 months); results for infants were not provided separately. Eighty-eight percent of the children were atopic. Investigators measured serum IgE (using the Pharmacia CAP-system fluorescence enzyme immunoassay) before administering the OFCs.

Of 992 OFCs performed, 445 (45%) were positive (defined as producing urticaria, angioedema, wheezing, vomiting, diarrhea, abdominal pain, shock, or exacerbation of eczema). Most OFCs (73%) were double-blind placebo-controlled, but investigators performed open OFCs in infants and in children with a history of immediate allergic reactions. Investigators retrospectively analyzed serum-specific IgE levels for the 4 food antigens and compared them with the results of the OFCs. Positive likelihood ratios (LR+) for IgE testing ranged from 1.3 to 2.0 for the 4 antigens; negative likelihood ratios (LR–) ranged from 0.31 to 0.59.²

The second cohort study compared APT and SPT with OFCs for the same 4 food antigens (milk, eggs, wheat, soy) in 437 children. The study population comprised consecutive referrals to a pediatric immunology department based on either parental suspicion of a food allergy or a positive IgE test. The children ranged in age from 3 months to 14 years (median age 13 months); results for infants weren’t provided separately. Ninety percent of the children were atopic. Investigators performed APTs and SPTs for the 4 food antigens on all children and OFCs only for foods that were clinically suspect (total OFCs=873).

As in the previous study, investigators performed open OFCs (23%) in infants and children with a history of immediate reaction. A positive APT was defined by erythema with infiltration or papules, and a positive SPT by a wheal ≥3 mm. For the SPT, the LR+ ranged from 1.9 to 2.8 for the 4 antigens, and the LR–ranged from 0.13 (for egg) to 0.84. For the APT, the LR+ ranged from 1.6 to 6.2 (for milk), whereas the LR– was of little value, ranging from 0.68 to 0.90.³

For milk and eggs, the larger the wheal, the more sensitive the skin test
The size of the wheal may increase the sensitivity of the SPT in some situations. A cohort study similar to the ones described previously compared SPT with OFCs in children with possible food allergies and found that a large SPT wheal was highly correlated with OFC-confirmed allergy to milk and eggs.⁴

Investigators recruited 385 children—3 months to 14 years of age (median age 22 months), results for infants not provided separately—from consecutive referrals to a pediatric immunology department. Most children (87%) were atopic. Investigators performed SPTs, followed by OFCs for milk, egg, wheat, and soy allergens. Overall, 312 (43%) of the OFCs were positive. Wheals measuring ≥13 mm for eggs and ≥12.5 mm for milk correlated well with OFC results (95% positive predictive value). Wheal sizes for wheat and soy were poorly predictive, however.⁴

No validation yet for new techniques to improve accuracy and safety
New techniques to improve the accuracy and safety of allergy testing have yet to be validated clinically. One cohort study of 58 children that used fresh fruit or vegetable preparations for SPT instead of commonly used commercial extracts found added sensitivity.⁵ Another cohort study of 142 children allowed suspect foods to contact only the labial mucosa in order to reduce the risk of systemic reactions (1 case of anaphylaxis occurred nevertheless).⁶

Recommendations

The AAAAI guidelines state that history and physical examination help determine that food is causing symptoms and that an OFC is diagnostic of food allergy (but risks and benefits must be considered, including the possibility of severe adverse reaction).¹ The guidelines note that other available tests, including food-specific IgE and skin tests, are not specific enough for screening but may be used when a particular food allergy is clinically suspected.

Evidence summary

A 2005 meta-analysis evaluated the effectiveness of HA injections for osteoarthritis of the knee compared with saline placebo. Researchers identified 22 studies of 8 HA products that used the common end point of pain with movement.¹ (TABLE 1 lists FDA-approved HA products available in the United States.²) A decrease in pain of 15% was deemed clinically meaningful.

Compared with placebo, the mean difference in pain scores with HA products was -4% (95% confidence interval [CI], -9% to 1%) after 2 to 6 weeks; -4% (95% CI, -8% to -1%) after 10 to 14 weeks; and -7% (95% CI, -12% to -2%) after 22 to 30 weeks. The authors note that the small measured effect of HA was magnified by trials that didn’t report intention-to-treat results. The effect of HA was also larger in studies that didn’t conceal allocation. A weakness of the analysis was its inability to assess potential differences between HA products.

In this 2005 meta-analysis, HA injection didn’t improve knee function in any time interval. But in a Cochrane meta-analysis conducted the following year, HA was found to have positive results.³

TABLE 1
FDA-approved hyaluronic acid products

HA relieves pain about as much as NSAIDs

The comprehensive 2006 Cochrane meta-analysis reviewed single- and double-blinded RCTs that evaluated the effect of 12 HA products on osteoarthritis of the knee.³ Studies compared HA products with placebo (40), intra-articular steroids (10), NSAIDs (6), physical therapy (3), exercise (2), and each other (15). Efficacy data for different products couldn’t be combined because the studies measured different sets of outcomes at different time points.

Overall, the authors concluded that HA injections effectively reduced pain scores, with the largest benefit occurring within 5 to 13 weeks (TABLE 2). The authors also noted that the reductions in pain with HA injections, although generally small, were comparable to oral NSAID therapy and intra-articular corticosteroids. The trials reported few adverse events.

Two RCTs show no difference in efficacy among HA products

The Cochrane review determined that not enough evidence existed to evaluate HA products against each other. Two subsequent RCTs compared HA products and found no differences in efficacy. One study compared Synvisc, Orthovisc, and Ostenil therapy in 660 patients over 6 months.⁴ The other compared Synvisc with Euflexxa in 321 patients over 3 months.⁵ Notably, 8% of patients in this study who used Synvisc developed an effusion, compared with 0.6% of patients who used Euflexxa (P=.0015).

Recommendations

A 2007 report from the Agency for Healthcare Research and Quality (AHRQ) states that “viscosupplementation trials generally report positive effects on pain and function scores compared with placebo, but the evidence on clinical benefit is uncertain.”⁶

The 2007 guidelines of the Institute for Clinical Systems Improvement note that synthetic hyaluronates “may be effective” in selected patients with mild to moderate degenerative joint disease (based on evidence of middle quality on a 3-tier grading system).⁷

The American Academy of Orthopaedic Surgeons 2008 guideline on osteoarthritis of the knee indicates that, based on the AHRQ report,⁶ it cannot recommend for or against the use of intra-articular hyaluronic acid for mild to moderate symptomatic OA of the knee.⁸

TABLE 2
How HA products affect pain measures

Evidence summary

A 2005 meta-analysis evaluated the effectiveness of HA injections for osteoarthritis of the knee compared with saline placebo. Researchers identified 22 studies of 8 HA products that used the common end point of pain with movement.¹ (TABLE 1 lists FDA-approved HA products available in the United States.²) A decrease in pain of 15% was deemed clinically meaningful.

Compared with placebo, the mean difference in pain scores with HA products was -4% (95% confidence interval [CI], -9% to 1%) after 2 to 6 weeks; -4% (95% CI, -8% to -1%) after 10 to 14 weeks; and -7% (95% CI, -12% to -2%) after 22 to 30 weeks. The authors note that the small measured effect of HA was magnified by trials that didn’t report intention-to-treat results. The effect of HA was also larger in studies that didn’t conceal allocation. A weakness of the analysis was its inability to assess potential differences between HA products.

In this 2005 meta-analysis, HA injection didn’t improve knee function in any time interval. But in a Cochrane meta-analysis conducted the following year, HA was found to have positive results.³

TABLE 1
FDA-approved hyaluronic acid products

HA relieves pain about as much as NSAIDs

The comprehensive 2006 Cochrane meta-analysis reviewed single- and double-blinded RCTs that evaluated the effect of 12 HA products on osteoarthritis of the knee.³ Studies compared HA products with placebo (40), intra-articular steroids (10), NSAIDs (6), physical therapy (3), exercise (2), and each other (15). Efficacy data for different products couldn’t be combined because the studies measured different sets of outcomes at different time points.

Overall, the authors concluded that HA injections effectively reduced pain scores, with the largest benefit occurring within 5 to 13 weeks (TABLE 2). The authors also noted that the reductions in pain with HA injections, although generally small, were comparable to oral NSAID therapy and intra-articular corticosteroids. The trials reported few adverse events.

Two RCTs show no difference in efficacy among HA products

The Cochrane review determined that not enough evidence existed to evaluate HA products against each other. Two subsequent RCTs compared HA products and found no differences in efficacy. One study compared Synvisc, Orthovisc, and Ostenil therapy in 660 patients over 6 months.⁴ The other compared Synvisc with Euflexxa in 321 patients over 3 months.⁵ Notably, 8% of patients in this study who used Synvisc developed an effusion, compared with 0.6% of patients who used Euflexxa (P=.0015).

Recommendations

A 2007 report from the Agency for Healthcare Research and Quality (AHRQ) states that “viscosupplementation trials generally report positive effects on pain and function scores compared with placebo, but the evidence on clinical benefit is uncertain.”⁶

The 2007 guidelines of the Institute for Clinical Systems Improvement note that synthetic hyaluronates “may be effective” in selected patients with mild to moderate degenerative joint disease (based on evidence of middle quality on a 3-tier grading system).⁷

The American Academy of Orthopaedic Surgeons 2008 guideline on osteoarthritis of the knee indicates that, based on the AHRQ report,⁶ it cannot recommend for or against the use of intra-articular hyaluronic acid for mild to moderate symptomatic OA of the knee.⁸

TABLE 2
How HA products affect pain measures

Evidence summary

A 2005 meta-analysis evaluated the effectiveness of HA injections for osteoarthritis of the knee compared with saline placebo. Researchers identified 22 studies of 8 HA products that used the common end point of pain with movement.¹ (TABLE 1 lists FDA-approved HA products available in the United States.²) A decrease in pain of 15% was deemed clinically meaningful.

Compared with placebo, the mean difference in pain scores with HA products was -4% (95% confidence interval [CI], -9% to 1%) after 2 to 6 weeks; -4% (95% CI, -8% to -1%) after 10 to 14 weeks; and -7% (95% CI, -12% to -2%) after 22 to 30 weeks. The authors note that the small measured effect of HA was magnified by trials that didn’t report intention-to-treat results. The effect of HA was also larger in studies that didn’t conceal allocation. A weakness of the analysis was its inability to assess potential differences between HA products.

In this 2005 meta-analysis, HA injection didn’t improve knee function in any time interval. But in a Cochrane meta-analysis conducted the following year, HA was found to have positive results.³

TABLE 1
FDA-approved hyaluronic acid products

HA relieves pain about as much as NSAIDs

The comprehensive 2006 Cochrane meta-analysis reviewed single- and double-blinded RCTs that evaluated the effect of 12 HA products on osteoarthritis of the knee.³ Studies compared HA products with placebo (40), intra-articular steroids (10), NSAIDs (6), physical therapy (3), exercise (2), and each other (15). Efficacy data for different products couldn’t be combined because the studies measured different sets of outcomes at different time points.

Overall, the authors concluded that HA injections effectively reduced pain scores, with the largest benefit occurring within 5 to 13 weeks (TABLE 2). The authors also noted that the reductions in pain with HA injections, although generally small, were comparable to oral NSAID therapy and intra-articular corticosteroids. The trials reported few adverse events.

Two RCTs show no difference in efficacy among HA products

The Cochrane review determined that not enough evidence existed to evaluate HA products against each other. Two subsequent RCTs compared HA products and found no differences in efficacy. One study compared Synvisc, Orthovisc, and Ostenil therapy in 660 patients over 6 months.⁴ The other compared Synvisc with Euflexxa in 321 patients over 3 months.⁵ Notably, 8% of patients in this study who used Synvisc developed an effusion, compared with 0.6% of patients who used Euflexxa (P=.0015).

Recommendations

A 2007 report from the Agency for Healthcare Research and Quality (AHRQ) states that “viscosupplementation trials generally report positive effects on pain and function scores compared with placebo, but the evidence on clinical benefit is uncertain.”⁶

The 2007 guidelines of the Institute for Clinical Systems Improvement note that synthetic hyaluronates “may be effective” in selected patients with mild to moderate degenerative joint disease (based on evidence of middle quality on a 3-tier grading system).⁷

The American Academy of Orthopaedic Surgeons 2008 guideline on osteoarthritis of the knee indicates that, based on the AHRQ report,⁶ it cannot recommend for or against the use of intra-articular hyaluronic acid for mild to moderate symptomatic OA of the knee.⁸

TABLE 2
How HA products affect pain measures

Evidence summary

Parent education reduces clinic visits for asthmatic children

A 2001 trial randomized 81 families with a smoking parent and an asthmatic child between 3 and 12 years of age to 3 sessions of behavioral and educational counseling or usual care at an outpatient asthma clinic.¹ Parental education included information on second-hand smoke, basic asthma education, and feedback about urine cotinine levels (a marker of nicotine absorption). Behavioral counseling focused on reducing second-hand smoke exposure by caregivers.

The education group had a significantly reduced risk of 2 or more asthma-related clinic visits in the following 12 months compared with usual care (odds ratio=0.32; P=.03; number needed to treat=5). No significant decrease was noted in mean urine cotinine levels between groups (adjusted mean difference=-0.38 ng/mg favoring education; P=.26).

A similar trial that measured changes in urine cotinine randomized 91 families with a smoking parent and an asthmatic child into 3 groups:²

• A control group received usual care (regular office visits at an asthma clinic and medication management)
• A monitoring group used a parental smoking diary and a children’s asthma symptom diary
• A counseling group received 5 counseling sessions and also kept diaries. An environmental monitor in the home was used to assess exposure to secondhand smoke.

In the counseling group, 21.4% of patients (6 of 28) maintained 0% exposure throughout the 30-month trial period compared with 3.6% and 3.8% in the monitoring and control groups, respectively (P<.05 for comparison of counseling group to monitoring and control).

Banning indoor smoking sharply cuts nicotine exposure

No data are available on education about second-hand smoke in families with nonasthmatic children. However, strong evidence suggests that smoking outside the house reduces exposure generally.

A 2003 cross-sectional survey of 164 households in the United Kingdom with at least 1 smoking parent and 1 bottle-fed infant looked for a correlation between strategies to reduce second-hand smoke and urine cotinine-to-creatinine ratios in the infants.³ Parents were classified into 3 groups according to whether they maintained a strict ban on smoking in the home, a less strict ban (smoking at home but not near the infant), or no ban.

The mean infant urinary cotinine-to-creatinine ratio was 2.43 in the no-ban group and 2.61 in the less-strict ban group (difference not significant). The combined mean for these 2 groups—2.58—was significantly higher than the mean of 1.26 in the strictest group (P<.001).

A later study recruited a convenience sample of 49 interested families with a smoking mother and a nonbreastfeeding infant between 2 and 12 months of age.⁴ Families were classified by smoking history into one of 3 groups: nonsmoking households, smoking households where efforts were made to limit smoke exposure, and smoking households where no efforts were made to limit exposure. Urine samples were obtained 3 times over 1 week. Urine cotinine levels in infants averaged 0.33 ng/mL in nonsmoking households, 2.47 ng/mL in smoking households with limited exposure, and 15.47 ng/mL in smoking households with unlimited exposure (P<.001 for all comparisons).

A case-control study that recruited families with asthmatic and nonasthmatic children assessed the effectiveness of parental behaviors to reduce second-hand smoke in 182 households with 1 smoking parent and a child between 6 and 12 years of age.⁵ Researchers measured room air nicotine and salivary cotinine concentrations.

The nicotine levels on children’s belts and in their bedrooms and the family room were approximately 3 log units lower in houses with strict smoking bans compared with households with any degree of indoor smoking (P<.0001). Similarly, salivary cotinine levels were approximately 4 log units lower in children of households with indoor smoking bans (P<.0001).

Recommendations

The United States Preventive Services Task Force (USPSTF) strongly recommends that physicians help all smoking adults to quit.⁶ The American Academy of Family Physicians endorses the USPSTF position and further advises that smoking parents be counseled about the health effects of environmental tobacco smoke on their children.⁷

The American Academy of Pediatrics⁸ and the Veterans Administration⁹ recommend urging parents to stop smoking to prevent serious health implications for their children; they further encourage pediatric clinicians to offer parents advice on quitting in order to limit children’s exposure to second-hand smoke.

Evidence summary

Parent education reduces clinic visits for asthmatic children

A 2001 trial randomized 81 families with a smoking parent and an asthmatic child between 3 and 12 years of age to 3 sessions of behavioral and educational counseling or usual care at an outpatient asthma clinic.¹ Parental education included information on second-hand smoke, basic asthma education, and feedback about urine cotinine levels (a marker of nicotine absorption). Behavioral counseling focused on reducing second-hand smoke exposure by caregivers.

The education group had a significantly reduced risk of 2 or more asthma-related clinic visits in the following 12 months compared with usual care (odds ratio=0.32; P=.03; number needed to treat=5). No significant decrease was noted in mean urine cotinine levels between groups (adjusted mean difference=-0.38 ng/mg favoring education; P=.26).

A similar trial that measured changes in urine cotinine randomized 91 families with a smoking parent and an asthmatic child into 3 groups:²

• A control group received usual care (regular office visits at an asthma clinic and medication management)
• A monitoring group used a parental smoking diary and a children’s asthma symptom diary
• A counseling group received 5 counseling sessions and also kept diaries. An environmental monitor in the home was used to assess exposure to secondhand smoke.

In the counseling group, 21.4% of patients (6 of 28) maintained 0% exposure throughout the 30-month trial period compared with 3.6% and 3.8% in the monitoring and control groups, respectively (P<.05 for comparison of counseling group to monitoring and control).

Banning indoor smoking sharply cuts nicotine exposure

No data are available on education about second-hand smoke in families with nonasthmatic children. However, strong evidence suggests that smoking outside the house reduces exposure generally.

A 2003 cross-sectional survey of 164 households in the United Kingdom with at least 1 smoking parent and 1 bottle-fed infant looked for a correlation between strategies to reduce second-hand smoke and urine cotinine-to-creatinine ratios in the infants.³ Parents were classified into 3 groups according to whether they maintained a strict ban on smoking in the home, a less strict ban (smoking at home but not near the infant), or no ban.

The mean infant urinary cotinine-to-creatinine ratio was 2.43 in the no-ban group and 2.61 in the less-strict ban group (difference not significant). The combined mean for these 2 groups—2.58—was significantly higher than the mean of 1.26 in the strictest group (P<.001).

A later study recruited a convenience sample of 49 interested families with a smoking mother and a nonbreastfeeding infant between 2 and 12 months of age.⁴ Families were classified by smoking history into one of 3 groups: nonsmoking households, smoking households where efforts were made to limit smoke exposure, and smoking households where no efforts were made to limit exposure. Urine samples were obtained 3 times over 1 week. Urine cotinine levels in infants averaged 0.33 ng/mL in nonsmoking households, 2.47 ng/mL in smoking households with limited exposure, and 15.47 ng/mL in smoking households with unlimited exposure (P<.001 for all comparisons).

A case-control study that recruited families with asthmatic and nonasthmatic children assessed the effectiveness of parental behaviors to reduce second-hand smoke in 182 households with 1 smoking parent and a child between 6 and 12 years of age.⁵ Researchers measured room air nicotine and salivary cotinine concentrations.

The nicotine levels on children’s belts and in their bedrooms and the family room were approximately 3 log units lower in houses with strict smoking bans compared with households with any degree of indoor smoking (P<.0001). Similarly, salivary cotinine levels were approximately 4 log units lower in children of households with indoor smoking bans (P<.0001).

Recommendations

The United States Preventive Services Task Force (USPSTF) strongly recommends that physicians help all smoking adults to quit.⁶ The American Academy of Family Physicians endorses the USPSTF position and further advises that smoking parents be counseled about the health effects of environmental tobacco smoke on their children.⁷

The American Academy of Pediatrics⁸ and the Veterans Administration⁹ recommend urging parents to stop smoking to prevent serious health implications for their children; they further encourage pediatric clinicians to offer parents advice on quitting in order to limit children’s exposure to second-hand smoke.

Evidence summary

Parent education reduces clinic visits for asthmatic children

A 2001 trial randomized 81 families with a smoking parent and an asthmatic child between 3 and 12 years of age to 3 sessions of behavioral and educational counseling or usual care at an outpatient asthma clinic.¹ Parental education included information on second-hand smoke, basic asthma education, and feedback about urine cotinine levels (a marker of nicotine absorption). Behavioral counseling focused on reducing second-hand smoke exposure by caregivers.

The education group had a significantly reduced risk of 2 or more asthma-related clinic visits in the following 12 months compared with usual care (odds ratio=0.32; P=.03; number needed to treat=5). No significant decrease was noted in mean urine cotinine levels between groups (adjusted mean difference=-0.38 ng/mg favoring education; P=.26).

A similar trial that measured changes in urine cotinine randomized 91 families with a smoking parent and an asthmatic child into 3 groups:²

• A control group received usual care (regular office visits at an asthma clinic and medication management)
• A monitoring group used a parental smoking diary and a children’s asthma symptom diary
• A counseling group received 5 counseling sessions and also kept diaries. An environmental monitor in the home was used to assess exposure to secondhand smoke.

In the counseling group, 21.4% of patients (6 of 28) maintained 0% exposure throughout the 30-month trial period compared with 3.6% and 3.8% in the monitoring and control groups, respectively (P<.05 for comparison of counseling group to monitoring and control).

Banning indoor smoking sharply cuts nicotine exposure

No data are available on education about second-hand smoke in families with nonasthmatic children. However, strong evidence suggests that smoking outside the house reduces exposure generally.

A 2003 cross-sectional survey of 164 households in the United Kingdom with at least 1 smoking parent and 1 bottle-fed infant looked for a correlation between strategies to reduce second-hand smoke and urine cotinine-to-creatinine ratios in the infants.³ Parents were classified into 3 groups according to whether they maintained a strict ban on smoking in the home, a less strict ban (smoking at home but not near the infant), or no ban.

The mean infant urinary cotinine-to-creatinine ratio was 2.43 in the no-ban group and 2.61 in the less-strict ban group (difference not significant). The combined mean for these 2 groups—2.58—was significantly higher than the mean of 1.26 in the strictest group (P<.001).

A later study recruited a convenience sample of 49 interested families with a smoking mother and a nonbreastfeeding infant between 2 and 12 months of age.⁴ Families were classified by smoking history into one of 3 groups: nonsmoking households, smoking households where efforts were made to limit smoke exposure, and smoking households where no efforts were made to limit exposure. Urine samples were obtained 3 times over 1 week. Urine cotinine levels in infants averaged 0.33 ng/mL in nonsmoking households, 2.47 ng/mL in smoking households with limited exposure, and 15.47 ng/mL in smoking households with unlimited exposure (P<.001 for all comparisons).

A case-control study that recruited families with asthmatic and nonasthmatic children assessed the effectiveness of parental behaviors to reduce second-hand smoke in 182 households with 1 smoking parent and a child between 6 and 12 years of age.⁵ Researchers measured room air nicotine and salivary cotinine concentrations.

The nicotine levels on children’s belts and in their bedrooms and the family room were approximately 3 log units lower in houses with strict smoking bans compared with households with any degree of indoor smoking (P<.0001). Similarly, salivary cotinine levels were approximately 4 log units lower in children of households with indoor smoking bans (P<.0001).

Recommendations

The United States Preventive Services Task Force (USPSTF) strongly recommends that physicians help all smoking adults to quit.⁶ The American Academy of Family Physicians endorses the USPSTF position and further advises that smoking parents be counseled about the health effects of environmental tobacco smoke on their children.⁷

The American Academy of Pediatrics⁸ and the Veterans Administration⁹ recommend urging parents to stop smoking to prevent serious health implications for their children; they further encourage pediatric clinicians to offer parents advice on quitting in order to limit children’s exposure to second-hand smoke.