Immunology

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

A 38-year-old woman presented with a pruriginous and erythematous lesion on her nose that appeared during periods of cold weather. She said she is completely asymptomatic during the summer months.

Q: What is the most likely diagnosis?

• Lupus pernio
• Rosacea
• Seborrheic dermatitis
• Chilblain lupus erythematosus
• Lupus vulgaris

A: The diagnosis is chilblain lupus erythematosus.

The differential diagnosis of an erythematous lesion on the nose of a middle-aged woman also includes rosacea, lupus pernio, lupus vulgaris, and seborrheic dermatitis. Some of these lesions are exacerbated by cold. Usually, the diagnosis is based on clinical findings, but in some cases histologic features on biopsy study confirm the diagnosis.

Lesions of lupus pernio (sarcoidosis) remain unaltered with changes in temperature, and biopsy study usually shows granulomas without caseous necrosis with little inflammatory infiltrate at the periphery.

Rosacea usually gets worse with heat and with alcohol consumption, although it can be exacerbated by cold. Biopsy study shows a nonspecific perivascular and perifollicular lymphohistiocytic infiltrate accompanied occasionally by multinucleated cells.

Seborrheic dermatitis is a papulosquamous disorder characterized by greasy scaling over inflamed skin on the scalp, face, and trunk. Disease activity is increased in winter and spring, with remissions commonly occurring in summer. The histologic features of seborrheic dermatitis are nonspecific; in this case, the histologic features were compatible with chilblain lupus without changes of seborrheic dermatitis.

Lupus vulgaris is a chronic form of cutaneous tuberculosis characterized by redbrown papules with central atrophy. The nose and ears are usually affected. Histologically, granulomatous tubercles with epithelioid cells and caseation necrosis are usually found.

CHILBLAIN LUPUS ERYTHEMATOSUS

Pernio, or chilblain, is a localized inflammatory lesion of the skin resulting from an abnormal response to cold.¹ The cutaneous lesions of chilblain may be classified as idiopathic, autoimmune-related (as in systemic lupus erythematosus, subacute cutaneous lupus), and induced by drugs such as terbinafine (Lamisil)² or infliximab (Remicade).^,3

Chilblain lupus is a rare form of cutaneous lupus erythematosus and should not be confused with lupus pernio, which is a misleading name used for a type of cutaneous sarcoidosis.⁴

Chilblain lupus is characterized by reddish-purple plaques in acral areas (more often the hands and feet, but also the nose and ears) that are induced by exposure to cold—unlike other lesions of lupus erythematosus, which worsen with exposure to sunlight. The main difference from the cutaneous variety of sarcoidosis (lupus pernio) is the histopathologic appearance. In patients with chilblain lupus, epidermal atrophy, perivascular and periadnexal inflammatory infiltrates, and degeneration of the basal layer are found, whereas in lupus pernio (sarcoidosis), we observe granulomas without caseous necrosis, but with few inflammatory infiltrates on the periphery.

PROPOSED DIAGNOSTIC CRITERIA

Su et al⁵ have proposed diagnostic criteria for chilblain lupus. Their two major criteria are skin lesions in acral locations induced by exposure to cold or a drop in temperature, and evidence of lupus erythematosus in the skin lesions by histopathologic examination or immunofluorescence study. Both of these criteria must be met, plus one of three minor criteria: the coexistence of systemic lupus erythematosus or of skin lesions of discoid lupus erythematosus; response to lupus therapy; and negative results of testing for cryoglobulin and cold agglutinins.

CHILBLAIN LUPUS VS SYSTEMIC LUPUS

Chilblain lupus is an uncommon manifestation of systemic lupus erythematosus, and it is reported to occur in about 20% of patients with that condition.⁶ Often, the onset of chilblain lupus precedes the systemic disease. Patients with systemic lupus erythematosus and chilblain lupus do not usually present with renal disease, mucosal lesions, or central nervous system involvement. However, Raynaud phenomenon and photosensitivity have been reported to be more frequently associated with chilblain lupus.⁷

A disorder of peripheral circulation could be involved in the pathogenesis of chilblain lupus, and the association with Raynaud phenomenon, livedo reticularis, antiphospholipid syndrome, and changes in nailfold capillaries supports this hypothesis. Antinuclear antibody and anti-Ro/SS-A antibody are commonly detected in the serum of patients with chilblain lupus, and anti-Ro/SS-A antibody seems to be a major serologic marker of chilblain lupus in patients with systemic lupus erythematosus.⁷

TREATMENT

Protection from cold by physical measures is very important, as well as the use of topical or oral antibiotics if the lesions are infected. In severe cases unresponsive to topical corticosteroids, a calcium channel blocker is a good therapeutic option; antimalarials, commonly used in the treatment of lupus erythematosus, can also have a positive effect in patients with chilblain lupus.

CASE CONCLUDED

Our patient was advised to protect herself from the cold. Topical corticosteroids and oral hydroxychloroquine (200 mg/day) were prescribed, and they produced a good response. In severe cases, oral corticosteroids, etretinate (Tegison), mycophenolate (CellCept), or thalidomide (Thalomid) may be used.⁸

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

For many of those long-term effects, such as osteoporosis, cushingoid features, skin fragility, and cataracts, all we can do is hope that they don’t occur, since there is little we can do to screen for or prevent them. We have previously discussed steroid-associated osteoporosis in the Journal,¹ and strategies for preventing it have been proposed by specialty societies.² For other complications such as hypertension, weight gain, and glucose intolerance, we can offer common-sense protective suggestions, monitor for them, and intervene if they occur.

In this issue, Dr. M. Cecilia Lansang and Ms. Leighanne Kramer Hustak³ discuss the management of steroid-induced adrenal suppression and diabetes. They offer practical management suggestions but also point out that the evidence base for our treatment decisions is surprisingly limited.

Nearly all patients chronically receiving high-dose glucocorticoid therapy develop glucose intolerance, but knowing when that is happening is not always easy. In patients destined to develop type 2 diabetes, the laboratory or clinical signs of hyperglycemia appear only when the pancreas can no longer maintain the insulin production necessary to overcome peripheral insulin resistance. Steroid-induced diabetes is characterized by increased gluconeogenesis, insulin resistance, and excessive postprandial surges, so fasting glucose levels are not sensitive for this clinical syndrome.

The degree and duration of the chronic hyperinsulinemia and hyperglycemia dictates the risk of microvascular complications and thus will be linked to duration of steroid therapy (unless the steroid is unmasking preexisting mild diabetes). Although issues surrounding tight control of blood glucose levels in the acute setting remain unresolved, I believe that even short-term significant steroid-induced hyperglycemia should be prevented when reasonably possible, at the least keeping in mind the additive ill effects of hyperglycemia and steroid therapy on the risk of nuisance infections such as oral and vaginal candidiasis and urinary tract infections that, in the setting of high-dose steroid therapy, can rapidly turn nasty.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES

Be alert for new-onset diabetes

For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.

Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.

Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.

If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.²⁰

Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.

The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.

If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.

A hemoglobin A_1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.

Diet and exercise may not be practical

Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.

In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.

For suspected type 1 diabetes, start insulin

If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.

Starting oral antidiabetic drugs

Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.

If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.

Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A_1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.²²

In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A_1c goal of less than 7%, we believe that our suggestions below are reasonable.

We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.

 

 

If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL

In this situation the choices are:

• Metformin
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
• Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.²⁰
• Glucagon-like protein-1 (GLP-1) agonists
• Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.

We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.

If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL

Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).^22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:

• Metformin plus a sulfonylurea^22,23
• Metformin plus a glinide²²
• Metformin plus a GLP-1 agonist²³
• Metformin plus a DPP-4 inhibitor.²²

If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL

In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.

Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.

The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.

If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.

If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:

• Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
• Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
• Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.

Capillary blood glucose (fingerstick) checks

The timing and frequency of fingerstick checks depend on the treatment.

Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.

For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.²¹ We have been recommending that our patients on once-daily insulin check at least twice a day.

Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general²¹:

• Before meals 70 to 130 mg/dL or
• 1 to 2 hours after meals < 180 mg/dL.

During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.

STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES

Fingerstick checks more often

Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.

 

 

Adjust medications if glucose is not at goal

Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.

If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.

Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.⁶ The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).

CUSHING SYNDROME AND ADRENAL SUPPRESSION

Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.

Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.

To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful^24,25:

However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).

Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m²/day, or closer to 10 to 15 mg/day.^26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.

Adrenal suppression vs insufficiency

Adrenal suppression is often confused with adrenal insufficiency.

Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.²⁹

In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).

Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.

In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.²⁹

Local steroids can suppress the adrenal glands

Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.^30–38

In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.³⁰

The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.³⁹ Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.^32–38

When is adrenal suppression more likely?

Adrenal suppression is more likely in the following situations:

• Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.^31,40
• Supraphysiologic doses, stronger formulations, longer-acting formulations.⁴¹

When is adrenal suppression less likely?

Adrenal suppression is less likely in the following situations:

• Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)⁴²
• Alternate-day dosing of steroids.⁴³

 

 

Steroid withdrawal vs adrenal insufficiency

Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.⁴² Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.

The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.

With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.

Identifying patients at risk of adrenal suppression

Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.

The ACTH stimulation test for adrenal recovery

Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).

The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.

The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.⁴² If adrenal suppression persists, weaning from steroids should continue.

In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.

Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.³³

Tapering from glucocorticoids

Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.

If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.

If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.⁴⁴

If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.

One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.⁴⁴ Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).⁴⁴ Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.

Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.⁴⁵

A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.⁴⁶ The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.

Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES

Be alert for new-onset diabetes

For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.

Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.

Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.

If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.²⁰

Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.

The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.

If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.

A hemoglobin A_1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.

Diet and exercise may not be practical

Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.

In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.

For suspected type 1 diabetes, start insulin

If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.

Starting oral antidiabetic drugs

Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.

If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.

Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A_1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.²²

In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A_1c goal of less than 7%, we believe that our suggestions below are reasonable.

We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.

 

 

If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL

In this situation the choices are:

• Metformin
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
• Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.²⁰
• Glucagon-like protein-1 (GLP-1) agonists
• Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.

We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.

If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL

Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).^22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:

• Metformin plus a sulfonylurea^22,23
• Metformin plus a glinide²²
• Metformin plus a GLP-1 agonist²³
• Metformin plus a DPP-4 inhibitor.²²

If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL

In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.

Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.

The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.

If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.

If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:

• Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
• Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
• Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.

Capillary blood glucose (fingerstick) checks

The timing and frequency of fingerstick checks depend on the treatment.

Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.

For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.²¹ We have been recommending that our patients on once-daily insulin check at least twice a day.

Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general²¹:

• Before meals 70 to 130 mg/dL or
• 1 to 2 hours after meals < 180 mg/dL.

During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.

STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES

Fingerstick checks more often

Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.

 

 

Adjust medications if glucose is not at goal

Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.

If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.

Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.⁶ The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).

CUSHING SYNDROME AND ADRENAL SUPPRESSION

Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.

Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.

To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful^24,25:

However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).

Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m²/day, or closer to 10 to 15 mg/day.^26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.

Adrenal suppression vs insufficiency

Adrenal suppression is often confused with adrenal insufficiency.

Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.²⁹

In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).

Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.

In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.²⁹

Local steroids can suppress the adrenal glands

Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.^30–38

In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.³⁰

The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.³⁹ Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.^32–38

When is adrenal suppression more likely?

Adrenal suppression is more likely in the following situations:

• Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.^31,40
• Supraphysiologic doses, stronger formulations, longer-acting formulations.⁴¹

When is adrenal suppression less likely?

Adrenal suppression is less likely in the following situations:

• Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)⁴²
• Alternate-day dosing of steroids.⁴³

 

 

Steroid withdrawal vs adrenal insufficiency

Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.⁴² Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.

The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.

With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.

Identifying patients at risk of adrenal suppression

Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.

The ACTH stimulation test for adrenal recovery

Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).

The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.

The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.⁴² If adrenal suppression persists, weaning from steroids should continue.

In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.

Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.³³

Tapering from glucocorticoids

Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.

If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.

If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.⁴⁴

If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.

One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.⁴⁴ Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).⁴⁴ Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.

Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.⁴⁵

A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.⁴⁶ The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.

Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.

Glucocorticoids are commonly prescribed by primary care physicians and specialists alike for multiple medical problems, acute as well as chronic.

However, these useful drugs have adverse effects on multiple endocrine systems, effects that include diabetes (or worsening of hyperglycemia in those with known diabetes), Cushing syndrome, adrenal suppression, osteoporosis (reviewed in the Cleveland Clinic Journal of Medicine in August 2010),¹ and dyslipidemia. In addition, suppression of gonadotropins, growth hormone, and, acutely, thyrotropin can ensue.

The focus of this review is on the diabetogenic and adrenal suppressive effects of glucocorticoids and their management. We describe the rationale for choosing specific drugs to counter hyperglycemia, tests for determining adrenal suppression and systemic glucocorticoid absorption, and how and why to taper these drugs.

WIDELY USED DRUGS

Although glucocorticoids (often simply called steroids or corticosteroids, although not all steroids are corticosteroids, and not all corticosteroids are glucocorticoids) are the core treatment for adrenal insufficiency, in most cases they are prescribed for their anti-inflammatory effects. They act through multiple pathways at the cellular and molecular levels, suppressing the cascades that would otherwise result in inflammation and promoting pathways that produce anti-inflammatory proteins.²

In addition to formulations that are intended to have systemic effects, other, “local” formulations are made for specific conditions, such as intra-articular injections for arthritis, epidural injections for lumbar disk pain, eye drops for uveitis, nasal sprays for allergic rhinitis, inhalers for asthma, and topical ointments and creams for eczema. However, as we will discuss, even these preparations can have systemic effects.

GLUCOCORTICOID-INDUCED DIABETES IS COMMON

Glucocorticoids are the most common cause of drug-induced diabetes. Though the exact prevalence is not known, a few observations suggest that glucocorticoid-induced diabetes or hyperglycemia is common:

• In patients with rheumatoid arthritis, mean age 62 years, nearly 9% developed diabetes in the 2 years after starting glucocorticoid treatment, which was a higher rate than expected.³
• In nondiabetic patients with primary renal disease treated with prednisolone 0.75 mg/kg/day, 42% were found to have 2-hour post-lunch plasma glucose concentrations higher than 200 mg/dL but normal fasting glucose levels.⁴
• In a case-control study, the odds ratio of starting an oral hypoglycemic agent or insulin was 1.77 for patients receiving a hydrocortisone-equivalent dose of 1 to 39 mg/day, 3.02 for 40 to 79 mg/day, 5.82 for 80 to 119 mg/day, and 10.34 for 120 mg/day or more.⁵ (For a full discussion of glucocorticoid equivalents, see the section below on Cushing syndrome and adrenal suppression.)
• In patients with type 1 diabetes, prednisone 60 mg/day raised the blood glucose levels starting 6 hours after the prednisone dose.⁶
• Diabetic ketoacidosis and hyperosmolar nonketotic syndrome have been reported as a result of glucocorticoid treatment.^7–9

GLUCOCORTICOIDS CAUSE DIABETES MAINLY VIA INSULIN RESISTANCE

The mechanism by which glucocorticoids cause diabetes predominantly involves insulin resistance rather than decreased insulin production. In fact, in a study in healthy volunteers, ¹⁰ hydrocortisone infusion resulted in higher insulin production than saline infusion did. (In high doses, however, glucocorticoids have been shown to decrease insulin secretion.¹¹)

Normally, in response to insulin, the liver decreases its output of glucose. Glucocorticoids decrease the liver’s sensitivity to insulin, thereby increasing hepatic glucose output.¹² They also inhibit glucose uptake in muscle and fat, reducing insulin sensitivity as much as 60% in healthy volunteers. This seems primarily due to a postreceptor effect, ie, inhibition of glucose transport.^13–15

THE PEAK EFFECT OCCURS 4 TO 6 HOURS AFTER DOSING

To understand the optimal time for checking plasma glucose and to apply appropriate treatment, we should consider the pharmacokinetic profile of glucocorticoids.

Studied using the whole-blood lymphocyte proliferation technique, prednisone shows a peak effect at about 4 to 6 hours and a duration of action of 13 to 16 hours.¹⁶ This closely resembles what we see in terms of glucose excursion with this drug.¹⁷ Two studies of intravenous dexamethasone 10 mg showed that glucose levels rose within 4 hours of injection, but did not pursue this beyond that time frame.^18,19

PATIENTS WITHOUT A PREVIOUS DIAGNOSIS OF DIABETES

Be alert for new-onset diabetes

For most diseases treated with glucocorticoids, clinicians can estimate in advance how long the patient will need to take the drug. We can arbitrarily classify the projected exposure as either short-term (3 to 4 weeks or less, such as a 6-day course of methylprednisolone for allergic conditions) or long-term (such as in transplant recipients to prevent rejection or to treat graft-vs-host disease). Hyperglycemia is a potential concern with both short-term and long-term treatment. However, guidelines on checking blood sugar levels, as opposed to relying on symptoms alone, are available only for long-term glucocorticoid treatment.

Patients beginning treatment should be warned of typical diabetes symptoms such as thirst and increased urination and, should these occur, to seek medical attention to have their blood glucose level checked. It is also reasonable to have them return in a week for a random postprandial plasma glucose test in the mid-afternoon.

Why this timing? In most once-daily regimens, glucocorticoids are given in the morning to prevent adrenal suppression (discussed below). In our experience, glucose levels start to rise mid-morning and continue to increase until bedtime. Measuring glucose levels 1 to 2 hours after lunch allows for both the glucocorticoid action and the carbohydrate absorption from lunch to reach their peaks. If hyperglycemia is going to happen, it should be detectable by then. A glucose level of 200 mg/dL or higher should prompt the practitioner to pursue this further.

If glucocorticoid treatment is to continue beyond 3 to 4 weeks, the only population for which there are published guidelines on managing glucocorticoid-related diabetes is transplant recipients. International consensus guidelines, published in 2003, suggest checking the fasting plasma glucose level once a week for the first 4 weeks after transplantation, then at 3 months, at 6 months, and then once a year.²⁰

Though practical, this suggestion does not reflect the fact that glucocorticoids often do not affect fasting plasma glucose, especially if given once daily in the morning at doses of 30 mg or less of prednisone or its equivalent. These guidelines thus may not be applicable to other populations with glucocorticoid-induced diabetes.

The transplant guidelines do mention that an oral glucose tolerance test may be more sensitive, but this is often cumbersome to perform. We believe that checking random postprandial plasma glucose levels is helpful in this regard.

If the patient was at risk of developing diabetes even before receiving a glucocorticoid (for example, if he or she is overweight, has a family history of diabetes, or had a previous hemoglobin A_1c of 5.7% or higher), then a fasting plasma glucose level of 126 mg/dL or higher or a hemoglobin A_1c of 6.5% or higher might suffice to diagnose diabetes. Results should be confirmed on a separate day in the absence of unequivocal hyperglycemia. Fasting hyperglycemia can also be seen in patients receiving higher once-daily glucocorticoid doses—in our experience, an equivalent of prednisone 40 mg once a day in the morning— or twice-daily dosing.

A hemoglobin A_1c checked less than 2 to 3 months after starting glucocorticoid treatment will not be sensitive in picking up glucocorticoid-induced diabetes if the patient did not have underlying diabetes.

Diet and exercise may not be practical

Though diet and exercise are important in managing diabetes, the condition for which the patient is receiving a glucocorticoid may prevent him or her from exercising, at least in the acute phase of the illness.

In addition, though the exact mechanism is not known, glucocorticoids increase hunger, and so decreasing food intake is not easy either. Nonetheless, patients should be familiarized with what carbohydrates are and should be advised to reduce their intake of them.

For suspected type 1 diabetes, start insulin

If type 1 diabetes is suspected, for example, in patients who are lean, younger than 30 years, or who had presented with diabetic ketoacidosis, then insulin should be started. In equivocal cases, insulin therapy can commence while testing is done for C-peptide, glutamic acid decarboxylase antibodies, islet cell antibodies, and insulinoma-associated protein antibodies.

Starting oral antidiabetic drugs

Some patients may have contraindications to specific drugs. For example, metformin (Glucophage) is contraindicated if the serum creatinine level is elevated, an abnormality that renal transplant patients may continue to have.

If the patient has no such contraindications, we have found the following medications suitable in view of their efficacy, low risk of hypoglycemia, or lack of distressing side effects. They will often lower glucose levels enough to achieve capillary blood glucose or fingerstick goals (discussed below). None of them has been specifically approved by the US Food and Drug Administration for glucocorticoid-induced diabetes, but they are approved for type 2 diabetes.

Guidelines from the American Association of Clinical Endocrinologists for type 2 diabetes call for starting monotherapy if the hemoglobin A_1c is 6.5% to 7.5%, dual therapy if it is 7.6% to 9%, triple therapy if it is higher than 9% and the patient has no symptoms, and insulin if it is higher than 9% and the patient does have symptoms.²²

In terms of estimated average glucose levels, these categories correspond to 140 to 169 mg/dL for monotherapy, 171 to 212 mg/dL for dual therapy, and higher than 212 mg/dL for triple therapy or insulin. Since estimated average levels also include fasting glucose levels (which are lower in glucocorticoid-induced diabetes compared with nonfasting levels), and because we use the American Diabetes Association general hemoglobin A_1c goal of less than 7%, we believe that our suggestions below are reasonable.

We divide our recommendations according to initial random (ideally, 1- to 2-hour postprandial) plasma glucose levels.

 

 

If the random or 1- to 2-hour post-meal plasma glucose is lower than 220 mg/dL

In this situation the choices are:

• Metformin
• Dipeptidyl peptidase-4 (DPP-4) inhibitors (“gliptins”)
• Meglitinides (“glinides”). The guidelines on new-onset diabetes after transplantation point out that meglitinides may be the safest agents apart from insulin in the renal transplant population, but does acknowledge that efficacies of different oral agents have not been compared in this group.²⁰
• Glucagon-like protein-1 (GLP-1) agonists
• Sulfonylureas. However, the longer-acting forms such as glimepiride (Amaryl) are not suitable if the fasting plasma glucose is not affected.

We have not used thiazolidinediones (“glitazones”) routinely because they can cause weight gain and edema—problems that are already seen with the use of steroids—and have a slower onset of action.

If the random or 1- to 2-hour post-meal plasma glucose is 220 to 300 mg/dL

Often, a combination of drugs or insulin (see below) is needed. However, you can start with one agent and add a second agent within 2 or 3 months (as is recommended for type 2 diabetes).^22,23 The following combinations of the agents listed above are supported by published guidelines for type 2 diabetes:

• Metformin plus a sulfonylurea^22,23
• Metformin plus a glinide²²
• Metformin plus a GLP-1 agonist²³
• Metformin plus a DPP-4 inhibitor.²²

If the random or 1- to 2-hour post-meal plasma glucose is higher than 300 mg/dL

In our experience, if their plasma glucose levels are this high, patients are experiencing frank symptoms of hyperglycemia.

Insulin addresses those symptoms and avoids the prolonged wait that often results from unsuccessfully starting one agent and then adding another. Of all the available drugs, insulin is the only one that can be used despite multiple underlying illnesses; it does not cause a lot of drug interactions, and the dose can be adjusted upward and downward in increments to fit the patient’s needs, especially when a larger glucocorticoid load is given up front and then is tapered either slowly or rapidly. However, it can cause hypoglycemia and weight gain.

The initial total daily dose of insulin can be based on the patient’s weight. A starting total daily dose of 0.15 to 0.3 U/kg is reasonable— on the lower end if only the postprandial glucose levels are elevated, and on the higher end if both fasting and postprandial glucose levels are affected.

If fasting glucose levels are not elevated, then Neutral Protamine Hagedorn insulin (which is intermediate-acting) or a premixed combination of an intermediate-acting plus a fast- or short-acting insulin can be given once a day before breakfast, or even before lunch if the glucose levels start to rise only after lunch.

If both the fasting and the postprandial glucose levels are elevated, regimens similar to those for type 1 or insulin-requiring type 2 diabetes can be used, except that the ratios of the doses are tilted more toward covering postprandial than fasting hyperglycemia:

• Long-acting insulin plus prandial insulin, in a ratio of 30:70 to 50:50. As glucocorticoids are tapered, the long-acting insulin may have to be discontinued while the prandial doses are continued, since the fasting glucose level decreases first.
• Premixed insulins, with one-half to two-thirds of the dose given before breakfast and the rest before the evening meal, with the possibility of a third injection before lunch. As glucocorticoids are tapered, the evening dose is tapered first.
• Intermediate-acting insulin plus short- or fast-acting insulin in the morning (these two will make up one-half to two-thirds of the total daily dose), short- or fast-acting insulin before the evening meal, and intermediate-acting insulin at bedtime. As glucocorticoids are tapered, the bedtime insulin is tapered first.

Capillary blood glucose (fingerstick) checks

The timing and frequency of fingerstick checks depend on the treatment.

Though postprandial testing is ideal, it is often not practical or convenient. Before lunch, before dinner, and at bedtime are good alternatives since they reflect the pattern of glucose rise throughout the day. For patients on diet and exercise with or without agents other than insulin, testing once or twice a day is reasonable, rotating times before meals (including fasting if this time is affected) and at bedtime.

For patients on insulin, checking two to four times a day initially would help match insulin doses with glucose excursions. For continued care, the American Diabetes Association recommends fingerstick checks three times daily in patients on multiple insulin injections, but it has no specific recommendations for those on once-a-day insulin.²¹ We have been recommending that our patients on once-daily insulin check at least twice a day.

Goal fingerstick glucose levels that we use are in accordance with the American Diabetes Association guidelines for diabetes in general²¹:

• Before meals 70 to 130 mg/dL or
• 1 to 2 hours after meals < 180 mg/dL.

During steroid taper, if the glucocorticoid dose is in the lower range (eg, a prednisone-equivalent dose of approximately 7.5 mg per day or less), the fingerstick glucose levels are at the lower end of the target range, and the patient is on a single antidiabetic agent that does not often cause hypoglycemia (eg, metformin), then it is reasonable to ask the patient to not take the antidiabetic medication for 3 to 7 days while continuing to check fingersticks to see if it needs to be resumed. Patients on agents that can cause hypoglycemia need to check more often during the 1 to 3 days after the glucocorticoid dose reduction, as it may take this much time for the glycemic effect to diminish and to adjust the diabetes medication to the appropriate dose.

STARTING GLUCOCORTICOIDS IN PATIENTS WITH KNOWN DIABETES

Fingerstick checks more often

Most patients will already have a glucose meter. They should be instructed to check as discussed above if they do not have a previous diagnosis of diabetes, or to continue as they are doing if they are already checking more often. Patients who have been checking only fasting levels should be instructed to check later in the day, either before or 1 to 2 hours after meals, as discussed above. Patients on oral medications may need additional oral agents or insulin.

 

 

Adjust medications if glucose is not at goal

Patients with type 2 diabetes treated with diet and exercise alone can be started on the medications discussed above if their fingerstick readings are not at goal.

If they are already on insulin, we advise them to increase the short- or fast-acting insulins and the morning intermediate-acting insulin by at least 10% to 20% as soon as an elevation in glucose is detected. Long-acting insulin or nighttime intermediate-acting insulin should be increased if fasting glucose levels are affected.

Insulin requirements can double depending on the glucocorticoid dose. In patients with type 1 diabetes who were given prednisone 60 mg orally for 3 days, mean blood glucose levels increased from a baseline of 110 mg/dL at baseline to 149 mg/dL on the days on prednisone.⁶ The average blood glucose level remained elevated at 141 mg/dL on the day after the last dose of prednisone. The insulin dose increased by 31% to 102% (mean 69%).

CUSHING SYNDROME AND ADRENAL SUPPRESSION

Unlike glucocorticoid-induced diabetes, in which the dilemma is often when to initiate antidiabetic treatment, the question for patients in whom Cushing syndrome or adrenal suppression has developed is when to discontinue glucocorticoids.

Adrenal suppression for the most part goes hand in hand with exogenous Cushing syndrome. If cushingoid features develop, we can infer that the dose of exogenous glucocorticoid exceeds the physiologic needs. This supraphysiologic dosing also leads to suppression of endogenous cortisol production. The suppression occurs at the level of the hypothalamus and pituitary gland, with subsequent atrophy of the part of the adrenal cortex that produces endogenous glucocorticoids.

To understand further the concept of supraphysiologic dosing, the following interconversion of systemic glucocorticoid effects is helpful^24,25:

However, there is not much information on interconversion for the local preparations (intra-articular, epidural, inhaled, topical).

Moreover, the definition of supraphysiologic dosing seems to be evolving. Though a total hydrocortisone-equivalent dose of 30 mg/day is still often touted as physiologic replacement, many patients require less. Several studies in the early 1990s, mostly in children and adolescents, showed the mean daily cortisol production rate to be 4.8 to 6.8 mg/m²/day, or closer to 10 to 15 mg/day.^26–28 For purposes of this discussion, a physiologic dose will be defined as up to 30 mg hydrocortisone per day or its equivalent.

Adrenal suppression vs insufficiency

Adrenal suppression is often confused with adrenal insufficiency.

Adrenal suppression occurs when cortisol production is decreased because of the presence of exogenous glucocorticoids or other drugs, such as megestrol acetate (Megace), that act on the glucocorticoid receptor. Another situation beyond the scope of this review is excess endogenous cortisol production by an adrenal adenoma or adrenal carcinoma that causes suppression of the contralateral adrenal gland.²⁹

In contrast, adrenal insufficiency is caused by failure of the adrenal gland to produce cortisol as a result of an innate disorder of the adrenal gland (eg, Addison disease) or pituitary gland (eg, pituitary surgery).

Hence, endogenous cortisol production in a patient taking supraphysiologic doses of exogenous glucocorticoids may be suppressed. Recovery of endogenous cortisol production is expected after stopping the exogenous glucocorticoid, though the time to recovery can vary and the patient can be adrenally insufficient if the glucocorticoid is stopped abruptly.

In addition, during times of intercurrent illness, a patient with adrenal suppression may be relatively adrenally insufficient and may need larger doses (“stress doses”) of glucocorticoids, since the adrenal glands may be unable to mount a stress response.²⁹

Local steroids can suppress the adrenal glands

Glucocorticoids are the most common cause of Cushing syndrome. Oral formulations such as dexamethasone, prednisone, and hydrocortisone taken in supraphysiologic doses and for prolonged durations are easily recognized as obvious causes of Cushing syndrome. However, intra-articular, epidural, inhaled, nasal, ocular, and topical steroids—so-called local preparations—have also been linked to Cushing syndrome, and physicians are less likely to recognize them as causes.^30–38

In a study in 16 pediatric patients with asthma and 48 controls, inhaled beclomethasone dipropionate (Qvar) 300 to 500 μg daily resulted in adrenal suppression in 100% of patients after 6 to 42 months, as determined by an insulin tolerance test.³⁰

The topical steroid betamethasone (Diprosone) carries a warning that systemic absorption of topical steroids can cause adrenal suppression.³⁹ Intra-articular, intranasal, epidural, and ocular routes are also reported to cause adrenal suppression.^32–38

When is adrenal suppression more likely?

Adrenal suppression is more likely in the following situations:

• Longer duration of treatment. Studies have shown that exposure to supraphysiologic steroid doses for 2 weeks or less might already suppress the adrenal glands, but the clinical significance of this is unclear since some recovery already occurs a few days after the glucocorticoids are discontinued.^31,40
• Supraphysiologic doses, stronger formulations, longer-acting formulations.⁴¹

When is adrenal suppression less likely?

Adrenal suppression is less likely in the following situations:

• Regimens that mimic the diurnal rhythm of cortisol (higher dose in the morning, lower dose in the afternoon)⁴²
• Alternate-day dosing of steroids.⁴³

 

 

Steroid withdrawal vs adrenal insufficiency

Another phenomenon that can be confused with adrenal insufficiency or glucocorticoid insufficiency is steroid withdrawal, in which patients experience lethargy, muscle aches, nausea, vomiting, and postural hypotension as glucocorticoids are tapered and their effects wane.⁴² Increasing the glucocorticoid dose for presumed adrenal insufficiency may delay recovery of the adrenal function and would have to be weighed against the patient’s symptoms.

The following may help distinguish the two: if the patient is on supraphysiologic glucocorticoid doses, then he or she is not glucocorticoid-deficient and is likely suffering from steroid withdrawal. At this point, patients may just need reassurance, symptomatic treatment, or if necessary, a brief (1-week) increase of the previous lowest dose, followed by reevaluation.

With local glucocorticoid preparations that may be systemically absorbed, however, there is no good way of estimating dose equivalence. In these situations, the decision to simply reassure the patient or give symptomatic treatment—as opposed to giving low-dose oral glucocorticoids such as hydrocortisone 5 to 10 mg daily for a week followed by reevaluation— depends on the severity of symptoms and whether the patient has quick access to medical attention should he or she develop an intercurrent illness.

Identifying patients at risk of adrenal suppression

Patients presenting with weight gain or symptoms suggesting Cushing syndrome should be asked about steroid intake and should be prompted to recall possible nonoral routes. In addition, patients presenting with muscle aches and fatigue—symptoms of steroid withdrawal— may have received unrecognized local glucocorticoids that were systemically absorbed, now with diminishing effects.

The ACTH stimulation test for adrenal recovery

Testing can be done to see if the adrenal glands have recovered and glucocorticoid therapy can be discontinued (see Tapering from glucocorticoids, below).

The test most often used is the corticotropin (ACTH) stimulation test. Since the suppression is at the level of the hypothalamus and the pituitary gland, the ACTH stimulation test is an indirect method of assessing hypothalamic and pituitary function in the context of glucocorticoid-induced adrenal suppression. It has good correlation with the insulin tolerance test, the gold-standard test for an intact hypothalamic-pituitary-adrenal axis.

The synthetic ACTH cosyntropin (Cortrosyn) 250 μg is injected intravenously or intramuscularly, and a cortisol level is drawn at baseline and 30 and 60 minutes later. Other doses such as 1 μg or 10 μg have been reported but are not yet widely accepted. A cortisol level of greater than 18 to 20 μg/dL at any time point shows that the adrenals have regained function and the steroids may be discontinued.⁴² If adrenal suppression persists, weaning from steroids should continue.

In reality, it may not be possible or practical to do an ACTH stimulation test, as not all physicians’ offices have a supply of cosyntropin or the manpower to perform the test correctly. In these cases, weaning can progress with monitoring of symptoms.

Testing for synthetic glucocorticoids in the urine and serum can demonstrate systemic absorption and may be helpful in patients who do not recall receiving steroids.³³

Tapering from glucocorticoids

Several tapering schedules have been suggested (although not necessarily validated). Whether and how to taper depend on how long the glucocorticoid has been taken.

If taken for less than 1 week, glucocorticoids can be stopped without tapering, regardless of the dose.

If taken for 1 to 3 weeks, the decision to taper depends on the clinician’s assessment of the patient’s general health or constitution and the illness for which the glucocorticoid was prescribed. For example, if the underlying disease is less likely to flare with a gradual dose reduction, then tapering would be suitable.⁴⁴

If taken for more than 3 weeks, the practice has been a more rapid taper at the beginning until a physiologic dose is reached. How quickly to reduce the dose depends on whether the underlying illness is expected to flare up, or if the patient might experience steroid withdrawal symptoms.

One schedule is to lower the glucocorticoid dose by an amount equivalent to prednisolone 2.5 mg every 3 to 4 days when above the physiologic dose, then to taper more slowly by 1 mg every 2 to 4 weeks.⁴⁴ Once the physiologic dose is reached, one can switch to the equivalent dose of hydrocortisone and decrease the dose by 2.5 mg a week until a daily dose of 10 mg a day is reached and maintained for 2 to 3 months, and then perform a test of adrenal function (see above).⁴⁴ Passing the test implies that the adrenal glands have recovered and the glucocorticoid can be stopped.

Another option is to switch to alternate-day therapy once a physiologic dose is reached and to test 8:00 am cortisol levels, continuing the glucocorticoid and retesting in 4 to 6 weeks if the value is less than 3 μg/dL; stopping the glucocorticoid if the value is higher than 20 μg/dL; and performing an ACTH stimulation test for values in between.⁴⁵

A review of other tapering regimens for chronic diseases, mostly pulmonary, did not find enough evidence to recommend one particular schedule over another.⁴⁶ The tapering schedule may have to be adjusted to prevent disease flare and symptoms of steroid withdrawal.

Locally administered steroids. Since the equivalence of systemically absorbed local glucocorticoids is not known, these patients are likely to present when they have symptoms of steroid withdrawal. In this situation, testing adrenal function will help.

Health care providers often need to evaluate allergic disorders such as allergic rhinoconjunctivitis, asthma, and allergies to foods, drugs, latex, and venom, both in the hospital and in the clinic.

Unfortunately, some symptoms, such as chronic nasal symptoms, can occur in both allergic and nonallergic disorders, and this overlap can confound the diagnosis and therapy. Studies suggest that when clinicians use the history and physical examination alone in evaluating possible allergic disease, the accuracy of their diagnoses rarely exceeds 50%.¹

Blood tests are now available that measure immunoglobulin E (IgE) directed against specific antigens. These in vitro tests can be important tools in assessing a patient whose history suggests an allergic disease.² However, neither allergy skin testing nor these blood tests are intended to be used for screening: they may be most useful as confirmatory diagnostic tests in cases in which the pretest clinical impression of allergic disease is high.

ALLERGY IS MEDIATED BY IgE

In susceptible people, IgE is produced by B cells in response to specific antigens such as foods, pollens, latex, and drugs. This antigen-specific (or allergen-specific) IgE circulates in the serum and binds to high-affinity IgE receptors on immune effector cells such as mast cells located throughout the body.

Upon subsequent exposure to the same allergen, IgE receptors cross-link and initiate downstream signaling events that trigger mast cell degranulation and an immediate allergic response—hence the term immediate (or Gell-Coombs type I) hypersensitivity.³

Common manifestations of type I hypersensitivity reactions include signs and symptoms that can be:

• Cutaneous (eg, acute urticaria, angioedema)
• Respiratory (eg, acute bronchospasm, rhinoconjunctivitis)
• Cardiovascular (eg, tachycardia, hypotension)
• Gastrointestinal (eg, vomiting, diarrhea)
• Generalized (eg, anaphylactic shock). By definition, anaphylaxis is a life-threatening reaction that occurs on exposure to an allergen and involves acute respiratory distress, cardiovascular failure, or involvement of two or more organ systems.⁴

MOST IgE BLOOD TESTS ARE IMMUNOASSAYS

The blood tests for allergic disease are immunoassays that measure the level of IgE specific to a particular allergen. The tests can be used to evaluate sensitivity to various allergens, for example, to common inhalants such as dust mites and pollens and to foods, drugs, venom, and latex.

Types of immunoassays include enzyme-linked immunosorbent assays (ELISAs), fluorescent enzyme immunoassays (FEIAs), and radioallergosorbent assays (RASTs). At present, most commercial laboratories use one of three autoanalyzer systems to measure specific IgE:

• ImmunoCAP (Phadia AB, Uppsala, Sweden)
• Immulite (Siemens AG, Berlin, Germany)
• HYTEC-288 (Hycor/Agilent, Garden Grove, CA).

These systems use a solid-phase polymer (cellulose or avidin) in which the antigen is embedded. The polymer also facilitates binding of IgE and, therefore, increases the sensitivity of the test.⁵ Specific IgE from the patient’s serum binds to the allergen embedded in the polymer, and then unbound antibodies are washed off.

Despite the term “RAST,” these systems do not use radiation. A fluorescent antibody is added that binds to the patient’s IgE, and the amount of IgE present is calculated from the amount of fluorescence.⁶ Results are reported in kilounits of antibody per liter (kU/L) or nanograms per milliliter (ng/mL).^5–7

INTERPRETATION IS INDIVIDUALIZED

In general, the sensitivity of these tests ranges from 60% to 95% and their specificity from 30% to 95%, with a concordance among different immunoassays of 75% to 90%.⁸

Levels of IgE for a particular allergen are also divided into semiquantitative classes, from class I to class V or VI. In general, class I and class II correlate with a low level of allergen sensitization and, often, with a low likelihood of a clinical reaction. On the other hand, classes V and VI reflect higher degrees of sensitization and generally correlate with IgE-mediated clinical reactions upon allergen exposure.

The interpretation of a positive (ie, “nonzero”) test result must be individualized on the basis of clinical presentation and risk factors. A specialist can make an important contribution by helping to interpret any positive test result or a negative test result that does not correlate with the patient’s history.

ADVANTAGES OF ALLERGY BLOOD TESTING

Allergy blood testing is convenient, since it involves only a standard blood draw.

In theory, allergy blood testing may be safer, since it does not expose the patient to any allergens. On the other hand, many patients experience bruising from venipuncture performed for any reason: 16% in one survey.⁹ In another survey,¹⁰ adverse reactions of any type occurred in 0.49% of patients undergoing venipuncture but only in 0.04% of those undergoing allergy skin testing. Therefore, allergy blood testing may be most appropriate in situations in which a patient’s history suggests that he or she may be at risk of a systemic reaction from a traditional skin test or in cases in which skin testing is not possible (eg, extensive eczema).

Another advantage of allergy blood testing is that it is not affected by drugs such as antihistamines or tricyclic antidepressants that suppress the histamine response, which is a problem with skin testing.

Allergy blood testing may also be useful in patients on long-term glucocorticoid therapy, although the data conflict. Prolonged oral glucocorticoid use is associated with a decrease in mast cell density and histamine content in the skin,^11,12 although in one study a corticosteroid was found not to affect the results of skin-prick testing for allergy.¹³ Thus, allergy blood testing can be performed in patients who have severe eczema or dermatographism or who cannot safely suspend taking antihistamines or tricyclic antidepressants.

LIMITATIONS OF THESE TESTS

A limitation of allergy blood tests is that there is no gold-standard test for many allergic conditions. (Double-blind, placebo-controlled oral food challenge testing has been proposed as the gold-standard test for food allergy, and nasal allergen provocation challenge has been proposed for allergic rhinitis.)

Also, allergy blood tests can give false-positive results because of nonspecific binding of antibody in the assay.

Of note: evidence of sensitization to a particular allergen (ie, a positive blood test result) is not synonymous with clinically relevant disease (ie, clinical sensitivity).

Conversely, these tests can give false-negative results in patients who have true IgE-mediated disease as confirmed by skin testing or allergen challenge. The sensitivity of blood allergy testing is approximately 25% to 30% lower than that of skin testing, based on comparative studies.² The blood tests are usually considered positive if the allergen-specific IgE level is greater than 0.35 kU/L; however, sensitization to certain inhalant allergens can occur at levels as low as 0.12 kU/L.¹⁴

Specific IgE levels measured by different commercial assays are not always interchangeable or equivalent, so a clinician should consistently select the same immunoassay if possible when assessing any given patient over time.¹⁵

Levels of specific IgE have been shown to depend on age, allergen specificity, total serum IgE, and, with inhalant allergens, the season of the year.^15,16

Other limitations of blood testing are its cost and a delay of several days to a week in obtaining the results.¹⁷

WHEN TO ORDER ALLERGY BLOOD TESTING

The allergy evaluation should begin with a thorough history to look for possible triggers for the patient’s symptoms.

For example, respiratory conditions such as asthma and rhinitis may be exacerbated during particular times of the year when certain pollens are commonly present. For patients with this pattern, blood testing for allergy to common inhalants, including pollens, may be appropriate. Similarly, peanut allergy evaluation is indicated for a child who has suffered an anaphylactic reaction after consuming peanut butter. Blood testing is also indicated in patients with a history of venom anaphylaxis, especially if venom skin testing was negative.

In cases in which the patient does not have a clear history of sensitization, blood testing for allergy to multiple foods may find evidence of sensitization that does not necessarily correlate with clinical disease.¹⁸

Likewise, blood tests are not likely to be clinically relevant in conditions not mediated by IgE, such as food intolerances (eg, lactose intolerance), celiac disease, the DRESS syndrome (drug rash, eosinophilia, and systemic symptoms), Stevens-Johnson syndrome, toxic epidermal necrolysis, or other types of drug hypersensitivity reactions, such as serum sickness.³

INTERPRETING COMMONLY ORDERED BLOOD TESTS FOR ALLERGY

Tests for allergy to hundreds of substances are available.

Foods

Milk, eggs, soy, wheat, peanuts, tree nuts, fish, and shellfish account for most cases of food allergy in the United States.¹⁸

IgE-mediated hypersensitivity to milk, eggs, and peanuts tends to be more common in children, whereas peanuts, tree nuts, fish, and shellfish are more commonly associated with reactions in adults.¹⁸ Children are more likely to outgrow allergy to milk, soy, wheat, and eggs than allergy to peanuts, tree nuts, fish, and shellfish—only about 20% of children outgrow peanut allergy.¹⁸

Patients with an IgE-mediated reaction to foods should be closely followed by a specialist, who can best help determine the appropriateness of additional testing (such as an oral challenge under observation), avoidance recommendations, and the introduction of foods back into the diet.¹⁹

Specific IgE tests for allergy to a variety of foods are available and can be very useful for diagnosis when used in the appropriate setting.

One caveat about these studies is that many were initially performed in children with a history of food allergy, many of whom had atopic dermatitis, and the findings have not been systematically reexamined in larger studies in more heterogeneous populations.

For example, at least eight studies tried to identify a diagnostic IgE level for cow’s milk allergy. The 95% confidence intervals varied widely, depending on the study design, the age of the study population, the prevalence of food allergy in the population, and the statistical method used for analysis.⁵ For most other foods for which blood tests are available, few studies have been performed to establish predictive values similar to those in Table 1.

Thus, slight elevations in antigen-specific IgE (> 0.35 kU/L) may correlate only with in vitro sensitization in a patient who has no clinical reactivity upon oral exposure to a particular antigen.

Broad food panels have been shown to have false-positive rates higher than 50%—ie, in more than half of cases, positive results have no clinical relevance. Therefore, these large food panels should not be used for screening.¹⁹ Instead, it is recommended that tests be limited to relevant foods based on the patient’s history when evaluating symptoms consistent with an IgE-mediated reaction to a particular food.

Food-specific IgE evaluation is also not helpful in evaluating non-IgE adverse reactions to foods (eg, intolerances).

Therefore, the patient’s history remains the most important tool for evaluation of food allergy. In cases in which the patient’s history suggests a food-associated IgE-mediated reaction and the blood test is negative, the patient should be referred to a specialist for skin testing with commercial extracts or even fresh food extracts, given the higher sensitivity of in vivo testing.²⁰

 

 

Inhalants

Common aeroallergens associated with allergic rhinitis, allergic conjunctivitis, and allergic asthma include dust mites, animal dander, cockroach debris, molds, trees, grasses, weeds, and ragweed. Dust mites, animal dander, and mold spores are perennial allergens and may trigger symptoms year-round. Pollen, including pollen from trees, grasses, and weeds, is generally present in a seasonal pattern in many parts of the United States.

A positive blood test for an inhalant allergen can reinforce the physician’s clinical impression in making a diagnosis of allergic rhinoconjunctivitis. Interestingly, studies have suggested a high rate of false-positives based on history alone when in vivo and in vitro allergy testing were negative for IgE-mediated respiratory disease.²¹

Various studies have aimed to establish threshold values of aeroallergen-specific IgE that predict the likelihood of clinically relevant disease. Unfortunately, other factors also contribute to clinical symptoms of rhinoconjunctivitis; these include concurrent inflammation, infection, physical stress, psychological stress, exposure to irritants, and hormonal changes. These factors introduce variability and make specific IgE cutoffs for inhalant allergens unreliable.²²

Prospective studies have suggested that skin testing correlates better with nasal allergen challenge (the gold standard) than blood testing for the diagnosis of inhalant allergy, though more recent studies using modern technologies demonstrate reasonable concordance (67%) between skin testing and blood testing (specifically, ImmunoCAP).^23,24 According to current guidelines, skin tests are the preferred method for diagnosing IgE-mediated sensitivity to inhalants.²⁵

Compared with skin prick tests as the gold standard, the sensitivity of specific IgE immunoassays is approximately 70% to 75%.²⁵ Nevertheless, specific IgE values greater than 0.35 kU/L are generally considered positive for aeroallergen sensitization, although lower levels of dog-specific IgE have recently been shown to correlate with clinical disease.¹⁴

Drugs, including penicillins

A variety of clinical reactions can occur in response to oral, intravenous, or topical medications.

At present, blood tests are available for the evaluation of IgE-mediated adverse reactions to only a limited number of drugs. Reactions involving other mechanisms, such as those related to the drug’s metabolism, intolerances (eg, nausea), idiosyncratic reactions (eg, Stevens-Johnson syndrome, the DRESS syndrome), or other types of reactions can be diagnosed only by history and physical examination.

The development of specific IgE tests for sensitivity to medications has been limited by incomplete characterization of metabolic products and the possibility that a single medication can have different epitopes or IgE binding sites in different individuals.²⁶

In vitro allergy testing has been most studied for beta-lactam antibiotics (eg, penicillin) and not so much for other drugs.

Table 2 summarizes the sensitivity and specificity of blood allergy tests that are commercially available for drugs.

Penicillin, a beta-lactam antibiotic, is degraded into various metabolites known as the major determinant (penicilloyl) and the minor determinants (eg, benzylpenicilloate and benzylpenilloate), which act as haptens. Specific IgE testing is not available for all these determinants.

The sensitivity of blood tests for allergy to penicilloyl (penicillin) and amino-penicillins such as amoxicilloyl (amoxicillin) is reported as between 32% and 50%, and the specificity as 96% to 98%.²⁹

By definition, any nonzero level of IgE specific for penicillin or its derivatives is considered a positive result and may be associated with a higher risk of IgE-mediated reaction to penicillins. However, in a situation analogous to that in people with food allergy who have a food-specific IgE titer lower than the empirically established threshold value (Table 1), low-titer values to penicillin may not predict anaphylactic sensitivity in a penicillin oral challenge.²⁸ Further studies are needed to determine if there is a threshold level of penicillin-specific IgE above which a patient has a higher likelihood of an IgE-mediated systemic reaction.

Other drugs. Specific IgE blood tests are also available for certain neuromuscular agents, insulin, cefaclor (Ceclor), chlorhexidine (contained in various antiseptic products), and gelatin (Table 2). These substances have not been as well studied as penicillins, and the sensitivity and specificity data reported in Table 2 are limited by few studies and small study sizes.

Neuromuscular blocking agents. Tests for IgE against neuromuscular blocking agents are reported to have low sensitivity (30%–60%) using a cutoff value of 0.35 kU/L.³⁰ In small studies, the sensitivity was higher (68% to 92%) when threshold values for rocuronium-specific IgE were lowered from 0.35 to 0.13 kU/L.²⁹

Chlorhexidine, an antiseptic commonly used in surgery, has been linked to IgE-mediated reactions.³¹ Chlorhexidine-specific IgE levels greater than 0.35 kU/L are considered positive, based on very limited data.

Insulin. Blood tests for allergy to insulin are also commercially available. However, studies have shown a significant overlap in the range of insulin-specific IgE in patients with a clinical history consistent with insulin allergy and in controls. Therefore, this test has a very limited ability to distinguish people who do not have a history of a reaction to insulin.³² More research is needed to determine the clinical utility of insulin-specific IgE testing.

Gelatin. IgE-mediated reactions have occurred after exposure to gelatin (from either cows or pigs) contained in foods and vaccines, including measles-mumps-rubella and yellow fever. One study identified gelatin-specific IgE in 10 of 11 children with a history of systemic reaction to measles or mumps vaccine.³³ In the same study, gelatin-specific IgE levels were negative in 24 children who had developed non-IgE-mediated reactions to the vaccine.³³

Tests for IgE against bovine gelatin are commercially available; results are considered positive for values higher than 0.35 kU/L. A negative test result does not exclude the possibility of an allergic reaction to porcine gelatin, which can also be found in foods and vaccines, but tests for anti-porcine gelatin IgE are not commercially available.

 

 

Latex

Latex, obtained from the rubber tree Hevea brasiliensis, has 13 known polypeptides (allergens Hev b 1–13) that cause IgE-mediated reactions, particularly in health care workers and patients with spina bifida.³⁴ Overall, the incidence of latex allergy has decreased in the United States as most medical institutions have implemented a latex-free environment.

In vitro testing is the only mode of evaluation for allergy to latex approved by the US Food and Drug Administration (FDA).³⁵ Its sensitivity is 80% and its specificity is 95%.³⁶

In a 2007 study, 145 people at risk for latex allergy, including 104 health care workers, 31 patients with spina bifida, and 10 patients requiring multiple surgeries, underwent latex-specific IgE analysis for sensitivity to various recombinant and native latex allergens.³⁴ The three groups differed in their latex allergy profiles, highlighting the diversity of clinical response to latex in high-risk groups and our current inability to establish specific cutoff points for quantitative latex-specific IgE. Thus, at present, any nonzero latex-specific IgE value is considered positive.

A formal evaluation for allergy is recommended for patients who have a strong history of an IgE-mediated reaction to latex and a latex-specific IgE value of zero. Blood tests for allergy to some native or recombinant latex allergens are available; these allergens may be underrepresented in the native total latex extract.³³ Skin testing for allergy to latex, although not FDA-approved or standardized, can also be useful in this setting.³⁷

Insect venom

Type I hypersensitivity reactions can occur from the stings of Vespidae (vespids), Apidae (bees), and Formicidae (fire ants). Large localized reactions after an insect sting are not infrequent and typically do not predict anaphylactic sensitivity with future stings, even though they are considered mild IgE-mediated reactions. However, systemic reactions are considered life-threatening and warrant allergy testing.³⁸

The level of venom-specific IgE usually increases weeks to months after a sting.³⁹ Therefore, blood tests can be falsely negative if performed within a short time of the sting.

Patients who have suffered a systemic reaction to venom and have evidence of sensitization by either in vitro or in vivo allergy testing are candidates for venom immunotherapy.⁴⁰

At present, any nonzero venom-specific IgE test is considered positive, as there is no specific value for venom-specific IgE that predicts clinical risk.

A negative blood test does not exclude the possibility of an IgE-mediated reaction.⁴¹ In cases in which a patient has a clinical history compatible with venom allergy but the blood test is negative, the patient should be referred to an allergist for further evaluation, including venom skin testing and possibly repeat blood testing at a later time.

Conversely, specific IgE testing to venom is recommended when a patient has a history consistent with venom allergy and negative skin test results.³⁸

As mentioned previously, in vitro test performance can vary with the laboratory and testing method used, and sending samples directly to a reference laboratory could be considered.⁴¹

TESTING FOR IgG AGAINST FOODS IS UNVALIDATED AND INAPPROPRIATE

In recent years, some practitioners of alternative medicine have started testing for allergen-specific IgG or IgG4 as part of evaluations for hypersensitivity, especially in cases in which patients describe atypical gastrointestinal, neurologic, or other symptoms after eating specific foods.¹⁹

However, this testing often finds IgG or IgG4 against foods that are well tolerated. At present, allergen-specific IgG testing lacks scientific evidence to support its clinical use in the evaluation of allergic disease.^5,19

Health care providers often need to evaluate allergic disorders such as allergic rhinoconjunctivitis, asthma, and allergies to foods, drugs, latex, and venom, both in the hospital and in the clinic.

Unfortunately, some symptoms, such as chronic nasal symptoms, can occur in both allergic and nonallergic disorders, and this overlap can confound the diagnosis and therapy. Studies suggest that when clinicians use the history and physical examination alone in evaluating possible allergic disease, the accuracy of their diagnoses rarely exceeds 50%.¹

Blood tests are now available that measure immunoglobulin E (IgE) directed against specific antigens. These in vitro tests can be important tools in assessing a patient whose history suggests an allergic disease.² However, neither allergy skin testing nor these blood tests are intended to be used for screening: they may be most useful as confirmatory diagnostic tests in cases in which the pretest clinical impression of allergic disease is high.

ALLERGY IS MEDIATED BY IgE

In susceptible people, IgE is produced by B cells in response to specific antigens such as foods, pollens, latex, and drugs. This antigen-specific (or allergen-specific) IgE circulates in the serum and binds to high-affinity IgE receptors on immune effector cells such as mast cells located throughout the body.

Upon subsequent exposure to the same allergen, IgE receptors cross-link and initiate downstream signaling events that trigger mast cell degranulation and an immediate allergic response—hence the term immediate (or Gell-Coombs type I) hypersensitivity.³

Common manifestations of type I hypersensitivity reactions include signs and symptoms that can be:

• Cutaneous (eg, acute urticaria, angioedema)
• Respiratory (eg, acute bronchospasm, rhinoconjunctivitis)
• Cardiovascular (eg, tachycardia, hypotension)
• Gastrointestinal (eg, vomiting, diarrhea)
• Generalized (eg, anaphylactic shock). By definition, anaphylaxis is a life-threatening reaction that occurs on exposure to an allergen and involves acute respiratory distress, cardiovascular failure, or involvement of two or more organ systems.⁴

MOST IgE BLOOD TESTS ARE IMMUNOASSAYS

The blood tests for allergic disease are immunoassays that measure the level of IgE specific to a particular allergen. The tests can be used to evaluate sensitivity to various allergens, for example, to common inhalants such as dust mites and pollens and to foods, drugs, venom, and latex.

Types of immunoassays include enzyme-linked immunosorbent assays (ELISAs), fluorescent enzyme immunoassays (FEIAs), and radioallergosorbent assays (RASTs). At present, most commercial laboratories use one of three autoanalyzer systems to measure specific IgE:

• ImmunoCAP (Phadia AB, Uppsala, Sweden)
• Immulite (Siemens AG, Berlin, Germany)
• HYTEC-288 (Hycor/Agilent, Garden Grove, CA).

These systems use a solid-phase polymer (cellulose or avidin) in which the antigen is embedded. The polymer also facilitates binding of IgE and, therefore, increases the sensitivity of the test.⁵ Specific IgE from the patient’s serum binds to the allergen embedded in the polymer, and then unbound antibodies are washed off.

Despite the term “RAST,” these systems do not use radiation. A fluorescent antibody is added that binds to the patient’s IgE, and the amount of IgE present is calculated from the amount of fluorescence.⁶ Results are reported in kilounits of antibody per liter (kU/L) or nanograms per milliliter (ng/mL).^5–7

INTERPRETATION IS INDIVIDUALIZED

In general, the sensitivity of these tests ranges from 60% to 95% and their specificity from 30% to 95%, with a concordance among different immunoassays of 75% to 90%.⁸

Levels of IgE for a particular allergen are also divided into semiquantitative classes, from class I to class V or VI. In general, class I and class II correlate with a low level of allergen sensitization and, often, with a low likelihood of a clinical reaction. On the other hand, classes V and VI reflect higher degrees of sensitization and generally correlate with IgE-mediated clinical reactions upon allergen exposure.

The interpretation of a positive (ie, “nonzero”) test result must be individualized on the basis of clinical presentation and risk factors. A specialist can make an important contribution by helping to interpret any positive test result or a negative test result that does not correlate with the patient’s history.

ADVANTAGES OF ALLERGY BLOOD TESTING

Allergy blood testing is convenient, since it involves only a standard blood draw.

In theory, allergy blood testing may be safer, since it does not expose the patient to any allergens. On the other hand, many patients experience bruising from venipuncture performed for any reason: 16% in one survey.⁹ In another survey,¹⁰ adverse reactions of any type occurred in 0.49% of patients undergoing venipuncture but only in 0.04% of those undergoing allergy skin testing. Therefore, allergy blood testing may be most appropriate in situations in which a patient’s history suggests that he or she may be at risk of a systemic reaction from a traditional skin test or in cases in which skin testing is not possible (eg, extensive eczema).

Another advantage of allergy blood testing is that it is not affected by drugs such as antihistamines or tricyclic antidepressants that suppress the histamine response, which is a problem with skin testing.

Allergy blood testing may also be useful in patients on long-term glucocorticoid therapy, although the data conflict. Prolonged oral glucocorticoid use is associated with a decrease in mast cell density and histamine content in the skin,^11,12 although in one study a corticosteroid was found not to affect the results of skin-prick testing for allergy.¹³ Thus, allergy blood testing can be performed in patients who have severe eczema or dermatographism or who cannot safely suspend taking antihistamines or tricyclic antidepressants.

LIMITATIONS OF THESE TESTS

A limitation of allergy blood tests is that there is no gold-standard test for many allergic conditions. (Double-blind, placebo-controlled oral food challenge testing has been proposed as the gold-standard test for food allergy, and nasal allergen provocation challenge has been proposed for allergic rhinitis.)

Also, allergy blood tests can give false-positive results because of nonspecific binding of antibody in the assay.

Of note: evidence of sensitization to a particular allergen (ie, a positive blood test result) is not synonymous with clinically relevant disease (ie, clinical sensitivity).

Conversely, these tests can give false-negative results in patients who have true IgE-mediated disease as confirmed by skin testing or allergen challenge. The sensitivity of blood allergy testing is approximately 25% to 30% lower than that of skin testing, based on comparative studies.² The blood tests are usually considered positive if the allergen-specific IgE level is greater than 0.35 kU/L; however, sensitization to certain inhalant allergens can occur at levels as low as 0.12 kU/L.¹⁴

Specific IgE levels measured by different commercial assays are not always interchangeable or equivalent, so a clinician should consistently select the same immunoassay if possible when assessing any given patient over time.¹⁵

Levels of specific IgE have been shown to depend on age, allergen specificity, total serum IgE, and, with inhalant allergens, the season of the year.^15,16

Other limitations of blood testing are its cost and a delay of several days to a week in obtaining the results.¹⁷

WHEN TO ORDER ALLERGY BLOOD TESTING

The allergy evaluation should begin with a thorough history to look for possible triggers for the patient’s symptoms.

For example, respiratory conditions such as asthma and rhinitis may be exacerbated during particular times of the year when certain pollens are commonly present. For patients with this pattern, blood testing for allergy to common inhalants, including pollens, may be appropriate. Similarly, peanut allergy evaluation is indicated for a child who has suffered an anaphylactic reaction after consuming peanut butter. Blood testing is also indicated in patients with a history of venom anaphylaxis, especially if venom skin testing was negative.

In cases in which the patient does not have a clear history of sensitization, blood testing for allergy to multiple foods may find evidence of sensitization that does not necessarily correlate with clinical disease.¹⁸

Likewise, blood tests are not likely to be clinically relevant in conditions not mediated by IgE, such as food intolerances (eg, lactose intolerance), celiac disease, the DRESS syndrome (drug rash, eosinophilia, and systemic symptoms), Stevens-Johnson syndrome, toxic epidermal necrolysis, or other types of drug hypersensitivity reactions, such as serum sickness.³

INTERPRETING COMMONLY ORDERED BLOOD TESTS FOR ALLERGY

Tests for allergy to hundreds of substances are available.

Foods

Milk, eggs, soy, wheat, peanuts, tree nuts, fish, and shellfish account for most cases of food allergy in the United States.¹⁸

IgE-mediated hypersensitivity to milk, eggs, and peanuts tends to be more common in children, whereas peanuts, tree nuts, fish, and shellfish are more commonly associated with reactions in adults.¹⁸ Children are more likely to outgrow allergy to milk, soy, wheat, and eggs than allergy to peanuts, tree nuts, fish, and shellfish—only about 20% of children outgrow peanut allergy.¹⁸

Patients with an IgE-mediated reaction to foods should be closely followed by a specialist, who can best help determine the appropriateness of additional testing (such as an oral challenge under observation), avoidance recommendations, and the introduction of foods back into the diet.¹⁹

Specific IgE tests for allergy to a variety of foods are available and can be very useful for diagnosis when used in the appropriate setting.

One caveat about these studies is that many were initially performed in children with a history of food allergy, many of whom had atopic dermatitis, and the findings have not been systematically reexamined in larger studies in more heterogeneous populations.

For example, at least eight studies tried to identify a diagnostic IgE level for cow’s milk allergy. The 95% confidence intervals varied widely, depending on the study design, the age of the study population, the prevalence of food allergy in the population, and the statistical method used for analysis.⁵ For most other foods for which blood tests are available, few studies have been performed to establish predictive values similar to those in Table 1.

Thus, slight elevations in antigen-specific IgE (> 0.35 kU/L) may correlate only with in vitro sensitization in a patient who has no clinical reactivity upon oral exposure to a particular antigen.

Broad food panels have been shown to have false-positive rates higher than 50%—ie, in more than half of cases, positive results have no clinical relevance. Therefore, these large food panels should not be used for screening.¹⁹ Instead, it is recommended that tests be limited to relevant foods based on the patient’s history when evaluating symptoms consistent with an IgE-mediated reaction to a particular food.

Food-specific IgE evaluation is also not helpful in evaluating non-IgE adverse reactions to foods (eg, intolerances).

Therefore, the patient’s history remains the most important tool for evaluation of food allergy. In cases in which the patient’s history suggests a food-associated IgE-mediated reaction and the blood test is negative, the patient should be referred to a specialist for skin testing with commercial extracts or even fresh food extracts, given the higher sensitivity of in vivo testing.²⁰

 

 

Inhalants

Common aeroallergens associated with allergic rhinitis, allergic conjunctivitis, and allergic asthma include dust mites, animal dander, cockroach debris, molds, trees, grasses, weeds, and ragweed. Dust mites, animal dander, and mold spores are perennial allergens and may trigger symptoms year-round. Pollen, including pollen from trees, grasses, and weeds, is generally present in a seasonal pattern in many parts of the United States.

A positive blood test for an inhalant allergen can reinforce the physician’s clinical impression in making a diagnosis of allergic rhinoconjunctivitis. Interestingly, studies have suggested a high rate of false-positives based on history alone when in vivo and in vitro allergy testing were negative for IgE-mediated respiratory disease.²¹

Various studies have aimed to establish threshold values of aeroallergen-specific IgE that predict the likelihood of clinically relevant disease. Unfortunately, other factors also contribute to clinical symptoms of rhinoconjunctivitis; these include concurrent inflammation, infection, physical stress, psychological stress, exposure to irritants, and hormonal changes. These factors introduce variability and make specific IgE cutoffs for inhalant allergens unreliable.²²

Prospective studies have suggested that skin testing correlates better with nasal allergen challenge (the gold standard) than blood testing for the diagnosis of inhalant allergy, though more recent studies using modern technologies demonstrate reasonable concordance (67%) between skin testing and blood testing (specifically, ImmunoCAP).^23,24 According to current guidelines, skin tests are the preferred method for diagnosing IgE-mediated sensitivity to inhalants.²⁵

Compared with skin prick tests as the gold standard, the sensitivity of specific IgE immunoassays is approximately 70% to 75%.²⁵ Nevertheless, specific IgE values greater than 0.35 kU/L are generally considered positive for aeroallergen sensitization, although lower levels of dog-specific IgE have recently been shown to correlate with clinical disease.¹⁴

Drugs, including penicillins

A variety of clinical reactions can occur in response to oral, intravenous, or topical medications.

At present, blood tests are available for the evaluation of IgE-mediated adverse reactions to only a limited number of drugs. Reactions involving other mechanisms, such as those related to the drug’s metabolism, intolerances (eg, nausea), idiosyncratic reactions (eg, Stevens-Johnson syndrome, the DRESS syndrome), or other types of reactions can be diagnosed only by history and physical examination.

The development of specific IgE tests for sensitivity to medications has been limited by incomplete characterization of metabolic products and the possibility that a single medication can have different epitopes or IgE binding sites in different individuals.²⁶

In vitro allergy testing has been most studied for beta-lactam antibiotics (eg, penicillin) and not so much for other drugs.

Table 2 summarizes the sensitivity and specificity of blood allergy tests that are commercially available for drugs.

Penicillin, a beta-lactam antibiotic, is degraded into various metabolites known as the major determinant (penicilloyl) and the minor determinants (eg, benzylpenicilloate and benzylpenilloate), which act as haptens. Specific IgE testing is not available for all these determinants.

The sensitivity of blood tests for allergy to penicilloyl (penicillin) and amino-penicillins such as amoxicilloyl (amoxicillin) is reported as between 32% and 50%, and the specificity as 96% to 98%.²⁹

By definition, any nonzero level of IgE specific for penicillin or its derivatives is considered a positive result and may be associated with a higher risk of IgE-mediated reaction to penicillins. However, in a situation analogous to that in people with food allergy who have a food-specific IgE titer lower than the empirically established threshold value (Table 1), low-titer values to penicillin may not predict anaphylactic sensitivity in a penicillin oral challenge.²⁸ Further studies are needed to determine if there is a threshold level of penicillin-specific IgE above which a patient has a higher likelihood of an IgE-mediated systemic reaction.

Other drugs. Specific IgE blood tests are also available for certain neuromuscular agents, insulin, cefaclor (Ceclor), chlorhexidine (contained in various antiseptic products), and gelatin (Table 2). These substances have not been as well studied as penicillins, and the sensitivity and specificity data reported in Table 2 are limited by few studies and small study sizes.

Neuromuscular blocking agents. Tests for IgE against neuromuscular blocking agents are reported to have low sensitivity (30%–60%) using a cutoff value of 0.35 kU/L.³⁰ In small studies, the sensitivity was higher (68% to 92%) when threshold values for rocuronium-specific IgE were lowered from 0.35 to 0.13 kU/L.²⁹

Chlorhexidine, an antiseptic commonly used in surgery, has been linked to IgE-mediated reactions.³¹ Chlorhexidine-specific IgE levels greater than 0.35 kU/L are considered positive, based on very limited data.

Insulin. Blood tests for allergy to insulin are also commercially available. However, studies have shown a significant overlap in the range of insulin-specific IgE in patients with a clinical history consistent with insulin allergy and in controls. Therefore, this test has a very limited ability to distinguish people who do not have a history of a reaction to insulin.³² More research is needed to determine the clinical utility of insulin-specific IgE testing.

Gelatin. IgE-mediated reactions have occurred after exposure to gelatin (from either cows or pigs) contained in foods and vaccines, including measles-mumps-rubella and yellow fever. One study identified gelatin-specific IgE in 10 of 11 children with a history of systemic reaction to measles or mumps vaccine.³³ In the same study, gelatin-specific IgE levels were negative in 24 children who had developed non-IgE-mediated reactions to the vaccine.³³

Tests for IgE against bovine gelatin are commercially available; results are considered positive for values higher than 0.35 kU/L. A negative test result does not exclude the possibility of an allergic reaction to porcine gelatin, which can also be found in foods and vaccines, but tests for anti-porcine gelatin IgE are not commercially available.

 

 

Latex

Latex, obtained from the rubber tree Hevea brasiliensis, has 13 known polypeptides (allergens Hev b 1–13) that cause IgE-mediated reactions, particularly in health care workers and patients with spina bifida.³⁴ Overall, the incidence of latex allergy has decreased in the United States as most medical institutions have implemented a latex-free environment.

In vitro testing is the only mode of evaluation for allergy to latex approved by the US Food and Drug Administration (FDA).³⁵ Its sensitivity is 80% and its specificity is 95%.³⁶

In a 2007 study, 145 people at risk for latex allergy, including 104 health care workers, 31 patients with spina bifida, and 10 patients requiring multiple surgeries, underwent latex-specific IgE analysis for sensitivity to various recombinant and native latex allergens.³⁴ The three groups differed in their latex allergy profiles, highlighting the diversity of clinical response to latex in high-risk groups and our current inability to establish specific cutoff points for quantitative latex-specific IgE. Thus, at present, any nonzero latex-specific IgE value is considered positive.

A formal evaluation for allergy is recommended for patients who have a strong history of an IgE-mediated reaction to latex and a latex-specific IgE value of zero. Blood tests for allergy to some native or recombinant latex allergens are available; these allergens may be underrepresented in the native total latex extract.³³ Skin testing for allergy to latex, although not FDA-approved or standardized, can also be useful in this setting.³⁷

Insect venom

Type I hypersensitivity reactions can occur from the stings of Vespidae (vespids), Apidae (bees), and Formicidae (fire ants). Large localized reactions after an insect sting are not infrequent and typically do not predict anaphylactic sensitivity with future stings, even though they are considered mild IgE-mediated reactions. However, systemic reactions are considered life-threatening and warrant allergy testing.³⁸

The level of venom-specific IgE usually increases weeks to months after a sting.³⁹ Therefore, blood tests can be falsely negative if performed within a short time of the sting.

Patients who have suffered a systemic reaction to venom and have evidence of sensitization by either in vitro or in vivo allergy testing are candidates for venom immunotherapy.⁴⁰

At present, any nonzero venom-specific IgE test is considered positive, as there is no specific value for venom-specific IgE that predicts clinical risk.

A negative blood test does not exclude the possibility of an IgE-mediated reaction.⁴¹ In cases in which a patient has a clinical history compatible with venom allergy but the blood test is negative, the patient should be referred to an allergist for further evaluation, including venom skin testing and possibly repeat blood testing at a later time.

Conversely, specific IgE testing to venom is recommended when a patient has a history consistent with venom allergy and negative skin test results.³⁸

As mentioned previously, in vitro test performance can vary with the laboratory and testing method used, and sending samples directly to a reference laboratory could be considered.⁴¹

TESTING FOR IgG AGAINST FOODS IS UNVALIDATED AND INAPPROPRIATE

In recent years, some practitioners of alternative medicine have started testing for allergen-specific IgG or IgG4 as part of evaluations for hypersensitivity, especially in cases in which patients describe atypical gastrointestinal, neurologic, or other symptoms after eating specific foods.¹⁹

However, this testing often finds IgG or IgG4 against foods that are well tolerated. At present, allergen-specific IgG testing lacks scientific evidence to support its clinical use in the evaluation of allergic disease.^5,19

Health care providers often need to evaluate allergic disorders such as allergic rhinoconjunctivitis, asthma, and allergies to foods, drugs, latex, and venom, both in the hospital and in the clinic.

Unfortunately, some symptoms, such as chronic nasal symptoms, can occur in both allergic and nonallergic disorders, and this overlap can confound the diagnosis and therapy. Studies suggest that when clinicians use the history and physical examination alone in evaluating possible allergic disease, the accuracy of their diagnoses rarely exceeds 50%.¹

Blood tests are now available that measure immunoglobulin E (IgE) directed against specific antigens. These in vitro tests can be important tools in assessing a patient whose history suggests an allergic disease.² However, neither allergy skin testing nor these blood tests are intended to be used for screening: they may be most useful as confirmatory diagnostic tests in cases in which the pretest clinical impression of allergic disease is high.

ALLERGY IS MEDIATED BY IgE

In susceptible people, IgE is produced by B cells in response to specific antigens such as foods, pollens, latex, and drugs. This antigen-specific (or allergen-specific) IgE circulates in the serum and binds to high-affinity IgE receptors on immune effector cells such as mast cells located throughout the body.

Upon subsequent exposure to the same allergen, IgE receptors cross-link and initiate downstream signaling events that trigger mast cell degranulation and an immediate allergic response—hence the term immediate (or Gell-Coombs type I) hypersensitivity.³

Common manifestations of type I hypersensitivity reactions include signs and symptoms that can be:

• Cutaneous (eg, acute urticaria, angioedema)
• Respiratory (eg, acute bronchospasm, rhinoconjunctivitis)
• Cardiovascular (eg, tachycardia, hypotension)
• Gastrointestinal (eg, vomiting, diarrhea)
• Generalized (eg, anaphylactic shock). By definition, anaphylaxis is a life-threatening reaction that occurs on exposure to an allergen and involves acute respiratory distress, cardiovascular failure, or involvement of two or more organ systems.⁴

MOST IgE BLOOD TESTS ARE IMMUNOASSAYS

The blood tests for allergic disease are immunoassays that measure the level of IgE specific to a particular allergen. The tests can be used to evaluate sensitivity to various allergens, for example, to common inhalants such as dust mites and pollens and to foods, drugs, venom, and latex.

Types of immunoassays include enzyme-linked immunosorbent assays (ELISAs), fluorescent enzyme immunoassays (FEIAs), and radioallergosorbent assays (RASTs). At present, most commercial laboratories use one of three autoanalyzer systems to measure specific IgE:

• ImmunoCAP (Phadia AB, Uppsala, Sweden)
• Immulite (Siemens AG, Berlin, Germany)
• HYTEC-288 (Hycor/Agilent, Garden Grove, CA).

These systems use a solid-phase polymer (cellulose or avidin) in which the antigen is embedded. The polymer also facilitates binding of IgE and, therefore, increases the sensitivity of the test.⁵ Specific IgE from the patient’s serum binds to the allergen embedded in the polymer, and then unbound antibodies are washed off.

Despite the term “RAST,” these systems do not use radiation. A fluorescent antibody is added that binds to the patient’s IgE, and the amount of IgE present is calculated from the amount of fluorescence.⁶ Results are reported in kilounits of antibody per liter (kU/L) or nanograms per milliliter (ng/mL).^5–7

INTERPRETATION IS INDIVIDUALIZED

In general, the sensitivity of these tests ranges from 60% to 95% and their specificity from 30% to 95%, with a concordance among different immunoassays of 75% to 90%.⁸

Levels of IgE for a particular allergen are also divided into semiquantitative classes, from class I to class V or VI. In general, class I and class II correlate with a low level of allergen sensitization and, often, with a low likelihood of a clinical reaction. On the other hand, classes V and VI reflect higher degrees of sensitization and generally correlate with IgE-mediated clinical reactions upon allergen exposure.

The interpretation of a positive (ie, “nonzero”) test result must be individualized on the basis of clinical presentation and risk factors. A specialist can make an important contribution by helping to interpret any positive test result or a negative test result that does not correlate with the patient’s history.

ADVANTAGES OF ALLERGY BLOOD TESTING

Allergy blood testing is convenient, since it involves only a standard blood draw.

In theory, allergy blood testing may be safer, since it does not expose the patient to any allergens. On the other hand, many patients experience bruising from venipuncture performed for any reason: 16% in one survey.⁹ In another survey,¹⁰ adverse reactions of any type occurred in 0.49% of patients undergoing venipuncture but only in 0.04% of those undergoing allergy skin testing. Therefore, allergy blood testing may be most appropriate in situations in which a patient’s history suggests that he or she may be at risk of a systemic reaction from a traditional skin test or in cases in which skin testing is not possible (eg, extensive eczema).

Another advantage of allergy blood testing is that it is not affected by drugs such as antihistamines or tricyclic antidepressants that suppress the histamine response, which is a problem with skin testing.

Allergy blood testing may also be useful in patients on long-term glucocorticoid therapy, although the data conflict. Prolonged oral glucocorticoid use is associated with a decrease in mast cell density and histamine content in the skin,^11,12 although in one study a corticosteroid was found not to affect the results of skin-prick testing for allergy.¹³ Thus, allergy blood testing can be performed in patients who have severe eczema or dermatographism or who cannot safely suspend taking antihistamines or tricyclic antidepressants.

LIMITATIONS OF THESE TESTS

A limitation of allergy blood tests is that there is no gold-standard test for many allergic conditions. (Double-blind, placebo-controlled oral food challenge testing has been proposed as the gold-standard test for food allergy, and nasal allergen provocation challenge has been proposed for allergic rhinitis.)

Also, allergy blood tests can give false-positive results because of nonspecific binding of antibody in the assay.

Of note: evidence of sensitization to a particular allergen (ie, a positive blood test result) is not synonymous with clinically relevant disease (ie, clinical sensitivity).

Conversely, these tests can give false-negative results in patients who have true IgE-mediated disease as confirmed by skin testing or allergen challenge. The sensitivity of blood allergy testing is approximately 25% to 30% lower than that of skin testing, based on comparative studies.² The blood tests are usually considered positive if the allergen-specific IgE level is greater than 0.35 kU/L; however, sensitization to certain inhalant allergens can occur at levels as low as 0.12 kU/L.¹⁴

Specific IgE levels measured by different commercial assays are not always interchangeable or equivalent, so a clinician should consistently select the same immunoassay if possible when assessing any given patient over time.¹⁵

Levels of specific IgE have been shown to depend on age, allergen specificity, total serum IgE, and, with inhalant allergens, the season of the year.^15,16

Other limitations of blood testing are its cost and a delay of several days to a week in obtaining the results.¹⁷

WHEN TO ORDER ALLERGY BLOOD TESTING

The allergy evaluation should begin with a thorough history to look for possible triggers for the patient’s symptoms.

For example, respiratory conditions such as asthma and rhinitis may be exacerbated during particular times of the year when certain pollens are commonly present. For patients with this pattern, blood testing for allergy to common inhalants, including pollens, may be appropriate. Similarly, peanut allergy evaluation is indicated for a child who has suffered an anaphylactic reaction after consuming peanut butter. Blood testing is also indicated in patients with a history of venom anaphylaxis, especially if venom skin testing was negative.

In cases in which the patient does not have a clear history of sensitization, blood testing for allergy to multiple foods may find evidence of sensitization that does not necessarily correlate with clinical disease.¹⁸

Likewise, blood tests are not likely to be clinically relevant in conditions not mediated by IgE, such as food intolerances (eg, lactose intolerance), celiac disease, the DRESS syndrome (drug rash, eosinophilia, and systemic symptoms), Stevens-Johnson syndrome, toxic epidermal necrolysis, or other types of drug hypersensitivity reactions, such as serum sickness.³

INTERPRETING COMMONLY ORDERED BLOOD TESTS FOR ALLERGY

Tests for allergy to hundreds of substances are available.

Foods

Milk, eggs, soy, wheat, peanuts, tree nuts, fish, and shellfish account for most cases of food allergy in the United States.¹⁸

IgE-mediated hypersensitivity to milk, eggs, and peanuts tends to be more common in children, whereas peanuts, tree nuts, fish, and shellfish are more commonly associated with reactions in adults.¹⁸ Children are more likely to outgrow allergy to milk, soy, wheat, and eggs than allergy to peanuts, tree nuts, fish, and shellfish—only about 20% of children outgrow peanut allergy.¹⁸

Patients with an IgE-mediated reaction to foods should be closely followed by a specialist, who can best help determine the appropriateness of additional testing (such as an oral challenge under observation), avoidance recommendations, and the introduction of foods back into the diet.¹⁹

Specific IgE tests for allergy to a variety of foods are available and can be very useful for diagnosis when used in the appropriate setting.

One caveat about these studies is that many were initially performed in children with a history of food allergy, many of whom had atopic dermatitis, and the findings have not been systematically reexamined in larger studies in more heterogeneous populations.

For example, at least eight studies tried to identify a diagnostic IgE level for cow’s milk allergy. The 95% confidence intervals varied widely, depending on the study design, the age of the study population, the prevalence of food allergy in the population, and the statistical method used for analysis.⁵ For most other foods for which blood tests are available, few studies have been performed to establish predictive values similar to those in Table 1.

Thus, slight elevations in antigen-specific IgE (> 0.35 kU/L) may correlate only with in vitro sensitization in a patient who has no clinical reactivity upon oral exposure to a particular antigen.

Broad food panels have been shown to have false-positive rates higher than 50%—ie, in more than half of cases, positive results have no clinical relevance. Therefore, these large food panels should not be used for screening.¹⁹ Instead, it is recommended that tests be limited to relevant foods based on the patient’s history when evaluating symptoms consistent with an IgE-mediated reaction to a particular food.

Food-specific IgE evaluation is also not helpful in evaluating non-IgE adverse reactions to foods (eg, intolerances).

Therefore, the patient’s history remains the most important tool for evaluation of food allergy. In cases in which the patient’s history suggests a food-associated IgE-mediated reaction and the blood test is negative, the patient should be referred to a specialist for skin testing with commercial extracts or even fresh food extracts, given the higher sensitivity of in vivo testing.²⁰

 

 

Inhalants

Common aeroallergens associated with allergic rhinitis, allergic conjunctivitis, and allergic asthma include dust mites, animal dander, cockroach debris, molds, trees, grasses, weeds, and ragweed. Dust mites, animal dander, and mold spores are perennial allergens and may trigger symptoms year-round. Pollen, including pollen from trees, grasses, and weeds, is generally present in a seasonal pattern in many parts of the United States.

A positive blood test for an inhalant allergen can reinforce the physician’s clinical impression in making a diagnosis of allergic rhinoconjunctivitis. Interestingly, studies have suggested a high rate of false-positives based on history alone when in vivo and in vitro allergy testing were negative for IgE-mediated respiratory disease.²¹

Various studies have aimed to establish threshold values of aeroallergen-specific IgE that predict the likelihood of clinically relevant disease. Unfortunately, other factors also contribute to clinical symptoms of rhinoconjunctivitis; these include concurrent inflammation, infection, physical stress, psychological stress, exposure to irritants, and hormonal changes. These factors introduce variability and make specific IgE cutoffs for inhalant allergens unreliable.²²

Prospective studies have suggested that skin testing correlates better with nasal allergen challenge (the gold standard) than blood testing for the diagnosis of inhalant allergy, though more recent studies using modern technologies demonstrate reasonable concordance (67%) between skin testing and blood testing (specifically, ImmunoCAP).^23,24 According to current guidelines, skin tests are the preferred method for diagnosing IgE-mediated sensitivity to inhalants.²⁵

Compared with skin prick tests as the gold standard, the sensitivity of specific IgE immunoassays is approximately 70% to 75%.²⁵ Nevertheless, specific IgE values greater than 0.35 kU/L are generally considered positive for aeroallergen sensitization, although lower levels of dog-specific IgE have recently been shown to correlate with clinical disease.¹⁴

Drugs, including penicillins

A variety of clinical reactions can occur in response to oral, intravenous, or topical medications.

At present, blood tests are available for the evaluation of IgE-mediated adverse reactions to only a limited number of drugs. Reactions involving other mechanisms, such as those related to the drug’s metabolism, intolerances (eg, nausea), idiosyncratic reactions (eg, Stevens-Johnson syndrome, the DRESS syndrome), or other types of reactions can be diagnosed only by history and physical examination.

The development of specific IgE tests for sensitivity to medications has been limited by incomplete characterization of metabolic products and the possibility that a single medication can have different epitopes or IgE binding sites in different individuals.²⁶

In vitro allergy testing has been most studied for beta-lactam antibiotics (eg, penicillin) and not so much for other drugs.

Table 2 summarizes the sensitivity and specificity of blood allergy tests that are commercially available for drugs.

Penicillin, a beta-lactam antibiotic, is degraded into various metabolites known as the major determinant (penicilloyl) and the minor determinants (eg, benzylpenicilloate and benzylpenilloate), which act as haptens. Specific IgE testing is not available for all these determinants.

The sensitivity of blood tests for allergy to penicilloyl (penicillin) and amino-penicillins such as amoxicilloyl (amoxicillin) is reported as between 32% and 50%, and the specificity as 96% to 98%.²⁹

By definition, any nonzero level of IgE specific for penicillin or its derivatives is considered a positive result and may be associated with a higher risk of IgE-mediated reaction to penicillins. However, in a situation analogous to that in people with food allergy who have a food-specific IgE titer lower than the empirically established threshold value (Table 1), low-titer values to penicillin may not predict anaphylactic sensitivity in a penicillin oral challenge.²⁸ Further studies are needed to determine if there is a threshold level of penicillin-specific IgE above which a patient has a higher likelihood of an IgE-mediated systemic reaction.

Other drugs. Specific IgE blood tests are also available for certain neuromuscular agents, insulin, cefaclor (Ceclor), chlorhexidine (contained in various antiseptic products), and gelatin (Table 2). These substances have not been as well studied as penicillins, and the sensitivity and specificity data reported in Table 2 are limited by few studies and small study sizes.

Neuromuscular blocking agents. Tests for IgE against neuromuscular blocking agents are reported to have low sensitivity (30%–60%) using a cutoff value of 0.35 kU/L.³⁰ In small studies, the sensitivity was higher (68% to 92%) when threshold values for rocuronium-specific IgE were lowered from 0.35 to 0.13 kU/L.²⁹

Chlorhexidine, an antiseptic commonly used in surgery, has been linked to IgE-mediated reactions.³¹ Chlorhexidine-specific IgE levels greater than 0.35 kU/L are considered positive, based on very limited data.

Insulin. Blood tests for allergy to insulin are also commercially available. However, studies have shown a significant overlap in the range of insulin-specific IgE in patients with a clinical history consistent with insulin allergy and in controls. Therefore, this test has a very limited ability to distinguish people who do not have a history of a reaction to insulin.³² More research is needed to determine the clinical utility of insulin-specific IgE testing.

Gelatin. IgE-mediated reactions have occurred after exposure to gelatin (from either cows or pigs) contained in foods and vaccines, including measles-mumps-rubella and yellow fever. One study identified gelatin-specific IgE in 10 of 11 children with a history of systemic reaction to measles or mumps vaccine.³³ In the same study, gelatin-specific IgE levels were negative in 24 children who had developed non-IgE-mediated reactions to the vaccine.³³

Tests for IgE against bovine gelatin are commercially available; results are considered positive for values higher than 0.35 kU/L. A negative test result does not exclude the possibility of an allergic reaction to porcine gelatin, which can also be found in foods and vaccines, but tests for anti-porcine gelatin IgE are not commercially available.

 

 

Latex

Latex, obtained from the rubber tree Hevea brasiliensis, has 13 known polypeptides (allergens Hev b 1–13) that cause IgE-mediated reactions, particularly in health care workers and patients with spina bifida.³⁴ Overall, the incidence of latex allergy has decreased in the United States as most medical institutions have implemented a latex-free environment.

In vitro testing is the only mode of evaluation for allergy to latex approved by the US Food and Drug Administration (FDA).³⁵ Its sensitivity is 80% and its specificity is 95%.³⁶

In a 2007 study, 145 people at risk for latex allergy, including 104 health care workers, 31 patients with spina bifida, and 10 patients requiring multiple surgeries, underwent latex-specific IgE analysis for sensitivity to various recombinant and native latex allergens.³⁴ The three groups differed in their latex allergy profiles, highlighting the diversity of clinical response to latex in high-risk groups and our current inability to establish specific cutoff points for quantitative latex-specific IgE. Thus, at present, any nonzero latex-specific IgE value is considered positive.

A formal evaluation for allergy is recommended for patients who have a strong history of an IgE-mediated reaction to latex and a latex-specific IgE value of zero. Blood tests for allergy to some native or recombinant latex allergens are available; these allergens may be underrepresented in the native total latex extract.³³ Skin testing for allergy to latex, although not FDA-approved or standardized, can also be useful in this setting.³⁷

Insect venom

Type I hypersensitivity reactions can occur from the stings of Vespidae (vespids), Apidae (bees), and Formicidae (fire ants). Large localized reactions after an insect sting are not infrequent and typically do not predict anaphylactic sensitivity with future stings, even though they are considered mild IgE-mediated reactions. However, systemic reactions are considered life-threatening and warrant allergy testing.³⁸

The level of venom-specific IgE usually increases weeks to months after a sting.³⁹ Therefore, blood tests can be falsely negative if performed within a short time of the sting.

Patients who have suffered a systemic reaction to venom and have evidence of sensitization by either in vitro or in vivo allergy testing are candidates for venom immunotherapy.⁴⁰

At present, any nonzero venom-specific IgE test is considered positive, as there is no specific value for venom-specific IgE that predicts clinical risk.

A negative blood test does not exclude the possibility of an IgE-mediated reaction.⁴¹ In cases in which a patient has a clinical history compatible with venom allergy but the blood test is negative, the patient should be referred to an allergist for further evaluation, including venom skin testing and possibly repeat blood testing at a later time.

Conversely, specific IgE testing to venom is recommended when a patient has a history consistent with venom allergy and negative skin test results.³⁸

As mentioned previously, in vitro test performance can vary with the laboratory and testing method used, and sending samples directly to a reference laboratory could be considered.⁴¹

TESTING FOR IgG AGAINST FOODS IS UNVALIDATED AND INAPPROPRIATE

In recent years, some practitioners of alternative medicine have started testing for allergen-specific IgG or IgG4 as part of evaluations for hypersensitivity, especially in cases in which patients describe atypical gastrointestinal, neurologic, or other symptoms after eating specific foods.¹⁹

However, this testing often finds IgG or IgG4 against foods that are well tolerated. At present, allergen-specific IgG testing lacks scientific evidence to support its clinical use in the evaluation of allergic disease.^5,19

In Reply: We know from autopsy studies that most patients with giant cell arteritis, if not all, develop aortitis at some point during the course of their disease, but we don’t know (and no study yet has completely addressed) the following questions:

• What is the most clinically appropriate and cost-effective method of screening?
• How often should we be screening these patients?

Given the high cost of the most accurate and detailed available test, ie, magnetic resonance angiography of the aorta, annual chest radiography has been recommended by some experts in the field.

Although the high frequency of thoracic aneurysm justifies high clinical vigilance, we don’t know the most adequate and cost-effective test for screening for aortic aneurysm. Until we have an answer to these questions it is difficult to formulate specific guidelines, and different experts will continue to have different practices that are based on their own experience.

At this time, I carefully listen for bruits and murmurs on physical examination and check the blood pressure in all four extremities during patient follow-up visits. If I detect any abnormalities suggesting pathology of the aorta or major branches, I order magnetic resonance angiography of the entire aorta and its main branches.

In Reply: We know from autopsy studies that most patients with giant cell arteritis, if not all, develop aortitis at some point during the course of their disease, but we don’t know (and no study yet has completely addressed) the following questions:

• What is the most clinically appropriate and cost-effective method of screening?
• How often should we be screening these patients?

Given the high cost of the most accurate and detailed available test, ie, magnetic resonance angiography of the aorta, annual chest radiography has been recommended by some experts in the field.

Although the high frequency of thoracic aneurysm justifies high clinical vigilance, we don’t know the most adequate and cost-effective test for screening for aortic aneurysm. Until we have an answer to these questions it is difficult to formulate specific guidelines, and different experts will continue to have different practices that are based on their own experience.

At this time, I carefully listen for bruits and murmurs on physical examination and check the blood pressure in all four extremities during patient follow-up visits. If I detect any abnormalities suggesting pathology of the aorta or major branches, I order magnetic resonance angiography of the entire aorta and its main branches.

In Reply: We know from autopsy studies that most patients with giant cell arteritis, if not all, develop aortitis at some point during the course of their disease, but we don’t know (and no study yet has completely addressed) the following questions:

• What is the most clinically appropriate and cost-effective method of screening?
• How often should we be screening these patients?

Given the high cost of the most accurate and detailed available test, ie, magnetic resonance angiography of the aorta, annual chest radiography has been recommended by some experts in the field.

Although the high frequency of thoracic aneurysm justifies high clinical vigilance, we don’t know the most adequate and cost-effective test for screening for aortic aneurysm. Until we have an answer to these questions it is difficult to formulate specific guidelines, and different experts will continue to have different practices that are based on their own experience.

At this time, I carefully listen for bruits and murmurs on physical examination and check the blood pressure in all four extremities during patient follow-up visits. If I detect any abnormalities suggesting pathology of the aorta or major branches, I order magnetic resonance angiography of the entire aorta and its main branches.

To the Editor: As a practicing internist, I found Dr. Alexandra Villa-Forte’s review of giant-cell arteritis (Cleve Clin J Med 2011; 78:265–270) both interesting and useful, as usual for the Cleveland Clinic Journal of Medicine. However, she did not mention the recommendation by some experts that patients who have had temporal arteritis should receive annual chest x-rays, for a decade or longer, to screen for the development of thoracic aortic aneurysm. Does she agree with this precaution? Is it advisable, in addition, to screen for abdominal aortic aneurysm by means of abdominal ultrasonography? If so, at what time intervals should this be done?

To the Editor: As a practicing internist, I found Dr. Alexandra Villa-Forte’s review of giant-cell arteritis (Cleve Clin J Med 2011; 78:265–270) both interesting and useful, as usual for the Cleveland Clinic Journal of Medicine. However, she did not mention the recommendation by some experts that patients who have had temporal arteritis should receive annual chest x-rays, for a decade or longer, to screen for the development of thoracic aortic aneurysm. Does she agree with this precaution? Is it advisable, in addition, to screen for abdominal aortic aneurysm by means of abdominal ultrasonography? If so, at what time intervals should this be done?

To the Editor: As a practicing internist, I found Dr. Alexandra Villa-Forte’s review of giant-cell arteritis (Cleve Clin J Med 2011; 78:265–270) both interesting and useful, as usual for the Cleveland Clinic Journal of Medicine. However, she did not mention the recommendation by some experts that patients who have had temporal arteritis should receive annual chest x-rays, for a decade or longer, to screen for the development of thoracic aortic aneurysm. Does she agree with this precaution? Is it advisable, in addition, to screen for abdominal aortic aneurysm by means of abdominal ultrasonography? If so, at what time intervals should this be done?