People have been marking the skin with pigments for at least 4,000 years.¹ Tattoos have been found on Egyptian mummies, and Roman gladiators are known to have used tattoos for identification.² Tattooing was considered fashionable among royalty in the first half of the 20th century.³ And today it is perhaps more popular than ever.

But tattooing is not confined to popular culture and decoration. It has established uses in medicine, as well as other medically related uses that represent more recent trends. In this review, we explore the range of medical tattooing.

MEDICAL ALERT TATTOOING

Medical alert tattooing is a form of medical identification similar to medical alert jewelry, ie, bracelets and necklaces, to alert first-responders to a medical condition or to specific desires for care, such as do-not-resuscitate (DNR) directives.

Some people choose to have their medical condition tattooed rather than wear medical alert jewelry, which can break or be misplaced. ^4–6

This practice is currently unregulated by the medical community, and the few reports of its use published to date include two people with diabetes who had the word “diabetic” tattooed on their bodies,^4,5 and a woman with a tattoo warning of a past severe reaction to succinylcholine during anesthesia.⁶ She had been advised to wear medical alert jewelry, but she instead chose a tattoo.

Blood-type tattooing was briefly used in a few communities in the United States in the early 1950s as part of a program to provide a “walking blood bank.”⁷ However, the practice fell out of favor as physicians questioned the reliability of tattoos for medical information.⁷

This type of tattooing could also benefit patients with adrenal insufficiency, O-negative blood type, and allergies, and patients taking an anticoagulant drug (after discussing the risks of bleeding with their primary physician).

Emergency medical technicians are trained to search unresponsive patients for health-related items, including medical alert necklaces and bracelets. Since tattooing for disease identification purposes is not an officially recognized procedure, these personnel need to be aware that this practice is increasing among the general public. Identifying medical alert tattoos in emergency situations is much more difficult in people with extensive decorative tattooing.

Tattoos indicating health directives

Reports of people with tattoos indicating health directives (DNR, do-not-defibrillate) have prompted debate over the validity of tattoos as a type of advance directive.^8–13 These types of tattoos pose practical and ethical problems: they may not reflect a person’s current wishes, and they may have even been applied as a joke.¹³ Furthermore, they are not recognized as meeting any of the legal requirements for advance directives, so they cannot be considered as valid health directives, but only as a way to guide treatment decisions.¹⁴

The same is true for the other ways of notifying first-responders to one’s treatment wishes, ie, wallet cards and medical alert bracelets and necklaces. One manufacturer of medical alert bracelets and necklaces offers to engrave that the wearer has a living will and to keep on file a copy of the document, which they can fax or read out loud to paramedics if they are contacted.¹¹

Organ donor tattoo

In the case of a man who had his consent to be an organ donor tattooed on his chest,¹⁵ the tattoo was viewed as not equivalent to signed documentation; however, such tattoos can be used to help guide management.¹⁵

DIABETIC PATIENTS AND MEDICAL ALERT TATTOOS

Medical alert tattooing is increasingly common in people with diabetes. Discussions on social-networking sites on the Internet indicate that diabetic patients often do this on their own without consulting their physician.

The photograph at left is reprinted with the permission of the American Academy of Family Physicians, from reference 5.

In our clinic, we have encountered patients with tattoos on the wrist (Figure 1), similar to those seen on the Internet, typically displaying a six-pointed star of life, a caduceus (physician’s staff), and the word “diabetic.” Patients we have encountered in the past 3 to 4 years have cited the same rationale for resorting to medical tattooing—ie, the cost of repeatedly replacing broken and lost medical alert jewelry.

We believe there is a convincing rationale for diabetic patients to undergo medical tattooing, and we believe that diabetes organizations need to evaluate this and provide education to patients and clinicians about it, so that patients can discuss it with their care providers before taking action on their own.

Risks of tattooing in diabetic patients

Diabetic patients who ask their physician about getting a diabetes-alert tattoo should be informed about the dangers of tattooing in diabetes. The diabetes should be optimally controlled, as gauged by both hemoglobin A_1c and mean blood glucose profile at the time of tattooing, in order to promote healing of the tattooed area and to prevent wound infection.

Also helpful is to advise diabetic patients to avoid tattooing of the feet or lower legs in view of the risk of diabetes-related neurovascular disease that may impair healing or incite infection.

RECONSTRUCTIVE AND COSMETIC TATTOOING

Areolar reconstruction

Breast reconstruction after mastectomy is fundamental to the psychosocial health of the patient and helps her regain a positive body image.^16,17 Tattooing of the nipple-areola complex¹⁶ is usually the final step of the breast reconstruction process.

Complications of areolar tattooing are rare but can include local erythema and infection. ¹⁸ And patients should be informed that the tattoos will likely fade over time and require re-tattooing.¹⁸

Tattooing as camouflage

Tattooing is used to repigment the skin in conditions that cause hypopigmentation or hyperpigmentation, ² including burns.¹⁹ It is also used as an alternative to laser treatment in port-wine stain and in cosmetic surgery of the scalp.²⁰

Tattooing is used for micropigmentation of the lips and fingertips in patients who have vitiligo. However, this should be reserved for those with stable vitiligo, since tattooing may trigger another patch of vitiligo at tattoo sites.²¹

Although medical management exists for vitiligo, it is often ineffective for lip vitiligo since the success of medical therapy depends on the pigment-cell reservoir at the site of depigmentation. The lips lack such a reservoir of melanocytes, so tattooing may be an option.²²

Corneal scarring

Perforating injury, measles keratitis, and other conditions can result in cosmetically disfiguring discoloration of the cornea. When microsurgical reconstruction is ineffective or is not an option, corneal tattooing has been reported to provide satisfactory results at up to 4 years.²³ Reopacification, increased opacity, fading of the tattoo pigment, and epithelial growth have been reported, and in one series, most patients required reoperation.²⁴

Tattooing to hide surgical scars

Spyropoulou and Fatah²⁵ reported three patients in a plastic surgery practice who underwent decorative tattooing to camouflage cosmetically undesirable scars. The authors suggested this as a valid option, especially in younger patients, among whom tattooing is common and acceptable.²⁵

‘Permanent makeup’

Tattooing is also used to simulate makeup (“permanent makeup”) and may be beneficial to people allergic to conventional makeup or people with disabilities that make applying makeup difficult.²⁶ Complications of this procedure include bleeding, crusting, swelling, infection, allergic reactions, hypertrophic scars, keloid, loss of eyelashes, eyelid necrosis, and ectropion, as well as complications related to magnetic resonance imaging (described further below).

Most pigments used for this purpose do not have an established history of safe use, and patients may experience severe allergic reactions. A recent report described severe allergic reactions resistant to topical or systemic therapy with steroids in combination with topical tacrolimus (Prograf), especially after exposure to red dye 181.²⁷ Researchers have recommended the regulation and control of colorants in permanent makeup.²⁷

RADIATION ONCOLOGY

Tattooing is used in radiation oncology to ensure accurate targeting of radiation therapy. Typically, several small, black marks 1 to 2 mm in size are applied by a medical professional using an 18- or 19-gauge hypodermic needle and india ink.² The marks are permanent.

Although these markings are clearly helpful during radiation treatment, they can be psychologically upsetting to patients, as they are a constant reminder of the disease and the treatment, both during the treatment course and long after it is finished.

An alternative is to use temporary marks for the 6 to 7 weeks that patients typically need them. However, temporary tattooing is prone to fading, and this is a key limitation.

ENDOSCOPIC TATTOOING

In laparoscopic gastrointestinal surgery, lesions are often difficult to visualize and localize since the surgeon is unable to palpate the bowel directly to identify the diseased segment; this increases the risk of resecting the wrong segment of bowel.²⁸ Endoscopic tattooing of the segment to be resected greatly improves the accuracy of laparoscopic procedures. Endoscopic tattooing is also used to facilitate identification of subtle mucosal lesions or endoscopic resection sites at the time of subsequent endoscopy.^29,30

India ink or a similar presterilized commercial preparation is commonly used.³¹ Complications are rare but include mild chronic inflammation, hyperplastic changes, inflammatory bowel disease, abdominal abscess, inflammatory pseudotumor, focal peritonitis, peritoneal staining, and, very rarely, seeding of tumor via the tattooing needle.³⁰

FORENSIC MEDICINE

Specialists in forensic medicine use primary markers such as fingerprints and dental records and secondary markers such as birthmarks, scarring, and tattoos to identify victims.³² Tattoos are useful for identification when finger-prints or dental records are unavailable,³³ as in the tsunami of December 2004 in Southeast Asia³⁴ and the London Paddington train crash of October 1999.³⁵ However, as the body decomposes, tattoos can discolor and fade, making them hard to identify. Application of 3% hydrogen peroxide to the tattoo site has been reported to aid in identification, and infrared imaging has shown promise.³²

GENERAL RISKS AND COMPLICATIONS OF TATTOOING

Improper sterilization of tattooing needles and tattoo ink in public tattoo parlors can cause a wide range of diseases and skin reactions.^36–44

Infection

Pyodermal infections can include temporary inflammation at the sites of needle punctures, superficial infections such as impetigo and ecthyma, and deeper infections such as cellulitis, erysipelas, and furunculosis.

Other transmissible infections include hepatitis, syphilis, leprosy, tuberculosis cutis, rubella, chancroid, tetanus, and molluscum contagiosum. An outbreak of infection with Mycobacterium chelonae from premixed tattoo ink has also been reported.⁴⁴

Hepatitis C has been shown in epidemiologic studies to be transmissible via nonsterile needles. Human immunodeficiency virus is also theoretically transmissible this way, but this is difficult to confirm because the virus has a long incubation period.³⁶

Cutaneous reactions

Skin reactions to tattooing include aseptic inflammation and acquired sensitivity to tattoo dyes, especially red dyes, but also to chromium in green dyes, cadmium in yellow dyes, and cobalt in blue dyes.³⁸ The reaction can manifest as either allergic contact dermatitis or photoallergic dermatitis.

Cutaneous conditions that localize in tattooed areas include vaccinia, verruca vulgaris, herpes simplex, herpes zoster, psoriasis, lichen planus, keratosis follicularis (Darier disease), chronic discoid lupus erythematosus, and keratoacanthoma.

Other possible conditions include keloid, sarcoidal granuloma, erythema multiforme, localized scleroderma, and lymphadenopathy.^36,37

Malignancy

Malignancies reported to arise within tattoos include squamous cell carcinoma, basal cell carcinoma, malignant melanoma, leiomyosarcoma, primary non-Hodgkin lymphoma, and dermatofibrosarcoma protuberans.³⁹ These malignancies may be considered coincidental, but carcinogenicity of the tattooing colorants is a concern to be addressed. Nevertheless, a malignancy within a tattoo is more difficult to identify on skin examination.

Burns during magnetic resonance imaging

The metallic ferric acid pigments used in tattoos can conduct heat on the skin during magnetic resonance imaging,⁴⁰ resulting in traumatic burns. This has also been reported to occur with tattoos with nonferrous pigments. ⁴¹ Patients should be asked before this procedure if they have tattooing so that this complication can be avoided.

Two other complications

Two interesting complications of tattooing have been described. First, tattoo pigments have been noted within lymph nodes in patients with melanoma.⁴² This finding during surgery could cause the surgeon to mistake tattoo pigment for disease and to complete a regional lymph node dissection if biopsy of the sentinel node is not performed.

The other involved disseminated hyperalgesia after volar wrist tattooing. The authors speculated that the pain associated with volar tattooing may have been related to the proximity of the tattoo to the palmar cutaneous branch of the median nerve.⁴³
 

Acknowledgment: The authors would like to acknowledge the patients in Figure 1 for their permission to use their photos and Nicolas Kluger, MD, Departments of Dermatology, Allergology, and Venereology, University of Helsinki, Finland, for his input into an early draft of this manuscript.

People have been marking the skin with pigments for at least 4,000 years.¹ Tattoos have been found on Egyptian mummies, and Roman gladiators are known to have used tattoos for identification.² Tattooing was considered fashionable among royalty in the first half of the 20th century.³ And today it is perhaps more popular than ever.

But tattooing is not confined to popular culture and decoration. It has established uses in medicine, as well as other medically related uses that represent more recent trends. In this review, we explore the range of medical tattooing.

MEDICAL ALERT TATTOOING

Medical alert tattooing is a form of medical identification similar to medical alert jewelry, ie, bracelets and necklaces, to alert first-responders to a medical condition or to specific desires for care, such as do-not-resuscitate (DNR) directives.

Some people choose to have their medical condition tattooed rather than wear medical alert jewelry, which can break or be misplaced. ^4–6

This practice is currently unregulated by the medical community, and the few reports of its use published to date include two people with diabetes who had the word “diabetic” tattooed on their bodies,^4,5 and a woman with a tattoo warning of a past severe reaction to succinylcholine during anesthesia.⁶ She had been advised to wear medical alert jewelry, but she instead chose a tattoo.

Blood-type tattooing was briefly used in a few communities in the United States in the early 1950s as part of a program to provide a “walking blood bank.”⁷ However, the practice fell out of favor as physicians questioned the reliability of tattoos for medical information.⁷

This type of tattooing could also benefit patients with adrenal insufficiency, O-negative blood type, and allergies, and patients taking an anticoagulant drug (after discussing the risks of bleeding with their primary physician).

Emergency medical technicians are trained to search unresponsive patients for health-related items, including medical alert necklaces and bracelets. Since tattooing for disease identification purposes is not an officially recognized procedure, these personnel need to be aware that this practice is increasing among the general public. Identifying medical alert tattoos in emergency situations is much more difficult in people with extensive decorative tattooing.

Tattoos indicating health directives

Reports of people with tattoos indicating health directives (DNR, do-not-defibrillate) have prompted debate over the validity of tattoos as a type of advance directive.^8–13 These types of tattoos pose practical and ethical problems: they may not reflect a person’s current wishes, and they may have even been applied as a joke.¹³ Furthermore, they are not recognized as meeting any of the legal requirements for advance directives, so they cannot be considered as valid health directives, but only as a way to guide treatment decisions.¹⁴

The same is true for the other ways of notifying first-responders to one’s treatment wishes, ie, wallet cards and medical alert bracelets and necklaces. One manufacturer of medical alert bracelets and necklaces offers to engrave that the wearer has a living will and to keep on file a copy of the document, which they can fax or read out loud to paramedics if they are contacted.¹¹

Organ donor tattoo

In the case of a man who had his consent to be an organ donor tattooed on his chest,¹⁵ the tattoo was viewed as not equivalent to signed documentation; however, such tattoos can be used to help guide management.¹⁵

DIABETIC PATIENTS AND MEDICAL ALERT TATTOOS

Medical alert tattooing is increasingly common in people with diabetes. Discussions on social-networking sites on the Internet indicate that diabetic patients often do this on their own without consulting their physician.

The photograph at left is reprinted with the permission of the American Academy of Family Physicians, from reference 5.

In our clinic, we have encountered patients with tattoos on the wrist (Figure 1), similar to those seen on the Internet, typically displaying a six-pointed star of life, a caduceus (physician’s staff), and the word “diabetic.” Patients we have encountered in the past 3 to 4 years have cited the same rationale for resorting to medical tattooing—ie, the cost of repeatedly replacing broken and lost medical alert jewelry.

We believe there is a convincing rationale for diabetic patients to undergo medical tattooing, and we believe that diabetes organizations need to evaluate this and provide education to patients and clinicians about it, so that patients can discuss it with their care providers before taking action on their own.

Risks of tattooing in diabetic patients

Diabetic patients who ask their physician about getting a diabetes-alert tattoo should be informed about the dangers of tattooing in diabetes. The diabetes should be optimally controlled, as gauged by both hemoglobin A_1c and mean blood glucose profile at the time of tattooing, in order to promote healing of the tattooed area and to prevent wound infection.

Also helpful is to advise diabetic patients to avoid tattooing of the feet or lower legs in view of the risk of diabetes-related neurovascular disease that may impair healing or incite infection.

RECONSTRUCTIVE AND COSMETIC TATTOOING

Areolar reconstruction

Breast reconstruction after mastectomy is fundamental to the psychosocial health of the patient and helps her regain a positive body image.^16,17 Tattooing of the nipple-areola complex¹⁶ is usually the final step of the breast reconstruction process.

Complications of areolar tattooing are rare but can include local erythema and infection. ¹⁸ And patients should be informed that the tattoos will likely fade over time and require re-tattooing.¹⁸

Tattooing as camouflage

Tattooing is used to repigment the skin in conditions that cause hypopigmentation or hyperpigmentation, ² including burns.¹⁹ It is also used as an alternative to laser treatment in port-wine stain and in cosmetic surgery of the scalp.²⁰

Tattooing is used for micropigmentation of the lips and fingertips in patients who have vitiligo. However, this should be reserved for those with stable vitiligo, since tattooing may trigger another patch of vitiligo at tattoo sites.²¹

Although medical management exists for vitiligo, it is often ineffective for lip vitiligo since the success of medical therapy depends on the pigment-cell reservoir at the site of depigmentation. The lips lack such a reservoir of melanocytes, so tattooing may be an option.²²

Corneal scarring

Perforating injury, measles keratitis, and other conditions can result in cosmetically disfiguring discoloration of the cornea. When microsurgical reconstruction is ineffective or is not an option, corneal tattooing has been reported to provide satisfactory results at up to 4 years.²³ Reopacification, increased opacity, fading of the tattoo pigment, and epithelial growth have been reported, and in one series, most patients required reoperation.²⁴

Tattooing to hide surgical scars

Spyropoulou and Fatah²⁵ reported three patients in a plastic surgery practice who underwent decorative tattooing to camouflage cosmetically undesirable scars. The authors suggested this as a valid option, especially in younger patients, among whom tattooing is common and acceptable.²⁵

‘Permanent makeup’

Tattooing is also used to simulate makeup (“permanent makeup”) and may be beneficial to people allergic to conventional makeup or people with disabilities that make applying makeup difficult.²⁶ Complications of this procedure include bleeding, crusting, swelling, infection, allergic reactions, hypertrophic scars, keloid, loss of eyelashes, eyelid necrosis, and ectropion, as well as complications related to magnetic resonance imaging (described further below).

Most pigments used for this purpose do not have an established history of safe use, and patients may experience severe allergic reactions. A recent report described severe allergic reactions resistant to topical or systemic therapy with steroids in combination with topical tacrolimus (Prograf), especially after exposure to red dye 181.²⁷ Researchers have recommended the regulation and control of colorants in permanent makeup.²⁷

RADIATION ONCOLOGY

Tattooing is used in radiation oncology to ensure accurate targeting of radiation therapy. Typically, several small, black marks 1 to 2 mm in size are applied by a medical professional using an 18- or 19-gauge hypodermic needle and india ink.² The marks are permanent.

Although these markings are clearly helpful during radiation treatment, they can be psychologically upsetting to patients, as they are a constant reminder of the disease and the treatment, both during the treatment course and long after it is finished.

An alternative is to use temporary marks for the 6 to 7 weeks that patients typically need them. However, temporary tattooing is prone to fading, and this is a key limitation.

ENDOSCOPIC TATTOOING

In laparoscopic gastrointestinal surgery, lesions are often difficult to visualize and localize since the surgeon is unable to palpate the bowel directly to identify the diseased segment; this increases the risk of resecting the wrong segment of bowel.²⁸ Endoscopic tattooing of the segment to be resected greatly improves the accuracy of laparoscopic procedures. Endoscopic tattooing is also used to facilitate identification of subtle mucosal lesions or endoscopic resection sites at the time of subsequent endoscopy.^29,30

India ink or a similar presterilized commercial preparation is commonly used.³¹ Complications are rare but include mild chronic inflammation, hyperplastic changes, inflammatory bowel disease, abdominal abscess, inflammatory pseudotumor, focal peritonitis, peritoneal staining, and, very rarely, seeding of tumor via the tattooing needle.³⁰

FORENSIC MEDICINE

Specialists in forensic medicine use primary markers such as fingerprints and dental records and secondary markers such as birthmarks, scarring, and tattoos to identify victims.³² Tattoos are useful for identification when finger-prints or dental records are unavailable,³³ as in the tsunami of December 2004 in Southeast Asia³⁴ and the London Paddington train crash of October 1999.³⁵ However, as the body decomposes, tattoos can discolor and fade, making them hard to identify. Application of 3% hydrogen peroxide to the tattoo site has been reported to aid in identification, and infrared imaging has shown promise.³²

GENERAL RISKS AND COMPLICATIONS OF TATTOOING

Improper sterilization of tattooing needles and tattoo ink in public tattoo parlors can cause a wide range of diseases and skin reactions.^36–44

Infection

Pyodermal infections can include temporary inflammation at the sites of needle punctures, superficial infections such as impetigo and ecthyma, and deeper infections such as cellulitis, erysipelas, and furunculosis.

Other transmissible infections include hepatitis, syphilis, leprosy, tuberculosis cutis, rubella, chancroid, tetanus, and molluscum contagiosum. An outbreak of infection with Mycobacterium chelonae from premixed tattoo ink has also been reported.⁴⁴

Hepatitis C has been shown in epidemiologic studies to be transmissible via nonsterile needles. Human immunodeficiency virus is also theoretically transmissible this way, but this is difficult to confirm because the virus has a long incubation period.³⁶

Cutaneous reactions

Skin reactions to tattooing include aseptic inflammation and acquired sensitivity to tattoo dyes, especially red dyes, but also to chromium in green dyes, cadmium in yellow dyes, and cobalt in blue dyes.³⁸ The reaction can manifest as either allergic contact dermatitis or photoallergic dermatitis.

Cutaneous conditions that localize in tattooed areas include vaccinia, verruca vulgaris, herpes simplex, herpes zoster, psoriasis, lichen planus, keratosis follicularis (Darier disease), chronic discoid lupus erythematosus, and keratoacanthoma.

Other possible conditions include keloid, sarcoidal granuloma, erythema multiforme, localized scleroderma, and lymphadenopathy.^36,37

Malignancy

Malignancies reported to arise within tattoos include squamous cell carcinoma, basal cell carcinoma, malignant melanoma, leiomyosarcoma, primary non-Hodgkin lymphoma, and dermatofibrosarcoma protuberans.³⁹ These malignancies may be considered coincidental, but carcinogenicity of the tattooing colorants is a concern to be addressed. Nevertheless, a malignancy within a tattoo is more difficult to identify on skin examination.

Burns during magnetic resonance imaging

The metallic ferric acid pigments used in tattoos can conduct heat on the skin during magnetic resonance imaging,⁴⁰ resulting in traumatic burns. This has also been reported to occur with tattoos with nonferrous pigments. ⁴¹ Patients should be asked before this procedure if they have tattooing so that this complication can be avoided.

Two other complications

Two interesting complications of tattooing have been described. First, tattoo pigments have been noted within lymph nodes in patients with melanoma.⁴² This finding during surgery could cause the surgeon to mistake tattoo pigment for disease and to complete a regional lymph node dissection if biopsy of the sentinel node is not performed.

The other involved disseminated hyperalgesia after volar wrist tattooing. The authors speculated that the pain associated with volar tattooing may have been related to the proximity of the tattoo to the palmar cutaneous branch of the median nerve.⁴³
 

Acknowledgment: The authors would like to acknowledge the patients in Figure 1 for their permission to use their photos and Nicolas Kluger, MD, Departments of Dermatology, Allergology, and Venereology, University of Helsinki, Finland, for his input into an early draft of this manuscript.

People have been marking the skin with pigments for at least 4,000 years.¹ Tattoos have been found on Egyptian mummies, and Roman gladiators are known to have used tattoos for identification.² Tattooing was considered fashionable among royalty in the first half of the 20th century.³ And today it is perhaps more popular than ever.

But tattooing is not confined to popular culture and decoration. It has established uses in medicine, as well as other medically related uses that represent more recent trends. In this review, we explore the range of medical tattooing.

MEDICAL ALERT TATTOOING

Medical alert tattooing is a form of medical identification similar to medical alert jewelry, ie, bracelets and necklaces, to alert first-responders to a medical condition or to specific desires for care, such as do-not-resuscitate (DNR) directives.

Some people choose to have their medical condition tattooed rather than wear medical alert jewelry, which can break or be misplaced. ^4–6

This practice is currently unregulated by the medical community, and the few reports of its use published to date include two people with diabetes who had the word “diabetic” tattooed on their bodies,^4,5 and a woman with a tattoo warning of a past severe reaction to succinylcholine during anesthesia.⁶ She had been advised to wear medical alert jewelry, but she instead chose a tattoo.

Blood-type tattooing was briefly used in a few communities in the United States in the early 1950s as part of a program to provide a “walking blood bank.”⁷ However, the practice fell out of favor as physicians questioned the reliability of tattoos for medical information.⁷

This type of tattooing could also benefit patients with adrenal insufficiency, O-negative blood type, and allergies, and patients taking an anticoagulant drug (after discussing the risks of bleeding with their primary physician).

Emergency medical technicians are trained to search unresponsive patients for health-related items, including medical alert necklaces and bracelets. Since tattooing for disease identification purposes is not an officially recognized procedure, these personnel need to be aware that this practice is increasing among the general public. Identifying medical alert tattoos in emergency situations is much more difficult in people with extensive decorative tattooing.

Tattoos indicating health directives

Reports of people with tattoos indicating health directives (DNR, do-not-defibrillate) have prompted debate over the validity of tattoos as a type of advance directive.^8–13 These types of tattoos pose practical and ethical problems: they may not reflect a person’s current wishes, and they may have even been applied as a joke.¹³ Furthermore, they are not recognized as meeting any of the legal requirements for advance directives, so they cannot be considered as valid health directives, but only as a way to guide treatment decisions.¹⁴

The same is true for the other ways of notifying first-responders to one’s treatment wishes, ie, wallet cards and medical alert bracelets and necklaces. One manufacturer of medical alert bracelets and necklaces offers to engrave that the wearer has a living will and to keep on file a copy of the document, which they can fax or read out loud to paramedics if they are contacted.¹¹

Organ donor tattoo

In the case of a man who had his consent to be an organ donor tattooed on his chest,¹⁵ the tattoo was viewed as not equivalent to signed documentation; however, such tattoos can be used to help guide management.¹⁵

DIABETIC PATIENTS AND MEDICAL ALERT TATTOOS

Medical alert tattooing is increasingly common in people with diabetes. Discussions on social-networking sites on the Internet indicate that diabetic patients often do this on their own without consulting their physician.

The photograph at left is reprinted with the permission of the American Academy of Family Physicians, from reference 5.

In our clinic, we have encountered patients with tattoos on the wrist (Figure 1), similar to those seen on the Internet, typically displaying a six-pointed star of life, a caduceus (physician’s staff), and the word “diabetic.” Patients we have encountered in the past 3 to 4 years have cited the same rationale for resorting to medical tattooing—ie, the cost of repeatedly replacing broken and lost medical alert jewelry.

We believe there is a convincing rationale for diabetic patients to undergo medical tattooing, and we believe that diabetes organizations need to evaluate this and provide education to patients and clinicians about it, so that patients can discuss it with their care providers before taking action on their own.

Risks of tattooing in diabetic patients

Diabetic patients who ask their physician about getting a diabetes-alert tattoo should be informed about the dangers of tattooing in diabetes. The diabetes should be optimally controlled, as gauged by both hemoglobin A_1c and mean blood glucose profile at the time of tattooing, in order to promote healing of the tattooed area and to prevent wound infection.

Also helpful is to advise diabetic patients to avoid tattooing of the feet or lower legs in view of the risk of diabetes-related neurovascular disease that may impair healing or incite infection.

RECONSTRUCTIVE AND COSMETIC TATTOOING

Areolar reconstruction

Breast reconstruction after mastectomy is fundamental to the psychosocial health of the patient and helps her regain a positive body image.^16,17 Tattooing of the nipple-areola complex¹⁶ is usually the final step of the breast reconstruction process.

Complications of areolar tattooing are rare but can include local erythema and infection. ¹⁸ And patients should be informed that the tattoos will likely fade over time and require re-tattooing.¹⁸

Tattooing as camouflage

Tattooing is used to repigment the skin in conditions that cause hypopigmentation or hyperpigmentation, ² including burns.¹⁹ It is also used as an alternative to laser treatment in port-wine stain and in cosmetic surgery of the scalp.²⁰

Tattooing is used for micropigmentation of the lips and fingertips in patients who have vitiligo. However, this should be reserved for those with stable vitiligo, since tattooing may trigger another patch of vitiligo at tattoo sites.²¹

Although medical management exists for vitiligo, it is often ineffective for lip vitiligo since the success of medical therapy depends on the pigment-cell reservoir at the site of depigmentation. The lips lack such a reservoir of melanocytes, so tattooing may be an option.²²

Corneal scarring

Perforating injury, measles keratitis, and other conditions can result in cosmetically disfiguring discoloration of the cornea. When microsurgical reconstruction is ineffective or is not an option, corneal tattooing has been reported to provide satisfactory results at up to 4 years.²³ Reopacification, increased opacity, fading of the tattoo pigment, and epithelial growth have been reported, and in one series, most patients required reoperation.²⁴

Tattooing to hide surgical scars

Spyropoulou and Fatah²⁵ reported three patients in a plastic surgery practice who underwent decorative tattooing to camouflage cosmetically undesirable scars. The authors suggested this as a valid option, especially in younger patients, among whom tattooing is common and acceptable.²⁵

‘Permanent makeup’

Tattooing is also used to simulate makeup (“permanent makeup”) and may be beneficial to people allergic to conventional makeup or people with disabilities that make applying makeup difficult.²⁶ Complications of this procedure include bleeding, crusting, swelling, infection, allergic reactions, hypertrophic scars, keloid, loss of eyelashes, eyelid necrosis, and ectropion, as well as complications related to magnetic resonance imaging (described further below).

Most pigments used for this purpose do not have an established history of safe use, and patients may experience severe allergic reactions. A recent report described severe allergic reactions resistant to topical or systemic therapy with steroids in combination with topical tacrolimus (Prograf), especially after exposure to red dye 181.²⁷ Researchers have recommended the regulation and control of colorants in permanent makeup.²⁷

RADIATION ONCOLOGY

Tattooing is used in radiation oncology to ensure accurate targeting of radiation therapy. Typically, several small, black marks 1 to 2 mm in size are applied by a medical professional using an 18- or 19-gauge hypodermic needle and india ink.² The marks are permanent.

Although these markings are clearly helpful during radiation treatment, they can be psychologically upsetting to patients, as they are a constant reminder of the disease and the treatment, both during the treatment course and long after it is finished.

An alternative is to use temporary marks for the 6 to 7 weeks that patients typically need them. However, temporary tattooing is prone to fading, and this is a key limitation.

ENDOSCOPIC TATTOOING

In laparoscopic gastrointestinal surgery, lesions are often difficult to visualize and localize since the surgeon is unable to palpate the bowel directly to identify the diseased segment; this increases the risk of resecting the wrong segment of bowel.²⁸ Endoscopic tattooing of the segment to be resected greatly improves the accuracy of laparoscopic procedures. Endoscopic tattooing is also used to facilitate identification of subtle mucosal lesions or endoscopic resection sites at the time of subsequent endoscopy.^29,30

India ink or a similar presterilized commercial preparation is commonly used.³¹ Complications are rare but include mild chronic inflammation, hyperplastic changes, inflammatory bowel disease, abdominal abscess, inflammatory pseudotumor, focal peritonitis, peritoneal staining, and, very rarely, seeding of tumor via the tattooing needle.³⁰

FORENSIC MEDICINE

Specialists in forensic medicine use primary markers such as fingerprints and dental records and secondary markers such as birthmarks, scarring, and tattoos to identify victims.³² Tattoos are useful for identification when finger-prints or dental records are unavailable,³³ as in the tsunami of December 2004 in Southeast Asia³⁴ and the London Paddington train crash of October 1999.³⁵ However, as the body decomposes, tattoos can discolor and fade, making them hard to identify. Application of 3% hydrogen peroxide to the tattoo site has been reported to aid in identification, and infrared imaging has shown promise.³²

GENERAL RISKS AND COMPLICATIONS OF TATTOOING

Improper sterilization of tattooing needles and tattoo ink in public tattoo parlors can cause a wide range of diseases and skin reactions.^36–44

Infection

Pyodermal infections can include temporary inflammation at the sites of needle punctures, superficial infections such as impetigo and ecthyma, and deeper infections such as cellulitis, erysipelas, and furunculosis.

Other transmissible infections include hepatitis, syphilis, leprosy, tuberculosis cutis, rubella, chancroid, tetanus, and molluscum contagiosum. An outbreak of infection with Mycobacterium chelonae from premixed tattoo ink has also been reported.⁴⁴

Hepatitis C has been shown in epidemiologic studies to be transmissible via nonsterile needles. Human immunodeficiency virus is also theoretically transmissible this way, but this is difficult to confirm because the virus has a long incubation period.³⁶

Cutaneous reactions

Skin reactions to tattooing include aseptic inflammation and acquired sensitivity to tattoo dyes, especially red dyes, but also to chromium in green dyes, cadmium in yellow dyes, and cobalt in blue dyes.³⁸ The reaction can manifest as either allergic contact dermatitis or photoallergic dermatitis.

Cutaneous conditions that localize in tattooed areas include vaccinia, verruca vulgaris, herpes simplex, herpes zoster, psoriasis, lichen planus, keratosis follicularis (Darier disease), chronic discoid lupus erythematosus, and keratoacanthoma.

Other possible conditions include keloid, sarcoidal granuloma, erythema multiforme, localized scleroderma, and lymphadenopathy.^36,37

Malignancy

Malignancies reported to arise within tattoos include squamous cell carcinoma, basal cell carcinoma, malignant melanoma, leiomyosarcoma, primary non-Hodgkin lymphoma, and dermatofibrosarcoma protuberans.³⁹ These malignancies may be considered coincidental, but carcinogenicity of the tattooing colorants is a concern to be addressed. Nevertheless, a malignancy within a tattoo is more difficult to identify on skin examination.

Burns during magnetic resonance imaging

The metallic ferric acid pigments used in tattoos can conduct heat on the skin during magnetic resonance imaging,⁴⁰ resulting in traumatic burns. This has also been reported to occur with tattoos with nonferrous pigments. ⁴¹ Patients should be asked before this procedure if they have tattooing so that this complication can be avoided.

Two other complications

Two interesting complications of tattooing have been described. First, tattoo pigments have been noted within lymph nodes in patients with melanoma.⁴² This finding during surgery could cause the surgeon to mistake tattoo pigment for disease and to complete a regional lymph node dissection if biopsy of the sentinel node is not performed.

The other involved disseminated hyperalgesia after volar wrist tattooing. The authors speculated that the pain associated with volar tattooing may have been related to the proximity of the tattoo to the palmar cutaneous branch of the median nerve.⁴³
 

Acknowledgment: The authors would like to acknowledge the patients in Figure 1 for their permission to use their photos and Nicolas Kluger, MD, Departments of Dermatology, Allergology, and Venereology, University of Helsinki, Finland, for his input into an early draft of this manuscript.

A previously healthy 39-year-old woman presented to the emergency department with 7 days of a gradually worsening rash. One week before the onset of the rash, her primary care physician had diagnosed streptococcal pharyngitis, for which she was treated with oral amoxicillin. She had no history of skin or joint problems and was not currently taking any medications.

She was afebrile and her vital signs were normal. She had mild pharyngeal erythema but no palpable cervical lymph nodes. The skin examination showed well demarcated, erythmatous papules 1 cm in diameter, with overlying scales over the entire body, sparing the palms and the soles of the feet (Figure 1).

Q: Which is the most likely diagnosis?

• Impetigo
• Drug reaction
• Guttate psoriasis
• Nummular eczema
• Pityriasis rosea

A: The most likely diagnosis is guttate psoriasis.

Guttate psoriasis is a relatively uncommon condition that affects less than 2% of patients with psoriasis, primarily children and young adults. It is strongly associated with recent or concomitant beta-hemolytic streptococcal infection.¹ The rash usually develops 1 to 2 weeks after the streptococcal pharyngitis or upper respiratory tract infection. Other organisms involved in guttate psoriasis are Staphylococcus aureus, Candida, and viruses such as human papillomavirus, human immunodeficiency virus, and human endogenous retrovirus. ² Several commonly used drugs are also implicated in psoriasiform eruptions, including beta-blockers, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, lithium, metformin, and digoxin.

Acute onset of skin lesions caused by streptococcal infection can be either the first manifestation in a previously unaffected person or an acute exacerbation of long-standing psoriasis. Skin lesions are usually scaly, erythematous, and guttate (drop-shaped); they primarily involve the trunk but can spread to the rest of the body, sparing the palms and soles.

Throat culture should be done to confirm streptococcal infection. Titers of antistreptolysin O are elevated in more than half of patients with guttate psoriasis. Histopathologic examination can differentiate guttate psoriasis from other psoriasiform conditions, such as pityriasis rosea, secondary syphilis, and lichen simplex chronicus; however, the clinical appearance of the rash is so characteristic that biopsy is not usually needed to confirm the diagnosis.

Guttate psoriasis responds well to phototherapy with ultraviolet B radiation and medium-potency topical corticosteroids.³ And since streptococcal throat infection triggers the condition, it must also be treated for complete recovery.

CASE CONTINUED

Our patient was treated with topical steroid creams. Her rash improved slowly and had completely resolved in 6 weeks.

A previously healthy 39-year-old woman presented to the emergency department with 7 days of a gradually worsening rash. One week before the onset of the rash, her primary care physician had diagnosed streptococcal pharyngitis, for which she was treated with oral amoxicillin. She had no history of skin or joint problems and was not currently taking any medications.

She was afebrile and her vital signs were normal. She had mild pharyngeal erythema but no palpable cervical lymph nodes. The skin examination showed well demarcated, erythmatous papules 1 cm in diameter, with overlying scales over the entire body, sparing the palms and the soles of the feet (Figure 1).

Q: Which is the most likely diagnosis?

• Impetigo
• Drug reaction
• Guttate psoriasis
• Nummular eczema
• Pityriasis rosea

A: The most likely diagnosis is guttate psoriasis.

Guttate psoriasis is a relatively uncommon condition that affects less than 2% of patients with psoriasis, primarily children and young adults. It is strongly associated with recent or concomitant beta-hemolytic streptococcal infection.¹ The rash usually develops 1 to 2 weeks after the streptococcal pharyngitis or upper respiratory tract infection. Other organisms involved in guttate psoriasis are Staphylococcus aureus, Candida, and viruses such as human papillomavirus, human immunodeficiency virus, and human endogenous retrovirus. ² Several commonly used drugs are also implicated in psoriasiform eruptions, including beta-blockers, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, lithium, metformin, and digoxin.

Acute onset of skin lesions caused by streptococcal infection can be either the first manifestation in a previously unaffected person or an acute exacerbation of long-standing psoriasis. Skin lesions are usually scaly, erythematous, and guttate (drop-shaped); they primarily involve the trunk but can spread to the rest of the body, sparing the palms and soles.

Throat culture should be done to confirm streptococcal infection. Titers of antistreptolysin O are elevated in more than half of patients with guttate psoriasis. Histopathologic examination can differentiate guttate psoriasis from other psoriasiform conditions, such as pityriasis rosea, secondary syphilis, and lichen simplex chronicus; however, the clinical appearance of the rash is so characteristic that biopsy is not usually needed to confirm the diagnosis.

Guttate psoriasis responds well to phototherapy with ultraviolet B radiation and medium-potency topical corticosteroids.³ And since streptococcal throat infection triggers the condition, it must also be treated for complete recovery.

CASE CONTINUED

Our patient was treated with topical steroid creams. Her rash improved slowly and had completely resolved in 6 weeks.

A previously healthy 39-year-old woman presented to the emergency department with 7 days of a gradually worsening rash. One week before the onset of the rash, her primary care physician had diagnosed streptococcal pharyngitis, for which she was treated with oral amoxicillin. She had no history of skin or joint problems and was not currently taking any medications.

She was afebrile and her vital signs were normal. She had mild pharyngeal erythema but no palpable cervical lymph nodes. The skin examination showed well demarcated, erythmatous papules 1 cm in diameter, with overlying scales over the entire body, sparing the palms and the soles of the feet (Figure 1).

Q: Which is the most likely diagnosis?

• Impetigo
• Drug reaction
• Guttate psoriasis
• Nummular eczema
• Pityriasis rosea

A: The most likely diagnosis is guttate psoriasis.

Guttate psoriasis is a relatively uncommon condition that affects less than 2% of patients with psoriasis, primarily children and young adults. It is strongly associated with recent or concomitant beta-hemolytic streptococcal infection.¹ The rash usually develops 1 to 2 weeks after the streptococcal pharyngitis or upper respiratory tract infection. Other organisms involved in guttate psoriasis are Staphylococcus aureus, Candida, and viruses such as human papillomavirus, human immunodeficiency virus, and human endogenous retrovirus. ² Several commonly used drugs are also implicated in psoriasiform eruptions, including beta-blockers, nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibitors, lithium, metformin, and digoxin.

Acute onset of skin lesions caused by streptococcal infection can be either the first manifestation in a previously unaffected person or an acute exacerbation of long-standing psoriasis. Skin lesions are usually scaly, erythematous, and guttate (drop-shaped); they primarily involve the trunk but can spread to the rest of the body, sparing the palms and soles.

Throat culture should be done to confirm streptococcal infection. Titers of antistreptolysin O are elevated in more than half of patients with guttate psoriasis. Histopathologic examination can differentiate guttate psoriasis from other psoriasiform conditions, such as pityriasis rosea, secondary syphilis, and lichen simplex chronicus; however, the clinical appearance of the rash is so characteristic that biopsy is not usually needed to confirm the diagnosis.

Guttate psoriasis responds well to phototherapy with ultraviolet B radiation and medium-potency topical corticosteroids.³ And since streptococcal throat infection triggers the condition, it must also be treated for complete recovery.

CASE CONTINUED

Our patient was treated with topical steroid creams. Her rash improved slowly and had completely resolved in 6 weeks.

No. Using N-acetylcysteine (NAC) routinely to prevent contrast-induced acute kidney injury is not supported by the evidence at this time.^1,2 However, there is evidence to suggest using it for patients at high risk, ie, those with significant baseline renal dysfunction.^3,4

INCIDENCE AND IMPACT OF ACUTE KIDNEY INJURY

Intraarterial use of contrast is associated with a higher risk of acute kidney injury than intravenous use. Most studies of NAC for the prevention of contrast-induced acute kidney injury have focused on patients receiving contrast intraarterially. The reported rates of contrast-induced acute kidney injury also vary depending on how acute kidney injury was defined.

Although the incidence is low (1% to 2%) in patients with normal renal function, it can be as high as 25% in patients with renal impairment or a chronic condition such as diabetes or congestive heart failure, or in elderly patients.⁵

The development of acute kidney injury after percutaneous coronary intervention is associated with a longer hospital stay, a higher cost of care, and higher rates of morbidity and death.⁶

RATIONALE FOR USING N-ACETYLCYSTEINE

Contrast-induced acute kidney injury is thought to involve vasoconstriction and medullary ischemia mediated by reactive oxygen species.⁵ As an antioxidant and a scavenger of free radicals, NAC showed early promise in reducing the risk of this complication, but subsequent trials raised doubts about its efficacy. ^1,2 In clinical practice, the drug is often used to prevent acute kidney injury because it is easy to give, cheap, and has few side effects. Recently, however, there have been suggestions that giving it intravenously may be associated with adverse effects that include anaphylactoid reactions.⁷

THE POSITIVE TRIALS

Tepel et al³ performed one of the earliest trials that found that NAC prevented contrast-induced acute kidney injury. The trial included 83 patients with stable chronic kidney disease (mean serum creatinine 2.4 mg/dL) who underwent computed tomography with about 75 mL of a nonionic, low-osmolality contrast agent. Participants were randomized to receive either NAC (600 mg orally twice daily) and 0.45% saline intravenously or placebo and saline. Acute kidney injury was defined as an increase of at least 0.5 mg/dL in the serum creatinine level 48 hours after the contrast dye was given.

The rate of acute kidney injury was significantly lower in the treatment group (2% vs 21%, P = .01). None of the patients who developed acute kidney injury needed hemodialysis.

Shyu et al⁴ studied 121 patients with chronic kidney disease (mean serum creatinine 2.8 mg/dL) who underwent a coronary procedure. Patients were randomized to receive NAC 400 mg orally twice daily or placebo in addition to 0.45% saline in both groups. Two (3.3%) of the 60 patients in the treated group and 15 (24.6%) of the 61 patients in the control group had an increase in creatinine concentration greater than 0.5 mg/dL at 48 hours (P < .001).

Both of these single-center studies were limited by small sample sizes and very short follow-up. Further, the impact of the drug on important clinical outcomes such as death and progression of chronic kidney disease was not reported.

Marenzi et al⁸ randomized 354 patients undergoing coronary angioplasty as the primary treatment for acute myocardial infarction to one of three treatment groups:

• NAC in a standard dosage (a 600-mg intravenous bolus before the procedure and then 600 mg orally twice daily for 48 hours afterward)
• NAC in a high dosage (a 1,200-mg intravenous bolus and then 1,200 mg orally twice daily for 48 hours)
• Placebo.

The two treatment groups had significantly lower rates of acute kidney injury than the placebo group. In addition, the hospital mortality rate and the rate of a composite end point of death, need for renal replacement therapy, or need for mechanical ventilation were significantly lower in the treated groups. However, the number of events was small, and a beneficial effect on the death rate has not been confirmed by other studies.⁵

THE NEGATIVE TRIALS

Several studies found that NAC did not prevent contrast-induced acute kidney injury.^1,2,9

The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,¹ was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.

The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).

Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.

Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).¹

The ACT differed from the “positive” study by Marenzi et al⁸ in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.

Webb et al² found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.

Gurm et al⁹ found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.

MIXED RESULTS IN META-ANALYSES

Results from meta-analyses have been mixed,^10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.

CURRENT GUIDELINES

After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.¹²

However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).⁵

WHAT WE RECOMMEND

The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m².

In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:

• Clarify whether contrast is truly needed
• When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
• Discontinue nephrotoxic agents
• Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
• Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m²), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
• Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.^7,13

We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.

No. Using N-acetylcysteine (NAC) routinely to prevent contrast-induced acute kidney injury is not supported by the evidence at this time.^1,2 However, there is evidence to suggest using it for patients at high risk, ie, those with significant baseline renal dysfunction.^3,4

INCIDENCE AND IMPACT OF ACUTE KIDNEY INJURY

Intraarterial use of contrast is associated with a higher risk of acute kidney injury than intravenous use. Most studies of NAC for the prevention of contrast-induced acute kidney injury have focused on patients receiving contrast intraarterially. The reported rates of contrast-induced acute kidney injury also vary depending on how acute kidney injury was defined.

Although the incidence is low (1% to 2%) in patients with normal renal function, it can be as high as 25% in patients with renal impairment or a chronic condition such as diabetes or congestive heart failure, or in elderly patients.⁵

The development of acute kidney injury after percutaneous coronary intervention is associated with a longer hospital stay, a higher cost of care, and higher rates of morbidity and death.⁶

RATIONALE FOR USING N-ACETYLCYSTEINE

Contrast-induced acute kidney injury is thought to involve vasoconstriction and medullary ischemia mediated by reactive oxygen species.⁵ As an antioxidant and a scavenger of free radicals, NAC showed early promise in reducing the risk of this complication, but subsequent trials raised doubts about its efficacy. ^1,2 In clinical practice, the drug is often used to prevent acute kidney injury because it is easy to give, cheap, and has few side effects. Recently, however, there have been suggestions that giving it intravenously may be associated with adverse effects that include anaphylactoid reactions.⁷

THE POSITIVE TRIALS

Tepel et al³ performed one of the earliest trials that found that NAC prevented contrast-induced acute kidney injury. The trial included 83 patients with stable chronic kidney disease (mean serum creatinine 2.4 mg/dL) who underwent computed tomography with about 75 mL of a nonionic, low-osmolality contrast agent. Participants were randomized to receive either NAC (600 mg orally twice daily) and 0.45% saline intravenously or placebo and saline. Acute kidney injury was defined as an increase of at least 0.5 mg/dL in the serum creatinine level 48 hours after the contrast dye was given.

The rate of acute kidney injury was significantly lower in the treatment group (2% vs 21%, P = .01). None of the patients who developed acute kidney injury needed hemodialysis.

Shyu et al⁴ studied 121 patients with chronic kidney disease (mean serum creatinine 2.8 mg/dL) who underwent a coronary procedure. Patients were randomized to receive NAC 400 mg orally twice daily or placebo in addition to 0.45% saline in both groups. Two (3.3%) of the 60 patients in the treated group and 15 (24.6%) of the 61 patients in the control group had an increase in creatinine concentration greater than 0.5 mg/dL at 48 hours (P < .001).

Both of these single-center studies were limited by small sample sizes and very short follow-up. Further, the impact of the drug on important clinical outcomes such as death and progression of chronic kidney disease was not reported.

Marenzi et al⁸ randomized 354 patients undergoing coronary angioplasty as the primary treatment for acute myocardial infarction to one of three treatment groups:

• NAC in a standard dosage (a 600-mg intravenous bolus before the procedure and then 600 mg orally twice daily for 48 hours afterward)
• NAC in a high dosage (a 1,200-mg intravenous bolus and then 1,200 mg orally twice daily for 48 hours)
• Placebo.

The two treatment groups had significantly lower rates of acute kidney injury than the placebo group. In addition, the hospital mortality rate and the rate of a composite end point of death, need for renal replacement therapy, or need for mechanical ventilation were significantly lower in the treated groups. However, the number of events was small, and a beneficial effect on the death rate has not been confirmed by other studies.⁵

THE NEGATIVE TRIALS

Several studies found that NAC did not prevent contrast-induced acute kidney injury.^1,2,9

The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,¹ was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.

The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).

Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.

Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).¹

The ACT differed from the “positive” study by Marenzi et al⁸ in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.

Webb et al² found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.

Gurm et al⁹ found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.

MIXED RESULTS IN META-ANALYSES

Results from meta-analyses have been mixed,^10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.

CURRENT GUIDELINES

After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.¹²

However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).⁵

WHAT WE RECOMMEND

The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m².

In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:

• Clarify whether contrast is truly needed
• When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
• Discontinue nephrotoxic agents
• Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
• Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m²), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
• Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.^7,13

We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.

No. Using N-acetylcysteine (NAC) routinely to prevent contrast-induced acute kidney injury is not supported by the evidence at this time.^1,2 However, there is evidence to suggest using it for patients at high risk, ie, those with significant baseline renal dysfunction.^3,4

INCIDENCE AND IMPACT OF ACUTE KIDNEY INJURY

Intraarterial use of contrast is associated with a higher risk of acute kidney injury than intravenous use. Most studies of NAC for the prevention of contrast-induced acute kidney injury have focused on patients receiving contrast intraarterially. The reported rates of contrast-induced acute kidney injury also vary depending on how acute kidney injury was defined.

Although the incidence is low (1% to 2%) in patients with normal renal function, it can be as high as 25% in patients with renal impairment or a chronic condition such as diabetes or congestive heart failure, or in elderly patients.⁵

The development of acute kidney injury after percutaneous coronary intervention is associated with a longer hospital stay, a higher cost of care, and higher rates of morbidity and death.⁶

RATIONALE FOR USING N-ACETYLCYSTEINE

Contrast-induced acute kidney injury is thought to involve vasoconstriction and medullary ischemia mediated by reactive oxygen species.⁵ As an antioxidant and a scavenger of free radicals, NAC showed early promise in reducing the risk of this complication, but subsequent trials raised doubts about its efficacy. ^1,2 In clinical practice, the drug is often used to prevent acute kidney injury because it is easy to give, cheap, and has few side effects. Recently, however, there have been suggestions that giving it intravenously may be associated with adverse effects that include anaphylactoid reactions.⁷

THE POSITIVE TRIALS

Tepel et al³ performed one of the earliest trials that found that NAC prevented contrast-induced acute kidney injury. The trial included 83 patients with stable chronic kidney disease (mean serum creatinine 2.4 mg/dL) who underwent computed tomography with about 75 mL of a nonionic, low-osmolality contrast agent. Participants were randomized to receive either NAC (600 mg orally twice daily) and 0.45% saline intravenously or placebo and saline. Acute kidney injury was defined as an increase of at least 0.5 mg/dL in the serum creatinine level 48 hours after the contrast dye was given.

The rate of acute kidney injury was significantly lower in the treatment group (2% vs 21%, P = .01). None of the patients who developed acute kidney injury needed hemodialysis.

Shyu et al⁴ studied 121 patients with chronic kidney disease (mean serum creatinine 2.8 mg/dL) who underwent a coronary procedure. Patients were randomized to receive NAC 400 mg orally twice daily or placebo in addition to 0.45% saline in both groups. Two (3.3%) of the 60 patients in the treated group and 15 (24.6%) of the 61 patients in the control group had an increase in creatinine concentration greater than 0.5 mg/dL at 48 hours (P < .001).

Both of these single-center studies were limited by small sample sizes and very short follow-up. Further, the impact of the drug on important clinical outcomes such as death and progression of chronic kidney disease was not reported.

Marenzi et al⁸ randomized 354 patients undergoing coronary angioplasty as the primary treatment for acute myocardial infarction to one of three treatment groups:

• NAC in a standard dosage (a 600-mg intravenous bolus before the procedure and then 600 mg orally twice daily for 48 hours afterward)
• NAC in a high dosage (a 1,200-mg intravenous bolus and then 1,200 mg orally twice daily for 48 hours)
• Placebo.

The two treatment groups had significantly lower rates of acute kidney injury than the placebo group. In addition, the hospital mortality rate and the rate of a composite end point of death, need for renal replacement therapy, or need for mechanical ventilation were significantly lower in the treated groups. However, the number of events was small, and a beneficial effect on the death rate has not been confirmed by other studies.⁵

THE NEGATIVE TRIALS

Several studies found that NAC did not prevent contrast-induced acute kidney injury.^1,2,9

The Acetylcysteine for Contrast-induced Nephropathy Trial (ACT), published in 2011,¹ was the largest of these trials. It included 2,308 patients undergoing an angiographic procedure who had at least one risk factor for contrast-induced acute kidney injury (age > 70, renal failure, diabetes mellitus, heart failure, or hypotension). Patients were randomly assigned to receive the drug (1,200 mg by mouth) or placebo.

The incidence of contrast-induced acute kidney injury was 12.7% in the treated group and 12.7% in the control group (relative risk 1.00; 95% confidence interval 0.81–1.25; P = .97). The rate of a combined end point of death or need for dialysis at 30 days was also similar in both groups (2.2% with treatment vs 2.3% with placebo).

Importantly, only about 15% of patients had a baseline serum creatinine greater than 1.5 mg/dL. Of these, most had an estimated glomerular filtration rate between 45 and 60 mL/min. Indeed, most patients in the ACT were at low risk of contrast-induced acute kidney injury. As a result, there were low event rates and, not surprisingly, no differences between the control and treatment groups.

Subgroup analysis did not suggest a benefit of treatment in those with a baseline serum creatinine greater than 1.5 mg/dL. However, as the authors pointed out, this subgroup was small, so definitive statistically powered conclusions cannot be drawn. There was no significant difference in the primary end point among several other predefined subgroups (age > 70, female sex, diabetes).¹

The ACT differed from the “positive” study by Marenzi et al⁸ in several ways. The ACT patients were at lower risk, the coronary catheterizations were being done mainly for diagnosis rather than intervention, a lower volume of contrast dye was used (100 mL in the ACT vs 250 mL in the Marenzi study), and patients with ST-elevation myocardial infarction were excluded. Other weaknesses of the ACT include use of a baseline serum creatinine within 3 months of study entry, variations in the hydration protocol, and the use of a high-osmolar contrast agent in some patients.

Webb et al² found, in a large, randomized trial, that intravenous NAC did not prevent contrast-induced acute kidney injury. Patients with renal dysfunction (mean serum creatinine around 1.6 mg/dL) undergoing cardiac catheterization were randomly assigned to receive either NAC 500 mg or placebo immediately before the procedure. All patients first received isotonic saline 200 mL, then 1.5 mL/kg per hour for 6 hours, unless contraindicated. The study was terminated early because of a determination of futility.

Gurm et al⁹ found that a database of 90,578 consecutive patients undergoing nonemergency coronary angiography from 2006 to 2009 did not show differences in the rate of contrast-induced acute kidney injury between patients who received NAC and those who did not (5.5% vs 5.5%, P = .99). There was also no difference in the rate of death or the need for dialysis. These negative findings were consistent across many prespecified subgroups.

MIXED RESULTS IN META-ANALYSES

Results from meta-analyses have been mixed,^10,11 mainly because of study heterogeneity (eg, baseline risk, end points, dose of the drug) and publication bias. None of the previous meta-analyses included the recent negative results from the ACT.

CURRENT GUIDELINES

After the publication of the ACT, the joint guidelines of the American College of Cardiology and the American Heart Association were updated, designating NAC as class III (no benefit) and level of evidence A.¹²

However, recently published guidelines from the Kidney Disease: Improving Global Outcomes Acute Kidney Injury Working Group recommend using the drug together with intravenous isotonic crystalloids in patients at high risk of contrast-induced acute kidney injury, although the level of evidence is 2D (2 = suggestion, D = quality of evidence very low).⁵

WHAT WE RECOMMEND

The routine use of NAC to prevent contrast-induced acute kidney injury is not supported by the current evidence. However, clarification of its efficacy in high-risk patients is needed, especially those with baseline renal dysfunction and diabetes mellitus.

The Prevention of Serious Adverse Events Following Angiography (PRESERVE) study (ClinTrials.gov identifier NCT01467466) may clarify the role of this drug in a high-risk cohort using the important clinical outcomes of death, need for acute dialysis, or persistent decline in kidney function after angiography. This important study was set to begin in July 2012, with an anticipated enrollment of more than 8,000 patients who have glomerular filtration rates of 15 to 59 mL/min/1.73 m².

In the meantime, we recommend the following in patients at high risk of contrast-induced acute kidney injury:

• Clarify whether contrast is truly needed
• When possible, limit the volume of contrast, avoid repeated doses over a short time frame, and use an iso-osmolar or low-osmolar contrast agent
• Discontinue nephrotoxic agents
• Provide an evidence-based intravenous crystalloid regimen with isotonic sodium bicarbonate or saline
• Although it is not strictly evidence-based, use NAC in patients with significant baseline renal dysfunction (glomerular filtration rate < 45 mL/min/1.73 m²), multiple concurrent risk factors such as hypotension, diabetes, preexisting kidney injury, or congestive heart failure that limits the use of intravenous fluids, or who need a high volume of contrast dye
• Avoid using intravenous NAC, given its lack of benefit and risk of anaphylactoid reactions.^7,13

We do not yet have clear evidence on the optimal dosing regimen. But based on the limited data, we recommend 600 to 1,200 mg twice a day for 1 day before and 1 day after the dye is given.

As autumn arrives and thoughts turn to pumpkins, football, and Thanks-giving dinner, it is time for health systems and physicians to prepare for the upcoming influenza season. In this issue of the Journal, Drs. Jin and Mossad review some practical virology and remind us why we must continue to encourage our patients and staff to be immunized against the flu.

Last year the flu season was surprisingly mild. The infection incidence seemed to peak late in the season, a reasonable number of people got vaccinated, and the level of viral antigenic drift was low. New hybrid viral strains did appear, but apparently with low prevalence, and the avian strains did not mutate to permit efficient human-to-human infection. But the relatively benign 2011–2012 flu season should not lull us into a lackadaisical approach to offering vaccination to all of our patients.

Ever since my own encounter with the flu a number of years ago, I have been pushing the vaccine with the zeal of a telemarketer. I was pleased that the vaccine arrived early this time, but continue to be surprised by the reasons patients offer for not receiving it—some strike me as akin to “the dog ate my homework.” For example: “I got the vaccine once and I got walking pneumonia.” And the always-popular “I got the vaccine and I got the flu.” Many patients don’t think they need the vaccine because they have never gotten the flu. (To them, I relate my tale of spending a weekend lying curled up on the floor of my bedroom having chills despite a sweatsuit and blanket). Some voice the scientifically irrational but common concern that since their immune system has been weakened by medications, they don’t want to get sick from the shot. And creatively, this year several patients have told me that they heard it is too early to get the vaccine—the effect won’t last all season.

Whatever our patients’ reason for recalcitrance, we should persevere and follow the national recommendation to vaccinate all persons over the age of 6 months. The vaccine may not be perfect, but with an estimated success rate of about 60%, it is better than any alternative approach. Plus, as Drs. Jin and Mossad note in their article, there is concern about emerging strains that are resistant to available antiviral therapies—0.5 mL of prevention trumps a pound of ineffective treatment.

As autumn arrives and thoughts turn to pumpkins, football, and Thanks-giving dinner, it is time for health systems and physicians to prepare for the upcoming influenza season. In this issue of the Journal, Drs. Jin and Mossad review some practical virology and remind us why we must continue to encourage our patients and staff to be immunized against the flu.

Last year the flu season was surprisingly mild. The infection incidence seemed to peak late in the season, a reasonable number of people got vaccinated, and the level of viral antigenic drift was low. New hybrid viral strains did appear, but apparently with low prevalence, and the avian strains did not mutate to permit efficient human-to-human infection. But the relatively benign 2011–2012 flu season should not lull us into a lackadaisical approach to offering vaccination to all of our patients.

Ever since my own encounter with the flu a number of years ago, I have been pushing the vaccine with the zeal of a telemarketer. I was pleased that the vaccine arrived early this time, but continue to be surprised by the reasons patients offer for not receiving it—some strike me as akin to “the dog ate my homework.” For example: “I got the vaccine once and I got walking pneumonia.” And the always-popular “I got the vaccine and I got the flu.” Many patients don’t think they need the vaccine because they have never gotten the flu. (To them, I relate my tale of spending a weekend lying curled up on the floor of my bedroom having chills despite a sweatsuit and blanket). Some voice the scientifically irrational but common concern that since their immune system has been weakened by medications, they don’t want to get sick from the shot. And creatively, this year several patients have told me that they heard it is too early to get the vaccine—the effect won’t last all season.

Whatever our patients’ reason for recalcitrance, we should persevere and follow the national recommendation to vaccinate all persons over the age of 6 months. The vaccine may not be perfect, but with an estimated success rate of about 60%, it is better than any alternative approach. Plus, as Drs. Jin and Mossad note in their article, there is concern about emerging strains that are resistant to available antiviral therapies—0.5 mL of prevention trumps a pound of ineffective treatment.

As autumn arrives and thoughts turn to pumpkins, football, and Thanks-giving dinner, it is time for health systems and physicians to prepare for the upcoming influenza season. In this issue of the Journal, Drs. Jin and Mossad review some practical virology and remind us why we must continue to encourage our patients and staff to be immunized against the flu.

Last year the flu season was surprisingly mild. The infection incidence seemed to peak late in the season, a reasonable number of people got vaccinated, and the level of viral antigenic drift was low. New hybrid viral strains did appear, but apparently with low prevalence, and the avian strains did not mutate to permit efficient human-to-human infection. But the relatively benign 2011–2012 flu season should not lull us into a lackadaisical approach to offering vaccination to all of our patients.

Ever since my own encounter with the flu a number of years ago, I have been pushing the vaccine with the zeal of a telemarketer. I was pleased that the vaccine arrived early this time, but continue to be surprised by the reasons patients offer for not receiving it—some strike me as akin to “the dog ate my homework.” For example: “I got the vaccine once and I got walking pneumonia.” And the always-popular “I got the vaccine and I got the flu.” Many patients don’t think they need the vaccine because they have never gotten the flu. (To them, I relate my tale of spending a weekend lying curled up on the floor of my bedroom having chills despite a sweatsuit and blanket). Some voice the scientifically irrational but common concern that since their immune system has been weakened by medications, they don’t want to get sick from the shot. And creatively, this year several patients have told me that they heard it is too early to get the vaccine—the effect won’t last all season.

Whatever our patients’ reason for recalcitrance, we should persevere and follow the national recommendation to vaccinate all persons over the age of 6 months. The vaccine may not be perfect, but with an estimated success rate of about 60%, it is better than any alternative approach. Plus, as Drs. Jin and Mossad note in their article, there is concern about emerging strains that are resistant to available antiviral therapies—0.5 mL of prevention trumps a pound of ineffective treatment.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Despite our success in reducing the number of deaths from influenza in the last half-century, we must remain vigilant, since influenza still can kill.^1,2 Gene mutations and reassortment among different strains of influenza viruses pose a significant public health threat, especially in an increasingly mobile world.^3,4

In this article, we will present an update on influenza to better prepare primary care providers to prevent and treat this ongoing threat.

H3N2v: SWINE FLU DÉJÀ VU?

Outbreaks of swine flu at state and county fairs in 2012 are unprecedented and have raised concerns.

From 1990 to 2010, human infections with swine-origin influenza viruses were sporadic, and the US Centers for Disease Control and Prevention (CDC) confirmed a total of only 27 cases during this period.⁵ However, the number has been increasing since 2011: as of August 31, 2012, a total of 309 cases had been reported.⁶

Adapted from Lindstrom S, et al. Human infections with novel reassortant influenza A(H3N2)V viruses, United States, 2011. Emerg Infect Dis 2012; 18:834–837.

Analysis of viral RNA in clinical respiratory specimens from 12 cases in 2011 revealed a variant strain, called H3N2v, which is a hybrid containing genetic material from swine H3N2 and the 2009 human pandemic virus H1N1pdm09. The M gene in this new variant came from the human virus, while the other seven came from the swine virus when a host was infected with both viruses simultaneously (Figure 1). As a result of this genetic reassortment, this variant virus is genetically and antigenically different from seasonal H3N2.

Epidemiologic data showed that children under 10 years of age are especially susceptible to this new variant because they lack immunity, whereas adolescents and adults may have some immunity from cross-reacting antibodies.⁷ Most infected people had been exposed to swine in agriculture, including county and state fairs. So far, evidence suggests only limited human-to-human transmission.⁸ The clinical diagnosis of H3N2v infection relies on the epidemiologic link to exposure to pigs in the week before the onset of illness, since the symptoms are indistinguishable from those of seasonal influenza A or B infections.

In suspected cases, the clinician should notify the local or state public health department and arrange for a special test to be performed on respiratory specimens: the CDC Flu Real-Time Reverse Transcriptase Polymerase Chain Reaction Dx Panel. The reason is that a negative rapid influenza diagnostic test does not rule out influenza infection, and a positive immunofluorescence assay (direct fluorescent antibody staining) cannot specifically detect H3N2v.⁷

The current seasonal influenza vaccine will not protect against H3N2v. The isolates tested to date were susceptible to the neuraminidase inhibitor drugs oseltamivir (Tamiflu) and zanamivir (Relenza) but resistant to amantadine (Symmetrel) and rimantadine (Flumadine).⁹

Whether H3N2v will become a significant problem during the upcoming flu season largely depends on the extent of human-to-human transmission. We need to closely follow updates on this virus.

H5N1: THE LOOMING THREAT OF A BIRD FLU PANDEMIC

Since 2003, influenza A H5N1, a highly pathogenic avian virus, has broken out in Asia, Africa, and the Middle East, killing more than 100 million birds. It also has crossed the species barrier to infect humans, with an unusually high death rate.¹⁰

As of August 10, 2012, the World Health Organization had reported 608 confirmed cases of this virus infecting humans and 359 associated deaths.¹¹ Most infected patients had a history of close contact with diseased poultry, but limited, nonsustained human-to-human transmission can occur during very close, unprotected contact with a severely ill patient.¹²

Molecular studies of this virus revealed further insights into its pathogenesis. Some of the viruses isolated from humans have had mutations that allow them to bind to human-type receptors.¹³ Amino acid substitutions in the polymerase basic protein 2 (PB2) gene are associated with mammalian adaptation, virulence in mice, and viral replication at temperatures present in the upper respiratory tract.¹⁴ Furthermore, higher plasma levels of macrophage- and neutrophil-attractant chemokines and both inflammatory and anti-inflammatory cytokines (interleukin 6, interleukin 10, and interferon gamma) have been observed in patients with H5N1 infection, especially in fatal cases.¹⁵ A recent study found that H5N1 causes significant perturbations in the host’s protein synthesis machinery as early as 1 hour after infection, suggesting that this virus gains an early advantage in replication by using the host’s proteome.¹⁶ The effects of unrestrained viral infection and inflammatory responses induced by H5N1 infection certainly contributed to the primary pathologic process and to death in human fulminant viral pneumonia. The up-regulation of inflammatory cytokines in these infections contributes to the development of sepsis syndrome, acute respiratory distress syndrome, and an increased risk of death, particularly in pregnant women.

Most experts predict that pandemic influenza is probably inevitable.¹⁷ If avian H5N1 and a human influenza virus swap genes in a host such as swine, the new hybrid virus will contain genetic material from both strains and will have surface antigens that the human immune system does not recognize. This could lead to a devastating avian flu pandemic with a very high death rate.¹⁸

An inactivated whole-virus H5N1 vaccine has been developed by the US government to prevent H5N1 infection.¹⁹ For treatment, the neuraminidase inhibitor oseltamivir is the drug of choice.¹⁰ Oseltamivir resistance remains uncommon. ²⁰ Fortunately, zanamivir is still active against oseltamivir-resistant variants that have N1 neuraminidase mutations.²¹

THE 2009 H1N1 PANDEMIC KILLED MORE PEOPLE THAN WE THOUGHT

The fourth flu pandemic of the last 100 years occurred in 2009. (The other three were in 1918, 1957, and 1968.) It was caused by a novel strain, H1N1 of swine origin.²² This 2009 pandemic strain had six genes from the North American swine flu virus and two genes from the Eurasian swine flu virus. The pandemic affected more children and young people (who completely lacked prior immunity to this virus), while older people, who had cross-reacting antibodies, were less affected.

Worldwide, 18,500 people were reported initially to have died in this pandemic from April 2009 to August 2010.²³ However, a recent modeling study estimated the number of respiratory and cardiovascular deaths associated with this pandemic at 283,500—about 15 times higher.²⁴

AN AUSTRALIAN OUTBREAK OF OSELTAMIVIR-RESISTANT H1N1

Many strains of influenza A virus are resistant to amantadine and rimantadine, owing to amino acid substitutions in the M2 protein.²⁵ In contrast, resistance to the neuraminidase inhibitors oseltamivir and zanamivir has been reported only occasionally.²⁶

Until recently, most oseltamivir-resistant viruses were isolated from immunocompromised hosts treated with oseltamivir.^27–29 All the resistant viral isolates contained an amino acid substitution of histidine (H) to tyrosine (Y) at position 275 of the viral neuraminidase.³⁰ In general, transmission of these oseltamivir-resistant strains has been limited and unsustained, but it can occur in settings of close contact, such as hospitals, school camps, or long train rides.^31–35 Oseltamivir-resistant strains were detected in fewer than 1% of isolates from the community during the 2010–2011 influenza season in the Northern Hemisphere and most countries in the Southern Hemisphere during the 2011 flu season.^36,37

However, an outbreak of oseltamivir-resistant H1N1 occurred in Australia between June and August 2011.³⁸ In that outbreak, the isolates from only 15% of the 191 people infected with this virus, designated H1N1pdm09, carried the H257Y neuraminidase substitution.³⁹ Further, only 1 of the 191 patients had received oseltamivir before. More importantly, genetic analysis suggested that the infection spread from a single source.

This was the first reported sustained community transmission of oseltamivir-resistant H1N1 in a community previously unexposed to this drug. As such, it is a warning sign of the potential for a widespread outbreak of this virus. In the event of such an outbreak, inhaled zanamivir would be the only effective treatment available.

THIS SEASON’S TRIVALENT INACTIVATED VACCINE

The trivalent inactivated influenza vaccine for the 2012–2013 season contains three inactivated viruses⁴⁰:

• Influenza A/California/7/2009(H1N1)-like
• Influenza A/Victoria/361/2011(H3N2)-like
• Influenza B/Wisconsin/1/2010-like (Yamagata lineage).

The influenza A H3N2 and influenza B antigens are different from those in the 2011–2012 vaccine.⁴¹ The H1N1 strain is derived from H1N1pdm09, which had been contained in the 2011–2012 seasonal vaccine. This vaccine will not protect against H3N2v or H5N1.

LATEST RECOMMENDATIONS ON VACCINATION

Since 2010, the Advisory Committee on Immunization Practices (ACIP) has recommended annual flu shots for all people older than 6 months in the United States.⁴²

Vaccination should be done before the onset of influenza activity in the community as soon as vaccine is available for the season. However, one should continue offering vaccination throughout the influenza season as long as influenza viruses are circulating in the community.

Children ages 6 months through 8 years not previously vaccinated against influenza should receive two doses of influenza vaccine at least 4 weeks apart for an optimal immune response. The US-licensed Afluria vaccine (CSL Biotherapies, King of Prussia, PA), a trivalent inactivated vaccine, is not recommended for children under 9 years of age because of concern about febrile seizures.^43,44

There is no contraindication to giving inactivated trivalent influenza vaccine to immunosuppressed people.

The live-attenuated influenza vaccine is indicated only for healthy, nonpregnant people age 2 through 49 years and not for people who care for severely immunosuppressed patients who require a protective environment.

For indications for and details about the different available influenza vaccines, see the ACIP’s current recommendations (www.cdc.gov/mmwr/pdf/wk/mm6132.pdf).⁴⁰

Updated recommendations for people allergic to eggs

All currently available influenza vaccines are made by growing the virus in chicken eggs. Therefore, severe allergic and anaphylactic reactions can occur in people with egg allergy. The ACIP recommends that if people experienced only hives after egg exposure, they should still receive the trivalent inactivated vaccine. Recently, the ACIP reviewed data from the Vaccine Adverse Event Reporting System⁴⁵ and issued the following recommendations for the 2012–2013 influenza season⁴⁰:

• In people who are allergic to eggs, only trivalent inactivated vaccine should be used, not the live-attenuated vaccine, because of lack of data for use of the latter in this group.
• Vaccine should be given by providers who are familiar with the signs of egg allergy.
• Patients with a history of egg allergy who have experienced only hives after exposure to eggs should be observed for a minimum of 30 minutes after vaccination.
• Patients who experience lightheadedness, respiratory distress, angioedema, or recurrent emesis or who require epinephrine or emergency medical attention after egg exposure should be referred before vaccination to a physician who has expertise in managing allergic conditions.
• Tolerance to egg-containing foods does not exclude the possibility of egg allergy. Egg allergy can be confirmed by a consistent medical history of adverse reactions to eggs or egg-containing foods, plus skin or blood testing for immunoglobulin E antibodies to egg proteins.

A high-dose vaccine is available for people 65 years and older

The rates of hospitalization and death due to seasonal flu in elderly people have increased significantly in the last 20 years despite rising rates of vaccination.^46–48 This is largely due to lower serologic response rates and vaccine efficacy in older adults with weaker immune systems.

Several studies have shown that the development of protective antibody titers depends on the dose of antigen.^49–53 A randomized, controlled clinical trial compared the immunogenicity of a high-dose vaccine and a standard-dose vaccine in older adults and found that the level of antibody response was significantly higher with the high-dose vaccine, and that the rate of adverse reactions was the same.⁵⁴

In December 2009, the US Food and Drug Administration (FDA) licensed a new trivalent inactivated influenza vaccine with high doses of hemagglutinin antigens for adults over the age of 65.⁵⁵ Postlicensure safety surveillance in 2010 revealed no serious safety concerns.⁵⁶

At present, the ACIP expresses no preference for standard-dose or high-dose vaccine for adults 65 years of age and older.⁴⁰ Importantly, if only the standard-dose vaccine is at hand, the opportunity for influenza vaccination should not be missed with the intention of giving high-dose vaccine at a later date.

A NEW QUADRIVALENT LIVE-ATTENUATED INFLUENZA VACCINE FOR THE 2013–2014 SEASON

In February 2012, the FDA approved the first quadrivalent live-attenuated influenza vaccine, which is expected to replace the currently available trivalent live-attenuated influenza vaccine in the 2013–2014 flu season. The quadrivalent vaccine will include both lineages of the circulating influenza B viruses (the Victoria and Yamagata lineages). The reasons for this inclusion is the difficulty in predicting which of these viruses will predominate in any given season, and the limited cross-resistance by immunization against one of the lineages.

A recent analysis⁵⁷ estimated that such a vaccine is likely to further reduce influenza cases, related hospitalizations, and deaths compared with the current trivalent vaccine. Like the current trivalent live-attenuated vaccine, the quadrivalent vaccine is inhaled.

EVOLVING VACCINATION POLICY IN HEALTH CARE WORKERS

Starting in January 2013, the Centers for Medicare and Medicaid Services will require hospitals to report how many of their health care workers are vaccinated. These rates will be publicly reported as a measure of hospital quality. This has fueled the ongoing debate about mandating influenza vaccination for health care workers. Studies have shown that the most important factors in increasing influenza vaccination rates among health care workers are requiring vaccination as a condition for employment and making vaccination available on-site, for more than 1 day, at no cost to the worker.⁵⁸

As an alternative, some institutions have implemented a “shot-or-mask” policy whereby a health care worker who elects not to be vaccinated because of medical or religious reasons would be asked to wear a mask during all faceto-face encounters with patients.

NEW ANTIVIRAL DRUGS ON THE HORIZON

The emergence of oseltamivir-resistant strains in recent years caused a great deal of concern in public health regarding the potential for outbreaks of drug-resistant influenza.^{34,35,59–61}

A recent Asian randomized clinical trial reported the efficacy of a long-acting neuraminidase inhibitor, laninamivir octanoate, in the treatment of seasonal influenza.⁶² This study showed that a single inhalation of this drug is effective in treating seasonal influenza, including that caused by oseltamivir-resistant strains in adults. Laninamivir is currently approved in Japan.

CHALLENGES IN PREVENTING AND TREATING INFLUENZA

Despite the great advances that we have made in preventing and treating influenza in the last half-century, we still face many challenges. Each year in the United States, influenza infection results in an estimated 31 million outpatient visits, 226,000 hospital admissions, and 36,000 deaths.⁴²

Antigenic drift and shift. Influenza viruses circulating among animals and humans vary genetically from season to season and within seasons. As a result of this changing viral antigenicity, the virus can evade the human immune system, causing widespread outbreaks.

One of the unique and most remarkable features of influenza virus is the antigenic variation: antigenic drift and antigenic shift. Antigenic drift is the relatively minor antigenic changes that occur frequently within an influenza subtype, typically resulting from genetic mutation of viral RNA coding for hemagglutinin or neuraminidase. This causes annual regional epidemics. In contrast, antigenic shift is the result of genetic material reassortment: the emerging of new viral RNA from different strains of different species. This often leads to global pandemics.

Therefore, it is challenging to accurately predict the antigenic makeup of influenza viruses for each season and to include new emerging antigens in the vaccine production, as we are facing a moving target. We prepare influenza vaccines each season based on past experience.⁶³

Vaccination rates have hit a plateau of 60% to 70% in adults since the 1990s, in spite of greater vaccine supply and recommendations that all adults, regardless of underlying disease, be vaccinated annually.⁶⁴ Similarly, only 51% of children age 6 months to 17 years were vaccinated in the 2010–2011 season.⁶⁵ And vaccination rates are even lower in low-income populations.^66,67

The emergence of oseltamivir-resistant strains in recent years, not only in people exposed to oseltamivir but also in those who haven’t been exposed to this drug, with sustained transmission, certainly raises the possibility of a more difficult epidemic to control.³⁸

Global travel, global infection. Our last H1N1 pandemic in 2009 was an example of how easily the influenza virus can spread rapidly in today’s highly mobile global society.²²

What we must do

As primary health care providers, we must closely monitor the community outbreak and the emergence of drug-resistant strains and strongly recommend vaccination for all patients older than 6 months, since timely vaccination is the cornerstone of influenza prevention. Although many have questioned the efficacy of influenza vaccination, a recent meta-analysis showed a 59% pooled efficacy of the trivalent inactivated vaccine in adults age 18 to 65 years in preventing virologically confirmed influenza, and 83% pooled efficacy of the live-attenuated influenza vaccine in children age 6 months to 7 years.⁶⁸ Novel approaches for vaccination reminders, such as text messaging⁶⁹ in addition to traditional mail or telephone reminders, can improve vaccination compliance in today’s highly mobile world that is more than ever connected.

With the lessons learned from four pandemics in the last century, updated recommendations for prevention, and adequate vaccine supply, we should be ready to face the challenge of another flu season.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Hormone therapy may reduce the risk of Alzheimer’s disease for women who take the treatment at a time near menopause, but if hormone therapy is begun after menopause it may not reduce such risk, according to a study in the October 30 Neurology. Researchers followed 1,768 women who were part of a population-based study and found that 176 women developed Alzheimer’s disease between 1995 and 2006. Women who used any type of hormone therapy within five years of menopause had a 30% less risk of Alzheimer’s disease. However, those who began hormone therapy five or more years after menopause did not have a reduced disease risk. In addition, women who began opposed compounds in the three years prior to the baseline assessment had an increased risk of Alzheimer’s disease. The association of hormone therapy use and risk of Alzheimer’s disease may depend on the timing of use and deserves further study, the investigators concluded.

Engaging in physical activity may protect older adults from brain atrophy and white matter lesions, researchers reported in the October 23 Neurology. The study examined self-reported leisure and physical activity at age 70 among a sample of 691 adults. At age 73, participants were assessed for structural brain biomarkers, and the investigators found that a higher level of physical activity was significantly associated with higher fractional anisotropy, less atrophy, lower white matter load, and larger gray and normal-appearing white matter volumes. These associations remained significant after adjustments for age, social class, and health status. The researchers noted that although their results support the role of physical activity as a potential neuroprotective factor, “the direction of causation is unclear from this observational study.”

Poor physical performance is associated with greater odds of dementia in persons age 90 or older, according to a study published in the online October 22 Archives of Neurology. The 629 participants (72.5% women) were from The 90+ Study, a population-based, longitudinal, epidemiologic study of aging and dementia. Participants’ mean age was 94, and all-cause dementia was the main outcome measure. Measures of physical performance included a 4-m walk, five chair stands, standing balance, and grip strength. Researchers found that poor physical performance in all measures was significantly associated with an increased risk of dementia. “Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition,” the investigators concluded. “Additional research is necessary to determine the temporal relationship between poor physical activity and cognitive dysfunction.”

Exposure to selective serotonin reuptake inhibitors (SSRI) is associated with an increased risk of intracerebral and intracranial hemorrhage, though the absolute risk of those events is low, according to a study published in the October 30 Neurology. In this meta-analysis, investigators searched for controlled observational studies that compared SSRI users with a control group not receiving SSRIs. The researchers found that intracranial and intracerebral hemorrhage were related to SSRI exposure in unadjusted and adjusted analyses. A subset of five studies showed that SSRI exposure combined with oral anticoagulants was linked with an increased risk of bleeding, compared with use of oral anticoagulants alone. “When all studies were analyzed together, increased risk was seen across cohort studies, case-control studies, and case-crossover studies,” the study authors noted.

The herpes zoster vaccine is effective in preventing herpes zoster in older adults, according to research published in the online October 17 Cochrane Database of Systematic Reviews. The study authors conducted a meta-analysis of eight randomized controlled trials of adults who had a mean age older than 60. The trials had a total of 52,269 participants. Patients who received the vaccine had fewer confirmed cases of herpes zoster than those who received placebo. Analysis of age groups showed that vaccine benefits were greatest for patients ages 60 to 69, as well as for those 70 and older. However, persons ages 60 to 69 experienced more frequent side effects than did persons 70 and older. “In general, zoster vaccine is well tolerated; it produces few systemic adverse events and injection site adverse effects of mild to moderate intensity,” wrote the researchers.

Strokes are increasingly occurring in younger patients, researchers reported in the October 23 Neurology. Between 1993 and 1994 and between 1999 and 2005, strokes were recorded in an estimated population of 1.3 million. The investigators used a mixed-model approach to test for differences in age trends over time, and they found that the mean age at stroke decreased by a significant amount, from 71.2 years in 1993/1994 to 69.2 years in 2005. Furthermore, the proportion of all strokes in persons younger than 55 increased from 12.9% in 1993 to 18.6% in 2005. “This is of great public health significance because strokes in younger patients carry the potential for greater lifetime burden of disability and because some potential contributors identified for this trend are modifiable,” the researchers concluded.

The FDA has approved perampanel (Fycompa), an AMPA receptor agonist, as an adjunctive treatment for partial-onset seizures with or without secondarily generalized seizures in patients ages 12 and older with epilepsy. Perampanel is a novel agent that reduces neuronal hyperexcitation associated with seizures by inhibiting glutamate activity at postsynaptic AMPA receptors, and it is the first antiepileptic agent approved in the US to work in this manner. In three phase III, global, randomized, double-blind, placebo-controlled studies (1,480 patients), researchers concluded that perampanel significantly reduced seizure frequency in patients with partial-onset seizures with or without secondary generalized seizures. Patients experienced adverse events that included dizziness, somnolence, fatigue, irritability, falls, nausea, ataxia, balance disorder, gait disturbance, vertigo, and weight gain.

Persons who survive an ischemic stroke and continue smoking have a greater risk of heart attack, death, or another stroke, compared with those who have never smoked, researchers reported in the online October 25 Stroke. The study included 1,589 patients who experienced a first or recurrent ischemic stroke between 1996 and 1999. The investigators tracked the cohort for 10 years and found that patients who smoked when they had a stroke were 30% more likely to have a poor outcome and that current smokers who survived the first 28 days after a stroke had a 42% higher risk of poor outcome. In addition, former smokers had an 18% higher risk of poor outcomes. The authors also noted that smoking had the greatest effect on younger male patients, particularly those from a disadvantaged background.

For every 400 to 500 persons with an intermediate risk of cardiovascular disease who undergo screening for C-reactive protein or fibrinogen, one additional event in a period of 10 years may be prevented, researchers reported in the October 4 New England Journal of Medicine. In a meta-analysis of 52 prospective studies of persons without a history of cardiovascular disease, the investigators sought to determine whether assessing C-reactive protein or fibrinogen in addition to conventional cardiovascular risk factors leads to better prediction of cardiovascular risk.
Of 100,000 adults ages 40 and older, 15,025 would be classified as intermediate risk using conventional factors, and 13,199 would remain if statin therapy were initiated in accordance with guidelines. “Additional targeted assessment of C-reactive protein or fibrinogen levels in the 13,199 remaining participants at intermediate risk could help prevent approximately 30 additional cardiovascular events over the course of 10 years,” the researchers stated.

Extradural motor cortex stimulation for patients with Parkinson’s disease is a safe procedure that leads to moderate improvement of motor symptoms and in quality of life, according to a study published in the October Neurosurgery. Researchers assessed the safety and efficacy of one year of unilateral extradural motor cortex stimulation in nine patients with Parkinson’s disease. At baseline, participants were evaluated with the Unified Parkinson’s Disease Rating Scale and the Parkinson’s Disease Quality of Life Questionnaire. Quality of life scores increased at months three, six, and 12, and disease scores decreased from baseline during the year. Furthermore, bilateral motor effects were observed after three to four weeks. No surgical complications, adverse events, or cognitive and behavioral changes were observed, the study authors said.

The use of beta blockers is not associated with a lower risk of composite cardiovascular events in patients with either coronary artery disease (CAD) risk factors only, known prior myocardial infarction, or known CAD without myocardial infarction, according to an investigation published in the October 3 JAMA. In this longitudinal, observational study, 44,708 patients were categorized into three cohorts— 14,043 patients with known prior myocardial infarction, 12,012 patients with known CAD but without myocardial infarction, and 18,653 patients with CAD risk factors only. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. For all outcomes tested, investigators found that event rates were not significantly different in patients with beta-blocker use, compared with those without beta-blocker use, even among those in the prior myocardial infarction cohort.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.

Maggie, 42, presents to the emergency department with chronic intermittent abdominal pain and bloating with constipation and occasional diarrhea. She denies fever, chills, nausea, vomiting, melana, bright red blood per rectum, or changes in stool caliper, and she says she otherwise feels well. 

Relevant lab and study results include: a comprehensive metabolic panel, complete blood count with differential, beta hCG (human chorionic gonadotropin), urinalysis, and amylase and lipase, all within normal limits; pregnancy test, negative; abdominal x-ray, within normal limits except increased stool in distal colon; and abdominal CT, 2.3-cm right adrenal mass and a Hounsfield measurement of 4 units.

Maggie has a right adrenal incidentaloma (incidentally discovered adenoma that was not in the differential diagnosis). Such findings have become all too often the case, due to the immediate access to and overutilization of high-resolution CT, MRI, and ultrasound. We are now seeing a significantly increased number of incidental adrenal lesions/masses discovered on images not intended to look for adrenal-related diseases (eg, Cushing syndrome, pheochromocytomas, and aldosterone-producing adenomas).

Q: How common are adrenal adenomas, and what must I consider?

Incidental adrenal adenomas are found on 4.4% of abdominal CTs, and in one autopsy series were discovered in 8.7%. Prevalence increases with age, with occurrence of < 1% in patients younger than 30 and about 7% for patients 70 or older.

Evaluation is based on two concerns: First, is the adrenal mass benign or malignant? Second, is the mass secretory or nonsecretory (non-hormone secreting) in nature?

The fortunate news about adrenal incidentalomas is that 80% are benign and nonsecretory, which provides immediate reassuring news to the patient. Examples of benign adrenal masses are: adenoma, lipoma, cyst, ganglioneuroma, hematoma, and infection (eg, tuberculosis, fungal).

The other encouraging statistic is that only 1:4,000 adrenal incidentalomas are malignant. Examples of malignant adrenal masses are: adrenocortical carcinoma, metastatic neoplasm, lymphoma, and malignant pheochromocytoma.

Q: Does adrenal adenoma size matter?

 Yes, the larger the size of the adenoma, the higher the association with malignancy. The guide below (based on CT findings) shows not only malignancy potential as it relates to size, but also the importance of Hounsfield units and when surgical intervention is recommended.

Imaging (CT scan)

< 4 cm: homogeneous mass with smooth borders and < 10 Hounsfield units; suggests benign mass (likelihood of malignancy, about 2%)

4 to 6 cm: follow closely, consider surgery (likelihood of malignancy, about 6%)

> 6 cm: surgery indicated (likelihood of malignancy, about 25%)

Some providers and patients inquire whether it is helpful or necessary to biopsy. It is generally not advisable to biopsy, especially if the findings are favorable for benign nonsecretory masses, since there is a high false-negative rate. An indication for biopsy is if the patient has a history of extra-adrenal malignancy; this will distinguish recurrence or metastatic disease from a benign mass. A final proviso: If biopsy is performed, make sure the adrenal mass is not a pheochromocytoma, as biopsy of a hormone-secreting neoplasm can lead to a hypertensive emergency.

Q: How do I determine whether the mass is hormone-secreting?

Although 80% are nonsecretory, you must still maintain a high index of suspicion so as not to miss a potentially problematic and fully treatable adenoma. A thorough history is essential in screening for hormonal excess arising from adrenal adenomas, since the signs and symptoms can be insidious. The three hormones secreted by adrenal adenomas are cortisol, aldosterone, and catecholamines (seen in Cushing syndrome, aldosterone-producing adenoma [APA], and pheochromocytoma, respectively).

It is important to note that Cushing syndrome has an insidious onset and can be easily missed. Hyperaldosteronism presents with hypertension (requiring several medications) and commonly hypokalemia. And pheochromocytoma can be “written off as” anxiety disorder, panic attack, or even hypoglycemia symptoms (especially if patients are treated for diabetes with agents that cause hypoglycemia). To help in your differential diagnosis of secretory adenomas, know that APA accounts for only 1%, and therefore the majority will secrete cortisol and (far less likely) catecholamines.

Q: What is the appropriate laboratory work-up?

The best simple screening test for hypercortisolemia is a 1-mg overnight dexamethasone suppression test. If this value is increased to ≥ 3 µg/dL, it should be followed up with a more sensitive test (a 24-hour urine for creatinine and free cortisol) to further assess for hypercortisolemia.

Patients thought to have a potential pheochromocytoma should undergo measurement of plasma fractionated metanephrines and normetanephrines or 24-hour urine for total metanephrines and fractionated catecholamines.

Finally, for patients with hypokalemia and hypertension or refractory hypertension requiring multiple (> 3) antihypertensive medications, plasma renin activity (PRA) and plasma aldosterone concentration (PAC) should be obtained. A low PRA and a PAC > 15 ng/dL, along with a PAC/PRA ratio of > 20, is highly suggestive of an APA.

Q: What is the treatment and follow-up?

Here is a quick reference guide regarding surgical treatment and medical follow-up and surveillance:

• Adrenalectomy (pheochromocytoma, APA, Cushing syndrome): for masses 4 to 6 cm, consider surgery, especially if > 10 Hounsfield units; for masses > 6 cm, there is an increased risk for malignancy and surgery is required.

• Follow-up for low-suspicion, nonsecretory masses: abdominal CT 3 to 6 months after the initial scan, then annually for 1 to 2 years; hormonal evaluation and follow-up annually for 5 years, to evaluate for signs and symptoms of hormonal excess.

SUGGESTED READING
American Association of Clinical Endocrinologists/American Association of Endocrine Surgeons Medical Guidelines for the Management of Adrenal Incidentalomas. Endocr Pract. 2009;15(Suppl 1).

Management of the Clinically Inapparent Adrenal Mass (Incidentaloma). NIH State-of-the-Science Conference Statement; February 4-6, 2002.

Slawik M, Reincke M. Adrenal incidentalomas (Chapter 20). EndoText.com. www.endotext.org/adrenal/adrenal20/adrenal20.htm. Accessed October 12, 2012.

Fitzgerald PA, Goldfien A. Adrenal medulla. In: Greenspan F, Gardner D, eds. Basic and Clinical Endocrinology. 7th ed. McGraw-Hill: 2003;453-473.

The Washington Manual Endocrinology Specialty Consult. 2005;57-61, 71-84.

Endocrine Secrets. 4th ed. 2005;197-204, 241-252, 257-265.

Cleveland Clinic Endocrine & Metabolism Board Review. www.clevelandclinicmeded.com/live/courses/ann/endoreview/default.asp. Accessed October 12, 2012.