Applied Evidence

CASE  Shane O, a 16-year-old on his high school wrestling team, presents with red, scaly, well-defined plaques on his forehead. The coach spotted the lesions and removed him from play. The patient reports that he’s training for a competitive event and is anxious to return to practice.

You take skin scrapings for a potassium chloride (KOH) test, which is negative, and for a dermatophyte culture. The culture will take 7 to 14 days, however. What should you do in the meantime?

Chances are you’ve cared for countless patients with cutaneous infections. But when the individual who’s infected participates in a team sport, it’s a game changer. In addition to treating the infection, it is necessary to take steps to prevent an outbreak among other players.

More than half of the infections incurred by athletes are cutaneous lesions¹—not surprising considering the numerous opportunities sports play provides for common skin conditions to spread. Predisposing factors, in addition to skin-to-skin contact and abrasions, include shared close quarters (eg, locker rooms and showers), shared sports equipment, and poor hygiene.^2-5

For a competitive athlete like Shane, the loss of practice may be the most worrisome aspect of a cutaneous infection. From a medical perspective, there are far more pressing concerns. Contact with a teammate’s active herpes simplex lesion (HSV-1), for example, could result in a lifelong infection, and a methicillin-resistant Staphylococcus aureus (MRSA) infection can be a source of significant morbidity for anyone who is infected. There is also the potential for a public health hazard. In addition to prompt, accurate diagnosis, a treatment approach that considers both the need to protect others and the importance of getting the player back in the game as soon as it is safe to do so is critical.

Athlete’s foot, ringworm, jock itch—fungal infections are easily spread

Fungal infections are a common cause of skin disease in athletes. Dermatophytes can spread from fomites such as mats, floors, laundry items, and shared clothing, combs, and brushes, as well as in swimming pools and from direct contact with carriers.²

National Collegiate Athletic Association (NCAA) data show that fungi account for 22% of the skin infections that athletes involved in competitive wrestling develop.⁶ Sports with skin-to-skin contact, such as wrestling, pose the greatest risk. Fungal infection is the No. 1 reason cited for missing wrestling practice, according to the NCAA.⁶

Fungal infections are not just a wrestler’s problem, however. Tinea pedis (athlete’s foot) is common among runners and swimmers, and tinea corporis (ringworm), in prepubertal athletes.⁵

Fungal skin infections are caused by 3 dermatophyte genera: Trichophyton, Epidermophyton, and Microsporum. In the United States, T rubrum is responsible for most cutaneous fungal infections, including tinea corporis, tinea unguium (nail), tinea pedis, and tinea cruris (commonly called jock itch).⁵

Tinea corporis (Figure 1) may present with areas of central hypopigmentation that give it a ring-like appearance. This type of fungal infection also includes tinea gladiatorum, so named for its high prevalence among wrestlers and characterized by well-defined, red scaling plaques on the head, neck, and upper extremities, often with an irregular border.⁷

Tinea pedis typically develops in the web spaces of the toes, with skin maceration often accompanied by thick scaling or desquamation. Tinea cruris presents as erythematous plaques in the pubic and inguinal areas.⁸

Onychomycosis can affect the nail plate, resulting in thickening, change in color, and alteration of nail texture.⁹

T tonsurans is the dominant pathogen for tinea capitis—fungal infection of the scalp,⁵ which can be inflammatory or noninflammatory. The noninflammatory form may present with gray-patch scaling, seborrheic dermatitis-like scale, hair thinning without significant scaling, or patches of “black-dot” alopecia. Inflammatory forms of tinea capitis may present as anything from localized pustules to widespread abscesses, or may remain in an asymptomatic carrier state.¹⁰

When to confirm a clinical diagnosis
Fungal infections can often be diagnosed based on clinical presentation, but confirmation is important when systemic therapy is required—for tinea capitis, in particular. The traditional method is an examination of skin scraped from the edge of a lesion and treated with 10% to 20% KOH, gently heated, and viewed under light microscopy.⁸

Alternatively, fungal infection can be confirmed retrospectively, by culture on selective media. Dermatophyte test medium (DTM) is convenient and easy to use, and usually reveals fungal growth within 7 days. A newer selective media, DBM (bromothymol blue is the pH indicator) is a modification of the DTM formulation that may offer earlier and more accurate identification of fungi.¹¹

Keep in mind, however, that a negative KOH preparation or culture does not necessarily rule out a fungal infection.¹² Polymerase chain reaction (PCR), an emerging technology performed on a specimen swab, has a greater sensitivity than either KOH or culture in identifying fungal pathogens. PCR can identify the presence of fungi even if the dermatophyte growth on culture is hidden by the overgrowth of Candida albicans.¹³

In patients with onychomycosis, dermatophytes may be exceedingly difficult to isolate on either KOH or culture medium, and the results of these tests often conflict. Onychomycosis is best diagnosed histopathologically by examination of periodic acid-Schiff-stained nail clippings.¹⁴

Topical or systemic treatment?
Treatment of dermatophyte infections is site-dependent. For simple epidermal infection, other than scalp or nail, topical therapy is first-line treatment. In a recent Cochrane review, topical allylamines, azoles, butenafine, ciclopirox olamine, tolciclate, and tolnaftate were all found to be effective. However, the allylamines had the greatest efficacy, which increased with duration of use.¹⁵

Topical terbinafine was found to be effective in as little as one to 3 days of treat-ment for tinea pedis. Mycological cure with near total symptom elimination at 28 days was reported in 61% and 78% of those receiving topical treatment for one day and 3 days, respectively; the difference was not statistically significant.¹⁶

 Use this topical when bacterial infection complicates care. Although 1% naftifine gel requires a prescription and costs more than many other topicals, its advantages may offset the higher costs. Once-daily naftifine gel is as effective as other allylamines that require twice-daily application, and has both antihistamine and corticosteroid effects to offset inflammation. What’s more, naftifine is active against both gram-positive and gram-negative bacteria; therefore, it should be considered in instances in which bacterial superinfection is a possibility, as suggested by a high degree of inflammation with bright red and yellow crusts.^17,18

Scalp, nail, and complicated foot infections typically require systemic therapy. Griseofulvin is the most widely used systemic treatment for tinea capitis.¹⁰ While terbinafine requires a shorter duration of treatment (4-6 weeks) and is similar in efficacy—except in cases of microsporum infection of the scalp, for which griseofulvin has been found to have higher cure rates¹⁹—it is often not used because it has a higher cost.

Tinea pedis and onychomycosis often occur concurrently, making eradication difficult and increasing the potential for reinfection. For recalcitrant cases of onychomycosis, a combination of topical and systemic therapy may be required, along with trimming, debridement, nail abrasion, and partial nail avulsion.²⁰ A recent study found laser therapy to be a promising treatment for onychomycosis, but randomized controlled trials have yet to be done.²¹

NCAA and NFHS rules. Both the NCAA and the National Federation of State
High School Associations (NFHS) mandate that a wrestler with tinea corporis receive a minimum of 72 hours of topical therapy prior to participation; 14 days of systemic antifungal therapy are required for athletes with tinea capitis.^22,23 The NCAA allows wrestlers to be cleared to participate on an individual basis, at the discretion of the examining physician or certified trainer.

The degree of disease involvement, the activity of disease as judged by KOH preparation, or the review of therapeutic regimen and the ability to properly cover lesions securely are taken into account.²² Proper coverage could consist of a semiocclusive or occlusive dressing such as film, foam, hydrogel, or hydrocolloid covered with stretch tape.²⁴ Similarly, the NFHS permits a wrestler to participate once the lesion is deemed to be no longer contagious and can be covered with a bio-occlusive dressing.²³

Prophylactic oral fluconazole, given in a 3-day regimen twice during the season to all team members, has been shown to be successful in reducing a high burden of tinea gladiatorum in a high school wrestling setting.²⁵

CASE You presumptively diagnose tinea gladiatorum based on both the presentation and the patient’s history as a wrestler and prescribe topical terbinafine therapy twice daily. You schedule a follow-up appointment in 3 days, and tell Shane he must refrain from wrestling practice at least until then.

Staph and strep infections

Bacterial skin infections are also common among athletes, with S aureus reported to be responsible for 22% of infectious disease outbreaks.²⁶ Here, too, infections occur primarily in contact sports such as football, rugby, and soccer, as well as wrestling.

There are several types of bacterial dermatoses: impetigo, folliculitis, furuncles, carbuncles, abscesses, and cellulitis. Most are caused by group A beta-hemolytic Streptococcus or S aureus and can be easily treated, but identification of the pathogen is needed to facilitate healing and a safe return to play (TABLE 1).²⁷

When to suspect CA-MRSA
Community-acquired methicillin-resistant S aureus (CA-MRSA) was first reported in an athletic population in the 1960s, and in 1993 the first documented outbreak of CA-MRSA in a sports setting—involving 6 high school wrestlers from Vermont—was reported.²⁸

The athlete with CA-MRSA usually presents with a painful, purulent, swollen, red abscess-like lesion, sometimes described as (or mistaken for) a spider bite. The patient may also develop fever, fatigue, and malaise. Culturing the wound for identification of the bacterium and for susceptibility to antibiotic therapy is needed for a definitive diagnosis of CA-MRSA.

Is incision and drainage sufficient treatment? The standard treatment for uncomplicated CA-MRSA lesions is incision and drainage. Several studies have found this to be adequate for simple lesions.²⁹ Others have reported increased treatment failure with simple incision and drainage and shown that the addition of antimicrobial therapy helps decrease further tissue damage and morbidity.²⁹

With no clear consensus as to when and whether to add oral antibiotic therapy after incision and drainage of a CA-MRSA lesion, decisions should be based on the severity of the lesion, the presence or absence of systemic symptoms, and the potential risk of bacterial spread to other team members.

Choosing an antimicrobial agent. Antimicrobial treatment should be guided by culture and sensitivity results, as well as the regional incidence of CA-MRSA. Empiric treatments for CA-MRSA are trimethoprim-sulfamethoxazole, doxycycline, and clindamycin, taken for 7 to 14 days. If you’re considering the use of clindamycin and there is known resistance to erythromycin from antimicrobial sensitivities, a double disc diffusion (D-test) should be ordered to detect inducible macrolide resistance that can occur in some strains of CA-MRSA.^29,30

Fluoroquinolones and certain macrolides should not be used, due to resistance to these antibiotics.¹

Topicals for superficial lesions. Topical antibiotic therapy with mupirocin or retapamulin should be reserved for superficial CA-MRSA lesions, such as impetigo.^31,32 Caution must be used when mupirocin is prescribed, however, due to recent studies showing increasing resistance to mupirocin, especially when used for nasal decolonizing purposes.²⁹

Once treatment is initiated, see the athlete every 2 to 3 days. Resolution usually occurs in 10 to 14 days. The athlete can return to play after 72 hours of treatment, however, provided there is evidence of clinical improvement, no further drainage from the infected lesion, and no new lesions have developed.^1,30

Containing CA-MRSA. Mass nasal decolonization—applying topical mupirocin in the nares of infected athletes as well as their teammates—has been attempted to prevent the spread of CA-MRSA. But there is no evidence to suggest that mupirocin or any other intranasal antimicrobial is effective in preventing the spread of CA-MRSA, and nasal decolonization should not be attempted in any community setting.²⁹ In fact, studies have found that attempts at nasal decolonization can actually lead to increased bacterial resistance and a recurrence of colonization.^29,31,32

HSV-1 is highly prevalent

Herpes simplex virus-1 (HSV-1) is a common problem in athletes who play team sports that involve skin-to-skin contact. It is particularly prevalent among competitive wrestlers—earning it the name herpes gladiatorum.

In fact, HSV-1 is widespread throughout the country: Its prevalence in the general population is 58%.³³ It is estimated that nearly half (47%) of cutaneous infections in collegiate athletes are caused by the herpes virus, making HSV-1 the most common pathogen of skin infections in this group.³⁴ The clinical presentation of active HSV-1 depends on whether the infection is primary or recurrent.

So which form of HSV-1 is it?
Primary lesions may be preceded by a prodromal period with systemic symptoms, such as fever. Oral lesions and enlarged cervical and submandibular lymph nodes follow.35 The lesions, which are typically painful, can be found on the lips, buccal mucosa, or tongue—nearly anywhere in and around the oral cavity (Figure 2). They are vesicular at first, then ulcerate. Healing typically takes 10 to 14 days.36

In recurrent HSV-1, clusters of vesicles with erythematous borders typically occur. In those who play contact sports, HSV lesions can be found not only in the typical facial and oral areas, but anywhere on the head, face, torso, or extremities, as well.

Identifying herpetic whitlow. Presenting as a cluster of herpetic vesicles on the hands, fingers, or toes, herpetic whitlow is a common presentation of recurrent HSV-1. Recognition of these lesions is usually adequate for a diagnosis of recurrent infection, but confirmation can be obtained by laboratory or serologic testing.

Testing should be considered when you suspect that a patient has a primary herpes infection, as HSV-1 is a lifelong diagnosis. Viral culture is technique dependent and limited by 50% sensitivity, as cultures can take from 2 to 4 days to grow.³⁵ The Tzanck test (direct microscopic examination of skin scrapings) has fallen out of favor, and PCR is now the gold standard.

Compared with viral culture, PCR has been shown to detect 80% of positive cases.³⁵ However, PCR—using swab specimens taken from the lesions—is expensive and must be sent to a lab for analysis. One study suggests that while less sensitive than PCR, the Tzanck test can still be a reliably sensitive method of diagnosis when done properly, at less cost and with quicker
results.³⁷

Serologic tests of HSV-1 IgM and IgG antibodies are also available. Serum IgG levels remain elevated in patients with previous infections. In primary infections, IgM is most useful as it can detect recent or active infection, but results may be falsely negative for several days after infection.³⁸

Once diagnosed, management of HSV-1 in athletes is based on whether the infection is primary or recurrent. In both cases, oral antivirals are needed. Acyclovir is the gold standard, but famciclovir and valacyclovir have been proven to be equally effective.39 Both the NCAA and NFHS have published guidelines addressing the question of return to play (TABLE 2).^22,23

In addition to the management of primary and recurrent infections of HSV-1, it is recommended that athletes and coaches known to be HSV-1 seropositive be treated with prophylactic suppressive therapy.⁴⁰

The Centers for Disease Control and Prevention recommends acyclovir 400 mg bid or valacyclovir 500 mg/d as prophylaxis for anyone with ≤10 recurrences per year. For those with >10 recurrences annually, valacyclovir 1000 mg/d is recommended for the rest of the season.⁴⁰ This has been shown to be effective in the reduction of outbreaks among wrestlers after a large outbreak occurred in 2007 in Minnesota,^40,41 and NCAA and NFHS guidelines now support prophylactic therapy during competitive season.^22,23 Before prescribing it, clinicians need to consider both the benefits of prophylactic antiviral therapy and the risks of promoting HSV-1 resistance.

Focus on prevention and squelching outbreaks

For cutaneous infections, as with so many medical conditions, prevention is paramount. With good preventive practices, many, if not all, of the skin infections common among athletes can be eliminated and outbreaks can be squelched.

Good hygienic practice is the cornerstone of prevention. Patients who participate in team sports should be advised to:

• shower immediately after practice
• refrain from sharing personal equipment like uniforms, towels, razors, and headgear
• launder workout clothes and towels after each use
• immediately cleanse and cover any abrasions that occur during practice.

Athletes should also be advised to ask their trainer or coach to check their skin for lesions on a regular basis. Surveillance should be instituted to prohibit athletes with cutaneous lesions from participating until they are sufficiently treated.

Although the role that environmental contamination plays in transmission of infection is uncertain, it is recommended that all sports equipment, playing surfaces, and locker rooms be disinfected daily with either a freshly made bactericidal (1/100 bleach/water solution)^23,24 or an appropriate product. The Environmental Protection Agency provides a list of commercial products that have been proven to prevent the spread of MRSA on such surfaces (http://epa.gov/oppad001/chemregindex.htm) on its Web site.⁴²

CASE  When Shane returned 3 days later, the erythema had resolved, and minimal scaling remained. You tell him to continue to use the topical terbinafine twice a day for 10 days. You also show him how to apply a bio-occlusive dressing and clear him for practice, provided the lesions are fully covered.

You also talk to Shane about prevention, recommending that he immediately clean and cover any abrasion or other skin trauma that occurs during practice and suggesting that he ask his trainer to regularly check team members for skin lesions.

At Day 7, the DTM culture is positive, confirming a dermatophyte infection.

CORRESPONDENCE
Nilesh Shah, MD, 20 Olive Street, Suite 201, Akron, OH 44310;
[email protected]

ACKNOWLEDGEMENT
The authors would like to thank Tom Bartsokas, MD, for his help with this manuscript.
 

CASE  Shane O, a 16-year-old on his high school wrestling team, presents with red, scaly, well-defined plaques on his forehead. The coach spotted the lesions and removed him from play. The patient reports that he’s training for a competitive event and is anxious to return to practice.

You take skin scrapings for a potassium chloride (KOH) test, which is negative, and for a dermatophyte culture. The culture will take 7 to 14 days, however. What should you do in the meantime?

Chances are you’ve cared for countless patients with cutaneous infections. But when the individual who’s infected participates in a team sport, it’s a game changer. In addition to treating the infection, it is necessary to take steps to prevent an outbreak among other players.

More than half of the infections incurred by athletes are cutaneous lesions¹—not surprising considering the numerous opportunities sports play provides for common skin conditions to spread. Predisposing factors, in addition to skin-to-skin contact and abrasions, include shared close quarters (eg, locker rooms and showers), shared sports equipment, and poor hygiene.^2-5

For a competitive athlete like Shane, the loss of practice may be the most worrisome aspect of a cutaneous infection. From a medical perspective, there are far more pressing concerns. Contact with a teammate’s active herpes simplex lesion (HSV-1), for example, could result in a lifelong infection, and a methicillin-resistant Staphylococcus aureus (MRSA) infection can be a source of significant morbidity for anyone who is infected. There is also the potential for a public health hazard. In addition to prompt, accurate diagnosis, a treatment approach that considers both the need to protect others and the importance of getting the player back in the game as soon as it is safe to do so is critical.

Athlete’s foot, ringworm, jock itch—fungal infections are easily spread

Fungal infections are a common cause of skin disease in athletes. Dermatophytes can spread from fomites such as mats, floors, laundry items, and shared clothing, combs, and brushes, as well as in swimming pools and from direct contact with carriers.²

National Collegiate Athletic Association (NCAA) data show that fungi account for 22% of the skin infections that athletes involved in competitive wrestling develop.⁶ Sports with skin-to-skin contact, such as wrestling, pose the greatest risk. Fungal infection is the No. 1 reason cited for missing wrestling practice, according to the NCAA.⁶

Fungal infections are not just a wrestler’s problem, however. Tinea pedis (athlete’s foot) is common among runners and swimmers, and tinea corporis (ringworm), in prepubertal athletes.⁵

Fungal skin infections are caused by 3 dermatophyte genera: Trichophyton, Epidermophyton, and Microsporum. In the United States, T rubrum is responsible for most cutaneous fungal infections, including tinea corporis, tinea unguium (nail), tinea pedis, and tinea cruris (commonly called jock itch).⁵

Tinea corporis (Figure 1) may present with areas of central hypopigmentation that give it a ring-like appearance. This type of fungal infection also includes tinea gladiatorum, so named for its high prevalence among wrestlers and characterized by well-defined, red scaling plaques on the head, neck, and upper extremities, often with an irregular border.⁷

Tinea pedis typically develops in the web spaces of the toes, with skin maceration often accompanied by thick scaling or desquamation. Tinea cruris presents as erythematous plaques in the pubic and inguinal areas.⁸

Onychomycosis can affect the nail plate, resulting in thickening, change in color, and alteration of nail texture.⁹

T tonsurans is the dominant pathogen for tinea capitis—fungal infection of the scalp,⁵ which can be inflammatory or noninflammatory. The noninflammatory form may present with gray-patch scaling, seborrheic dermatitis-like scale, hair thinning without significant scaling, or patches of “black-dot” alopecia. Inflammatory forms of tinea capitis may present as anything from localized pustules to widespread abscesses, or may remain in an asymptomatic carrier state.¹⁰

When to confirm a clinical diagnosis
Fungal infections can often be diagnosed based on clinical presentation, but confirmation is important when systemic therapy is required—for tinea capitis, in particular. The traditional method is an examination of skin scraped from the edge of a lesion and treated with 10% to 20% KOH, gently heated, and viewed under light microscopy.⁸

Alternatively, fungal infection can be confirmed retrospectively, by culture on selective media. Dermatophyte test medium (DTM) is convenient and easy to use, and usually reveals fungal growth within 7 days. A newer selective media, DBM (bromothymol blue is the pH indicator) is a modification of the DTM formulation that may offer earlier and more accurate identification of fungi.¹¹

Keep in mind, however, that a negative KOH preparation or culture does not necessarily rule out a fungal infection.¹² Polymerase chain reaction (PCR), an emerging technology performed on a specimen swab, has a greater sensitivity than either KOH or culture in identifying fungal pathogens. PCR can identify the presence of fungi even if the dermatophyte growth on culture is hidden by the overgrowth of Candida albicans.¹³

In patients with onychomycosis, dermatophytes may be exceedingly difficult to isolate on either KOH or culture medium, and the results of these tests often conflict. Onychomycosis is best diagnosed histopathologically by examination of periodic acid-Schiff-stained nail clippings.¹⁴

Topical or systemic treatment?
Treatment of dermatophyte infections is site-dependent. For simple epidermal infection, other than scalp or nail, topical therapy is first-line treatment. In a recent Cochrane review, topical allylamines, azoles, butenafine, ciclopirox olamine, tolciclate, and tolnaftate were all found to be effective. However, the allylamines had the greatest efficacy, which increased with duration of use.¹⁵

Topical terbinafine was found to be effective in as little as one to 3 days of treat-ment for tinea pedis. Mycological cure with near total symptom elimination at 28 days was reported in 61% and 78% of those receiving topical treatment for one day and 3 days, respectively; the difference was not statistically significant.¹⁶

 Use this topical when bacterial infection complicates care. Although 1% naftifine gel requires a prescription and costs more than many other topicals, its advantages may offset the higher costs. Once-daily naftifine gel is as effective as other allylamines that require twice-daily application, and has both antihistamine and corticosteroid effects to offset inflammation. What’s more, naftifine is active against both gram-positive and gram-negative bacteria; therefore, it should be considered in instances in which bacterial superinfection is a possibility, as suggested by a high degree of inflammation with bright red and yellow crusts.^17,18

Scalp, nail, and complicated foot infections typically require systemic therapy. Griseofulvin is the most widely used systemic treatment for tinea capitis.¹⁰ While terbinafine requires a shorter duration of treatment (4-6 weeks) and is similar in efficacy—except in cases of microsporum infection of the scalp, for which griseofulvin has been found to have higher cure rates¹⁹—it is often not used because it has a higher cost.

Tinea pedis and onychomycosis often occur concurrently, making eradication difficult and increasing the potential for reinfection. For recalcitrant cases of onychomycosis, a combination of topical and systemic therapy may be required, along with trimming, debridement, nail abrasion, and partial nail avulsion.²⁰ A recent study found laser therapy to be a promising treatment for onychomycosis, but randomized controlled trials have yet to be done.²¹

NCAA and NFHS rules. Both the NCAA and the National Federation of State
High School Associations (NFHS) mandate that a wrestler with tinea corporis receive a minimum of 72 hours of topical therapy prior to participation; 14 days of systemic antifungal therapy are required for athletes with tinea capitis.^22,23 The NCAA allows wrestlers to be cleared to participate on an individual basis, at the discretion of the examining physician or certified trainer.

The degree of disease involvement, the activity of disease as judged by KOH preparation, or the review of therapeutic regimen and the ability to properly cover lesions securely are taken into account.²² Proper coverage could consist of a semiocclusive or occlusive dressing such as film, foam, hydrogel, or hydrocolloid covered with stretch tape.²⁴ Similarly, the NFHS permits a wrestler to participate once the lesion is deemed to be no longer contagious and can be covered with a bio-occlusive dressing.²³

Prophylactic oral fluconazole, given in a 3-day regimen twice during the season to all team members, has been shown to be successful in reducing a high burden of tinea gladiatorum in a high school wrestling setting.²⁵

CASE You presumptively diagnose tinea gladiatorum based on both the presentation and the patient’s history as a wrestler and prescribe topical terbinafine therapy twice daily. You schedule a follow-up appointment in 3 days, and tell Shane he must refrain from wrestling practice at least until then.

Staph and strep infections

Bacterial skin infections are also common among athletes, with S aureus reported to be responsible for 22% of infectious disease outbreaks.²⁶ Here, too, infections occur primarily in contact sports such as football, rugby, and soccer, as well as wrestling.

There are several types of bacterial dermatoses: impetigo, folliculitis, furuncles, carbuncles, abscesses, and cellulitis. Most are caused by group A beta-hemolytic Streptococcus or S aureus and can be easily treated, but identification of the pathogen is needed to facilitate healing and a safe return to play (TABLE 1).²⁷

When to suspect CA-MRSA
Community-acquired methicillin-resistant S aureus (CA-MRSA) was first reported in an athletic population in the 1960s, and in 1993 the first documented outbreak of CA-MRSA in a sports setting—involving 6 high school wrestlers from Vermont—was reported.²⁸

The athlete with CA-MRSA usually presents with a painful, purulent, swollen, red abscess-like lesion, sometimes described as (or mistaken for) a spider bite. The patient may also develop fever, fatigue, and malaise. Culturing the wound for identification of the bacterium and for susceptibility to antibiotic therapy is needed for a definitive diagnosis of CA-MRSA.

Is incision and drainage sufficient treatment? The standard treatment for uncomplicated CA-MRSA lesions is incision and drainage. Several studies have found this to be adequate for simple lesions.²⁹ Others have reported increased treatment failure with simple incision and drainage and shown that the addition of antimicrobial therapy helps decrease further tissue damage and morbidity.²⁹

With no clear consensus as to when and whether to add oral antibiotic therapy after incision and drainage of a CA-MRSA lesion, decisions should be based on the severity of the lesion, the presence or absence of systemic symptoms, and the potential risk of bacterial spread to other team members.

Choosing an antimicrobial agent. Antimicrobial treatment should be guided by culture and sensitivity results, as well as the regional incidence of CA-MRSA. Empiric treatments for CA-MRSA are trimethoprim-sulfamethoxazole, doxycycline, and clindamycin, taken for 7 to 14 days. If you’re considering the use of clindamycin and there is known resistance to erythromycin from antimicrobial sensitivities, a double disc diffusion (D-test) should be ordered to detect inducible macrolide resistance that can occur in some strains of CA-MRSA.^29,30

Fluoroquinolones and certain macrolides should not be used, due to resistance to these antibiotics.¹

Topicals for superficial lesions. Topical antibiotic therapy with mupirocin or retapamulin should be reserved for superficial CA-MRSA lesions, such as impetigo.^31,32 Caution must be used when mupirocin is prescribed, however, due to recent studies showing increasing resistance to mupirocin, especially when used for nasal decolonizing purposes.²⁹

Once treatment is initiated, see the athlete every 2 to 3 days. Resolution usually occurs in 10 to 14 days. The athlete can return to play after 72 hours of treatment, however, provided there is evidence of clinical improvement, no further drainage from the infected lesion, and no new lesions have developed.^1,30

Containing CA-MRSA. Mass nasal decolonization—applying topical mupirocin in the nares of infected athletes as well as their teammates—has been attempted to prevent the spread of CA-MRSA. But there is no evidence to suggest that mupirocin or any other intranasal antimicrobial is effective in preventing the spread of CA-MRSA, and nasal decolonization should not be attempted in any community setting.²⁹ In fact, studies have found that attempts at nasal decolonization can actually lead to increased bacterial resistance and a recurrence of colonization.^29,31,32

HSV-1 is highly prevalent

Herpes simplex virus-1 (HSV-1) is a common problem in athletes who play team sports that involve skin-to-skin contact. It is particularly prevalent among competitive wrestlers—earning it the name herpes gladiatorum.

In fact, HSV-1 is widespread throughout the country: Its prevalence in the general population is 58%.³³ It is estimated that nearly half (47%) of cutaneous infections in collegiate athletes are caused by the herpes virus, making HSV-1 the most common pathogen of skin infections in this group.³⁴ The clinical presentation of active HSV-1 depends on whether the infection is primary or recurrent.

So which form of HSV-1 is it?
Primary lesions may be preceded by a prodromal period with systemic symptoms, such as fever. Oral lesions and enlarged cervical and submandibular lymph nodes follow.35 The lesions, which are typically painful, can be found on the lips, buccal mucosa, or tongue—nearly anywhere in and around the oral cavity (Figure 2). They are vesicular at first, then ulcerate. Healing typically takes 10 to 14 days.36

In recurrent HSV-1, clusters of vesicles with erythematous borders typically occur. In those who play contact sports, HSV lesions can be found not only in the typical facial and oral areas, but anywhere on the head, face, torso, or extremities, as well.

Identifying herpetic whitlow. Presenting as a cluster of herpetic vesicles on the hands, fingers, or toes, herpetic whitlow is a common presentation of recurrent HSV-1. Recognition of these lesions is usually adequate for a diagnosis of recurrent infection, but confirmation can be obtained by laboratory or serologic testing.

Testing should be considered when you suspect that a patient has a primary herpes infection, as HSV-1 is a lifelong diagnosis. Viral culture is technique dependent and limited by 50% sensitivity, as cultures can take from 2 to 4 days to grow.³⁵ The Tzanck test (direct microscopic examination of skin scrapings) has fallen out of favor, and PCR is now the gold standard.

Compared with viral culture, PCR has been shown to detect 80% of positive cases.³⁵ However, PCR—using swab specimens taken from the lesions—is expensive and must be sent to a lab for analysis. One study suggests that while less sensitive than PCR, the Tzanck test can still be a reliably sensitive method of diagnosis when done properly, at less cost and with quicker
results.³⁷

Serologic tests of HSV-1 IgM and IgG antibodies are also available. Serum IgG levels remain elevated in patients with previous infections. In primary infections, IgM is most useful as it can detect recent or active infection, but results may be falsely negative for several days after infection.³⁸

Once diagnosed, management of HSV-1 in athletes is based on whether the infection is primary or recurrent. In both cases, oral antivirals are needed. Acyclovir is the gold standard, but famciclovir and valacyclovir have been proven to be equally effective.39 Both the NCAA and NFHS have published guidelines addressing the question of return to play (TABLE 2).^22,23

In addition to the management of primary and recurrent infections of HSV-1, it is recommended that athletes and coaches known to be HSV-1 seropositive be treated with prophylactic suppressive therapy.⁴⁰

The Centers for Disease Control and Prevention recommends acyclovir 400 mg bid or valacyclovir 500 mg/d as prophylaxis for anyone with ≤10 recurrences per year. For those with >10 recurrences annually, valacyclovir 1000 mg/d is recommended for the rest of the season.⁴⁰ This has been shown to be effective in the reduction of outbreaks among wrestlers after a large outbreak occurred in 2007 in Minnesota,^40,41 and NCAA and NFHS guidelines now support prophylactic therapy during competitive season.^22,23 Before prescribing it, clinicians need to consider both the benefits of prophylactic antiviral therapy and the risks of promoting HSV-1 resistance.

Focus on prevention and squelching outbreaks

For cutaneous infections, as with so many medical conditions, prevention is paramount. With good preventive practices, many, if not all, of the skin infections common among athletes can be eliminated and outbreaks can be squelched.

Good hygienic practice is the cornerstone of prevention. Patients who participate in team sports should be advised to:

• shower immediately after practice
• refrain from sharing personal equipment like uniforms, towels, razors, and headgear
• launder workout clothes and towels after each use
• immediately cleanse and cover any abrasions that occur during practice.

Athletes should also be advised to ask their trainer or coach to check their skin for lesions on a regular basis. Surveillance should be instituted to prohibit athletes with cutaneous lesions from participating until they are sufficiently treated.

Although the role that environmental contamination plays in transmission of infection is uncertain, it is recommended that all sports equipment, playing surfaces, and locker rooms be disinfected daily with either a freshly made bactericidal (1/100 bleach/water solution)^23,24 or an appropriate product. The Environmental Protection Agency provides a list of commercial products that have been proven to prevent the spread of MRSA on such surfaces (http://epa.gov/oppad001/chemregindex.htm) on its Web site.⁴²

CASE  When Shane returned 3 days later, the erythema had resolved, and minimal scaling remained. You tell him to continue to use the topical terbinafine twice a day for 10 days. You also show him how to apply a bio-occlusive dressing and clear him for practice, provided the lesions are fully covered.

You also talk to Shane about prevention, recommending that he immediately clean and cover any abrasion or other skin trauma that occurs during practice and suggesting that he ask his trainer to regularly check team members for skin lesions.

At Day 7, the DTM culture is positive, confirming a dermatophyte infection.

CORRESPONDENCE
Nilesh Shah, MD, 20 Olive Street, Suite 201, Akron, OH 44310;
[email protected]

ACKNOWLEDGEMENT
The authors would like to thank Tom Bartsokas, MD, for his help with this manuscript.
 

CASE  Shane O, a 16-year-old on his high school wrestling team, presents with red, scaly, well-defined plaques on his forehead. The coach spotted the lesions and removed him from play. The patient reports that he’s training for a competitive event and is anxious to return to practice.

You take skin scrapings for a potassium chloride (KOH) test, which is negative, and for a dermatophyte culture. The culture will take 7 to 14 days, however. What should you do in the meantime?

Chances are you’ve cared for countless patients with cutaneous infections. But when the individual who’s infected participates in a team sport, it’s a game changer. In addition to treating the infection, it is necessary to take steps to prevent an outbreak among other players.

More than half of the infections incurred by athletes are cutaneous lesions¹—not surprising considering the numerous opportunities sports play provides for common skin conditions to spread. Predisposing factors, in addition to skin-to-skin contact and abrasions, include shared close quarters (eg, locker rooms and showers), shared sports equipment, and poor hygiene.^2-5

For a competitive athlete like Shane, the loss of practice may be the most worrisome aspect of a cutaneous infection. From a medical perspective, there are far more pressing concerns. Contact with a teammate’s active herpes simplex lesion (HSV-1), for example, could result in a lifelong infection, and a methicillin-resistant Staphylococcus aureus (MRSA) infection can be a source of significant morbidity for anyone who is infected. There is also the potential for a public health hazard. In addition to prompt, accurate diagnosis, a treatment approach that considers both the need to protect others and the importance of getting the player back in the game as soon as it is safe to do so is critical.

Athlete’s foot, ringworm, jock itch—fungal infections are easily spread

Fungal infections are a common cause of skin disease in athletes. Dermatophytes can spread from fomites such as mats, floors, laundry items, and shared clothing, combs, and brushes, as well as in swimming pools and from direct contact with carriers.²

National Collegiate Athletic Association (NCAA) data show that fungi account for 22% of the skin infections that athletes involved in competitive wrestling develop.⁶ Sports with skin-to-skin contact, such as wrestling, pose the greatest risk. Fungal infection is the No. 1 reason cited for missing wrestling practice, according to the NCAA.⁶

Fungal infections are not just a wrestler’s problem, however. Tinea pedis (athlete’s foot) is common among runners and swimmers, and tinea corporis (ringworm), in prepubertal athletes.⁵

Fungal skin infections are caused by 3 dermatophyte genera: Trichophyton, Epidermophyton, and Microsporum. In the United States, T rubrum is responsible for most cutaneous fungal infections, including tinea corporis, tinea unguium (nail), tinea pedis, and tinea cruris (commonly called jock itch).⁵

Tinea corporis (Figure 1) may present with areas of central hypopigmentation that give it a ring-like appearance. This type of fungal infection also includes tinea gladiatorum, so named for its high prevalence among wrestlers and characterized by well-defined, red scaling plaques on the head, neck, and upper extremities, often with an irregular border.⁷

Tinea pedis typically develops in the web spaces of the toes, with skin maceration often accompanied by thick scaling or desquamation. Tinea cruris presents as erythematous plaques in the pubic and inguinal areas.⁸

Onychomycosis can affect the nail plate, resulting in thickening, change in color, and alteration of nail texture.⁹

T tonsurans is the dominant pathogen for tinea capitis—fungal infection of the scalp,⁵ which can be inflammatory or noninflammatory. The noninflammatory form may present with gray-patch scaling, seborrheic dermatitis-like scale, hair thinning without significant scaling, or patches of “black-dot” alopecia. Inflammatory forms of tinea capitis may present as anything from localized pustules to widespread abscesses, or may remain in an asymptomatic carrier state.¹⁰

When to confirm a clinical diagnosis
Fungal infections can often be diagnosed based on clinical presentation, but confirmation is important when systemic therapy is required—for tinea capitis, in particular. The traditional method is an examination of skin scraped from the edge of a lesion and treated with 10% to 20% KOH, gently heated, and viewed under light microscopy.⁸

Alternatively, fungal infection can be confirmed retrospectively, by culture on selective media. Dermatophyte test medium (DTM) is convenient and easy to use, and usually reveals fungal growth within 7 days. A newer selective media, DBM (bromothymol blue is the pH indicator) is a modification of the DTM formulation that may offer earlier and more accurate identification of fungi.¹¹

Keep in mind, however, that a negative KOH preparation or culture does not necessarily rule out a fungal infection.¹² Polymerase chain reaction (PCR), an emerging technology performed on a specimen swab, has a greater sensitivity than either KOH or culture in identifying fungal pathogens. PCR can identify the presence of fungi even if the dermatophyte growth on culture is hidden by the overgrowth of Candida albicans.¹³

In patients with onychomycosis, dermatophytes may be exceedingly difficult to isolate on either KOH or culture medium, and the results of these tests often conflict. Onychomycosis is best diagnosed histopathologically by examination of periodic acid-Schiff-stained nail clippings.¹⁴

Topical or systemic treatment?
Treatment of dermatophyte infections is site-dependent. For simple epidermal infection, other than scalp or nail, topical therapy is first-line treatment. In a recent Cochrane review, topical allylamines, azoles, butenafine, ciclopirox olamine, tolciclate, and tolnaftate were all found to be effective. However, the allylamines had the greatest efficacy, which increased with duration of use.¹⁵

Topical terbinafine was found to be effective in as little as one to 3 days of treat-ment for tinea pedis. Mycological cure with near total symptom elimination at 28 days was reported in 61% and 78% of those receiving topical treatment for one day and 3 days, respectively; the difference was not statistically significant.¹⁶

 Use this topical when bacterial infection complicates care. Although 1% naftifine gel requires a prescription and costs more than many other topicals, its advantages may offset the higher costs. Once-daily naftifine gel is as effective as other allylamines that require twice-daily application, and has both antihistamine and corticosteroid effects to offset inflammation. What’s more, naftifine is active against both gram-positive and gram-negative bacteria; therefore, it should be considered in instances in which bacterial superinfection is a possibility, as suggested by a high degree of inflammation with bright red and yellow crusts.^17,18

Scalp, nail, and complicated foot infections typically require systemic therapy. Griseofulvin is the most widely used systemic treatment for tinea capitis.¹⁰ While terbinafine requires a shorter duration of treatment (4-6 weeks) and is similar in efficacy—except in cases of microsporum infection of the scalp, for which griseofulvin has been found to have higher cure rates¹⁹—it is often not used because it has a higher cost.

Tinea pedis and onychomycosis often occur concurrently, making eradication difficult and increasing the potential for reinfection. For recalcitrant cases of onychomycosis, a combination of topical and systemic therapy may be required, along with trimming, debridement, nail abrasion, and partial nail avulsion.²⁰ A recent study found laser therapy to be a promising treatment for onychomycosis, but randomized controlled trials have yet to be done.²¹

NCAA and NFHS rules. Both the NCAA and the National Federation of State
High School Associations (NFHS) mandate that a wrestler with tinea corporis receive a minimum of 72 hours of topical therapy prior to participation; 14 days of systemic antifungal therapy are required for athletes with tinea capitis.^22,23 The NCAA allows wrestlers to be cleared to participate on an individual basis, at the discretion of the examining physician or certified trainer.

The degree of disease involvement, the activity of disease as judged by KOH preparation, or the review of therapeutic regimen and the ability to properly cover lesions securely are taken into account.²² Proper coverage could consist of a semiocclusive or occlusive dressing such as film, foam, hydrogel, or hydrocolloid covered with stretch tape.²⁴ Similarly, the NFHS permits a wrestler to participate once the lesion is deemed to be no longer contagious and can be covered with a bio-occlusive dressing.²³

Prophylactic oral fluconazole, given in a 3-day regimen twice during the season to all team members, has been shown to be successful in reducing a high burden of tinea gladiatorum in a high school wrestling setting.²⁵

CASE You presumptively diagnose tinea gladiatorum based on both the presentation and the patient’s history as a wrestler and prescribe topical terbinafine therapy twice daily. You schedule a follow-up appointment in 3 days, and tell Shane he must refrain from wrestling practice at least until then.

Staph and strep infections

Bacterial skin infections are also common among athletes, with S aureus reported to be responsible for 22% of infectious disease outbreaks.²⁶ Here, too, infections occur primarily in contact sports such as football, rugby, and soccer, as well as wrestling.

There are several types of bacterial dermatoses: impetigo, folliculitis, furuncles, carbuncles, abscesses, and cellulitis. Most are caused by group A beta-hemolytic Streptococcus or S aureus and can be easily treated, but identification of the pathogen is needed to facilitate healing and a safe return to play (TABLE 1).²⁷

When to suspect CA-MRSA
Community-acquired methicillin-resistant S aureus (CA-MRSA) was first reported in an athletic population in the 1960s, and in 1993 the first documented outbreak of CA-MRSA in a sports setting—involving 6 high school wrestlers from Vermont—was reported.²⁸

The athlete with CA-MRSA usually presents with a painful, purulent, swollen, red abscess-like lesion, sometimes described as (or mistaken for) a spider bite. The patient may also develop fever, fatigue, and malaise. Culturing the wound for identification of the bacterium and for susceptibility to antibiotic therapy is needed for a definitive diagnosis of CA-MRSA.

Is incision and drainage sufficient treatment? The standard treatment for uncomplicated CA-MRSA lesions is incision and drainage. Several studies have found this to be adequate for simple lesions.²⁹ Others have reported increased treatment failure with simple incision and drainage and shown that the addition of antimicrobial therapy helps decrease further tissue damage and morbidity.²⁹

With no clear consensus as to when and whether to add oral antibiotic therapy after incision and drainage of a CA-MRSA lesion, decisions should be based on the severity of the lesion, the presence or absence of systemic symptoms, and the potential risk of bacterial spread to other team members.

Choosing an antimicrobial agent. Antimicrobial treatment should be guided by culture and sensitivity results, as well as the regional incidence of CA-MRSA. Empiric treatments for CA-MRSA are trimethoprim-sulfamethoxazole, doxycycline, and clindamycin, taken for 7 to 14 days. If you’re considering the use of clindamycin and there is known resistance to erythromycin from antimicrobial sensitivities, a double disc diffusion (D-test) should be ordered to detect inducible macrolide resistance that can occur in some strains of CA-MRSA.^29,30

Fluoroquinolones and certain macrolides should not be used, due to resistance to these antibiotics.¹

Topicals for superficial lesions. Topical antibiotic therapy with mupirocin or retapamulin should be reserved for superficial CA-MRSA lesions, such as impetigo.^31,32 Caution must be used when mupirocin is prescribed, however, due to recent studies showing increasing resistance to mupirocin, especially when used for nasal decolonizing purposes.²⁹

Once treatment is initiated, see the athlete every 2 to 3 days. Resolution usually occurs in 10 to 14 days. The athlete can return to play after 72 hours of treatment, however, provided there is evidence of clinical improvement, no further drainage from the infected lesion, and no new lesions have developed.^1,30

Containing CA-MRSA. Mass nasal decolonization—applying topical mupirocin in the nares of infected athletes as well as their teammates—has been attempted to prevent the spread of CA-MRSA. But there is no evidence to suggest that mupirocin or any other intranasal antimicrobial is effective in preventing the spread of CA-MRSA, and nasal decolonization should not be attempted in any community setting.²⁹ In fact, studies have found that attempts at nasal decolonization can actually lead to increased bacterial resistance and a recurrence of colonization.^29,31,32

HSV-1 is highly prevalent

Herpes simplex virus-1 (HSV-1) is a common problem in athletes who play team sports that involve skin-to-skin contact. It is particularly prevalent among competitive wrestlers—earning it the name herpes gladiatorum.

In fact, HSV-1 is widespread throughout the country: Its prevalence in the general population is 58%.³³ It is estimated that nearly half (47%) of cutaneous infections in collegiate athletes are caused by the herpes virus, making HSV-1 the most common pathogen of skin infections in this group.³⁴ The clinical presentation of active HSV-1 depends on whether the infection is primary or recurrent.

So which form of HSV-1 is it?
Primary lesions may be preceded by a prodromal period with systemic symptoms, such as fever. Oral lesions and enlarged cervical and submandibular lymph nodes follow.35 The lesions, which are typically painful, can be found on the lips, buccal mucosa, or tongue—nearly anywhere in and around the oral cavity (Figure 2). They are vesicular at first, then ulcerate. Healing typically takes 10 to 14 days.36

In recurrent HSV-1, clusters of vesicles with erythematous borders typically occur. In those who play contact sports, HSV lesions can be found not only in the typical facial and oral areas, but anywhere on the head, face, torso, or extremities, as well.

Identifying herpetic whitlow. Presenting as a cluster of herpetic vesicles on the hands, fingers, or toes, herpetic whitlow is a common presentation of recurrent HSV-1. Recognition of these lesions is usually adequate for a diagnosis of recurrent infection, but confirmation can be obtained by laboratory or serologic testing.

Testing should be considered when you suspect that a patient has a primary herpes infection, as HSV-1 is a lifelong diagnosis. Viral culture is technique dependent and limited by 50% sensitivity, as cultures can take from 2 to 4 days to grow.³⁵ The Tzanck test (direct microscopic examination of skin scrapings) has fallen out of favor, and PCR is now the gold standard.

Compared with viral culture, PCR has been shown to detect 80% of positive cases.³⁵ However, PCR—using swab specimens taken from the lesions—is expensive and must be sent to a lab for analysis. One study suggests that while less sensitive than PCR, the Tzanck test can still be a reliably sensitive method of diagnosis when done properly, at less cost and with quicker
results.³⁷

Serologic tests of HSV-1 IgM and IgG antibodies are also available. Serum IgG levels remain elevated in patients with previous infections. In primary infections, IgM is most useful as it can detect recent or active infection, but results may be falsely negative for several days after infection.³⁸

Once diagnosed, management of HSV-1 in athletes is based on whether the infection is primary or recurrent. In both cases, oral antivirals are needed. Acyclovir is the gold standard, but famciclovir and valacyclovir have been proven to be equally effective.39 Both the NCAA and NFHS have published guidelines addressing the question of return to play (TABLE 2).^22,23

In addition to the management of primary and recurrent infections of HSV-1, it is recommended that athletes and coaches known to be HSV-1 seropositive be treated with prophylactic suppressive therapy.⁴⁰

The Centers for Disease Control and Prevention recommends acyclovir 400 mg bid or valacyclovir 500 mg/d as prophylaxis for anyone with ≤10 recurrences per year. For those with >10 recurrences annually, valacyclovir 1000 mg/d is recommended for the rest of the season.⁴⁰ This has been shown to be effective in the reduction of outbreaks among wrestlers after a large outbreak occurred in 2007 in Minnesota,^40,41 and NCAA and NFHS guidelines now support prophylactic therapy during competitive season.^22,23 Before prescribing it, clinicians need to consider both the benefits of prophylactic antiviral therapy and the risks of promoting HSV-1 resistance.

Focus on prevention and squelching outbreaks

For cutaneous infections, as with so many medical conditions, prevention is paramount. With good preventive practices, many, if not all, of the skin infections common among athletes can be eliminated and outbreaks can be squelched.

Good hygienic practice is the cornerstone of prevention. Patients who participate in team sports should be advised to:

• shower immediately after practice
• refrain from sharing personal equipment like uniforms, towels, razors, and headgear
• launder workout clothes and towels after each use
• immediately cleanse and cover any abrasions that occur during practice.

Athletes should also be advised to ask their trainer or coach to check their skin for lesions on a regular basis. Surveillance should be instituted to prohibit athletes with cutaneous lesions from participating until they are sufficiently treated.

Although the role that environmental contamination plays in transmission of infection is uncertain, it is recommended that all sports equipment, playing surfaces, and locker rooms be disinfected daily with either a freshly made bactericidal (1/100 bleach/water solution)^23,24 or an appropriate product. The Environmental Protection Agency provides a list of commercial products that have been proven to prevent the spread of MRSA on such surfaces (http://epa.gov/oppad001/chemregindex.htm) on its Web site.⁴²

CASE  When Shane returned 3 days later, the erythema had resolved, and minimal scaling remained. You tell him to continue to use the topical terbinafine twice a day for 10 days. You also show him how to apply a bio-occlusive dressing and clear him for practice, provided the lesions are fully covered.

You also talk to Shane about prevention, recommending that he immediately clean and cover any abrasion or other skin trauma that occurs during practice and suggesting that he ask his trainer to regularly check team members for skin lesions.

At Day 7, the DTM culture is positive, confirming a dermatophyte infection.

CORRESPONDENCE
Nilesh Shah, MD, 20 Olive Street, Suite 201, Akron, OH 44310;
[email protected]

ACKNOWLEDGEMENT
The authors would like to thank Tom Bartsokas, MD, for his help with this manuscript.
 

CASE Donna M is a 53-year-old woman with type 2 diabetes mellitus, who maintains fair glycemic control with metformin and glipizide. Her HbA1c level is 8.7%, but she has mixed feelings about initiating insulin treatment. Many of her family members also struggle with diabetes, and they frequently accompany Ms. M on her office visits. Ms. M is motivated to do whatever she can—in addition to taking her medications—to improve her diabetes. Her family asks if there is anything they can do to help. If you were Ms. M’s physician, what would you recommend?

The Centers for Disease Control and Prevention (CDC) estimates that diabetes affects 25.8 million people (or 8.3% of the population) in the United States, and that 7 million of them are undiagnosed.¹ Based on the known prevalence of prediabetes, the CDC estimates that 79 million Americans ≥20 years of age are at risk for diabetes. Approximately 5.7 million people with diabetes take insulin, with or without oral medications.²

As the spotlight shines brighter on efforts to promote patient-centeredness in health care—especially with respect to chronic illness—attention to the role of self-management has also grown. And family physicians have begun to reconsider how best to engage and motivate patients to manage their illness.

In this article, we review “what else” patients can do—and perhaps need not do—based on the evidence.

What is self-management anyway?

The concept of self-management is not foreign to most family physicians, yet they and their patients probably do not share a common understanding of what it entails. The American Diabetes Association (ADA) defines diabetes self-management as “the ongoing process of facilitating the knowledge, skill, and ability necessary for diabetes self-care. Self-management should incorporate the needs, goals, and life experiences of the person with diabetes and should be guided by evidence-based standards. The overall objectives of DSME (diabetes self-management education) are to support informed decision-making, self-care behaviors, problem solving, and active collaboration with the health care team and improve clinical outcomes, health status, and quality of life.”³

Few family physicians would disagree that self-management is a good thing for patients, but many would be surprised to find that the evidence for self-management is not as convincing as one might expect. The CDC reports that 57.4% of patients with diabetes have attended a self-management class for diabetes, and 63.6% perform daily self-monitoring of blood glucose (SMBG).⁴ Yet, there is only indirect evidence that self-management programs are associated with modest improvements in HbA1c.⁵ SMBG has long been considered a mainstay of diabetes self-care, yet a growing body of evidence has shown that this practice is not universally beneficial.⁶ Although self-management education may reduce HbA1c levels in the short term, the long-term clinical effectiveness of SMBG has not been established.^7-11

Know when to recommend SMBG

With clinical interventions, we want to give priority to those that significantly improve patient outcomes. Checking blood glucose makes good sense for insulin-treated patients to monitor for and prevent asymptomatic hypoglycemia or hyperglycemia, especially when the risk for these complications is high. In a large database study of almost 27,000 children and adolescents with type 1 diabetes, increased daily frequency of SMBG, after adjustment for multiple confounders, was significantly associated with lower HbA1c levels (–0.2% per additional test per day, leveling off at 5 tests per day) and fewer acute complications.¹²

Although it has been suggested that more frequent SMBG improves long-term glycemic control among patients with insulin-treated type 1 and type 2 diabetes, the benefits are modest.¹³ The ADA recommends SMBG 3 or more times daily for patients using multiple insulin injections or insulin pump therapy.¹⁴

In patients with type 2 diabetes who are not taking insulin, the benefits of SMBG are less clear. A meta-analysis of SMBG in non-insulin-treated patients with type 2 diabetes showed that it was associated with a reduction of HbA1c of –0.4%.¹⁵ A Cochrane review added that SMBG leads to small but significant decreases after 6 months, but that these improvements are not sustained at 12 months. The same review noted no improvements in patient satisfaction or general health-related quality of life resulting from SMBG.⁶ But many of the studies in this analysis included other interventions, making it difficult to isolate the impact of SMBG on glycemic control. Other studies show that SMBG does not improve glycemic control at all.¹⁶

For patients using less-frequent insulin injections, non-insulin therapies, or medical nutrition therapy alone, the ADA suggests that SMBG may be useful as a guide to management. Continuous glucose monitoring for patients with type 2 diabetes might improve glycemic control, but the evidence for this is inconsistent.¹⁷

Why wouldn’t you want to recommend self-monitoring? Despite the fact that the benefits of SMBG are unclear in patients with type 2 diabetes not treated with insulin, it’s hard to imagine why this practice could be harmful to patients. After all, it’s natural to assume that more knowledge must be a good thing. Unfortunately, it is not that simple. Even in newly diagnosed patients with type 2 diabetes not taking insulin, self-monitoring does not improve glycemic control and may increase depression.¹⁶

It is also important to remember that self-monitoring comes at considerable cost, monetarily for the health care system and in impaired quality of life for patients.¹⁸ While there is scant evidence in the empiric literature about patient attitudes toward self-monitoring, the available evidence suggests that patients are ambivalent about it. One qualitative study concluded that patients tended not to act on the results of self-monitoring, in part because of a lack of education about the appropriate response to readings.¹⁹ With better knowledge, it is possible that patients might find more value in SMBG.

Self-management programs: Not all are created equal

The driving principle in patient-centered care is engaging patients to be active participants in the management of their chronic conditions. At face value, this would seem to be a good thing. But although individual trials of self-management are promising, the balance of evidence for self-management is limited and inconclusive. In a systematic review of 72 randomized trials of DSME in patients ≥18 years with type 2 diabetes, short-term improvements in diabetes knowledge, frequency and accuracy of glucose self-monitoring, self-reported dietary habits, and better glycemic control were possible, but long-term clinical effectiveness was not shown. In this analysis, there was no significant effect on cardiovascular events or mortality.²⁰ In another systematic review and critique of the literature on self-management, investigators again found small to moderate effects, but with significant evidence of publication bias in the included trials.²¹

The uncertainty about self-management exists because not all self-management interventions have equal impact on patient outcomes. Motivational interviewing, collaborative problem solving, and negotiating individualized goals for each patient, for example, may have longer-standing benefit than those focused on education alone.²²

A 2009 meta-analysis of DSME and its efficacy differentiated teaching, behavioral, psychological, and “mixed” or combination approaches. Most of the interventions were behaviorally oriented, sometimes combined with one other format. Psychological interventions targeting negative or self-defeating moods and social and emotional coping skills yielded moderate effects on metabolic control and self-care behaviors.²³

Clinic-based self-management. One randomized prospective study compared intensive clinic-based education on complications of diabetes with standard care. After 4 years, patients exhibited significant reductions in HbA1c, blood pressure, and low-density lipoprotein cholesterol levels.²⁴

A large meta-analysis examining a range of self-management programs for multiple chronic conditions showed a statistically and clinically significant improvement in glycemic control equivalent to a 0.81% reduction in HbA1c. Features of self-management addressed in this meta-analysis included various forms of nurse- and provider-driven education about medications, diet and exercise, motivational interviewing, and biofeedback.²⁵

Nurse-led DSME has been associated with improvements in HbA1c and cardiovascular risk factors.²⁶ Dietician-led DSME has been associated improvements in HbA1c when compared with routine care.²⁶

Cognitive behavioral therapy. Overall, the most frequently reported and most widely used psychosocial intervention is cognitive behavioral therapy (CBT); it is often short term and skills based, targeting unhelpful negative thinking and increasing positive behavior, including problem solving and relaxation, which have been shown to be effective in treating depression.²⁷ An older randomized control trial (RCT) specifically focused on type 2 diabetes explored the impact of CBT on both diabetes and depression among patients with diabetes and comorbid major depressive disorder (MDD). Improvements in depression seen at the end of the intervention were still evident 6 months later. And while there was no difference in HbA1c levels immediately following the intervention, after 6 months the mean HbA1c level was significantly better in the CBT group than in the control group (9.5% vs 10.9%; P=.03). There was no statistically significant difference in SMBG between the groups.²⁸

Group-based vs individual training. The evidence comparing group-based and individual self-management support is inconsistent. In one RCT focused on personalized action-oriented goals for healthy eating, SMBG, taking medications, problem solving, risk reduction, healthy coping, and physical activity, individual education led to reductions in HbA1c levels (–0.51%) after 6 months that were not observed in the group-based education and usual care groups.¹⁰ On the other hand, a Cochrane review of trials comparing group-based and individual routine care suggested greater benefits overall in group-based approaches, but with the caveat that many of the included trials had methodological limitations.²⁹

Mobile phone and online interventions? Stay tuned
The jury is still out on interventions like peer advising and telephone, telemedicine, and online support. In a systematic review of 22 trials evaluating mobile phone interventions for self-management (eg, text messaging, phone reminders, and coaching interventions), investigators observed a 0.5% decrease in HbA1c levels over a median followup period of 6 months.³⁰ Various telephone interventions have shown modest and short-term improvements in HbA1c levels, but none of these interventions has improved clinical outcomes.^31-33 Combinations of telephone and online self-management are beginning to show promise, but so far the evidence shows only short-term benefit, and clinical outcomes have not been studied.^34,35

CASE Based on the available evidence, a number of ways to support Ms. M’s efforts at self-management would be justified. Eliciting her perspective on the options would be well worth the effort. She is not taking insulin, so we would not recommend daily SMBG, but we’d support her if she expressed a strong preference for self-monitoring. Once insulin treatment enters the picture, however, we would strongly recommend daily SMBG to promote patient engagement and safety. And although there is limited evidence to support referral to self-management programs, if a particular program fit Ms. M’s lifestyle, we would refer her nonetheless.

CORRESPONDENCE 
Michael Mendoza, MD, MPH, Highland Family Medicine, 777 S. Clinton Avenue, Rochester, NY 14620; [email protected]

CASE Donna M is a 53-year-old woman with type 2 diabetes mellitus, who maintains fair glycemic control with metformin and glipizide. Her HbA1c level is 8.7%, but she has mixed feelings about initiating insulin treatment. Many of her family members also struggle with diabetes, and they frequently accompany Ms. M on her office visits. Ms. M is motivated to do whatever she can—in addition to taking her medications—to improve her diabetes. Her family asks if there is anything they can do to help. If you were Ms. M’s physician, what would you recommend?

The Centers for Disease Control and Prevention (CDC) estimates that diabetes affects 25.8 million people (or 8.3% of the population) in the United States, and that 7 million of them are undiagnosed.¹ Based on the known prevalence of prediabetes, the CDC estimates that 79 million Americans ≥20 years of age are at risk for diabetes. Approximately 5.7 million people with diabetes take insulin, with or without oral medications.²

As the spotlight shines brighter on efforts to promote patient-centeredness in health care—especially with respect to chronic illness—attention to the role of self-management has also grown. And family physicians have begun to reconsider how best to engage and motivate patients to manage their illness.

In this article, we review “what else” patients can do—and perhaps need not do—based on the evidence.

What is self-management anyway?

The concept of self-management is not foreign to most family physicians, yet they and their patients probably do not share a common understanding of what it entails. The American Diabetes Association (ADA) defines diabetes self-management as “the ongoing process of facilitating the knowledge, skill, and ability necessary for diabetes self-care. Self-management should incorporate the needs, goals, and life experiences of the person with diabetes and should be guided by evidence-based standards. The overall objectives of DSME (diabetes self-management education) are to support informed decision-making, self-care behaviors, problem solving, and active collaboration with the health care team and improve clinical outcomes, health status, and quality of life.”³

Few family physicians would disagree that self-management is a good thing for patients, but many would be surprised to find that the evidence for self-management is not as convincing as one might expect. The CDC reports that 57.4% of patients with diabetes have attended a self-management class for diabetes, and 63.6% perform daily self-monitoring of blood glucose (SMBG).⁴ Yet, there is only indirect evidence that self-management programs are associated with modest improvements in HbA1c.⁵ SMBG has long been considered a mainstay of diabetes self-care, yet a growing body of evidence has shown that this practice is not universally beneficial.⁶ Although self-management education may reduce HbA1c levels in the short term, the long-term clinical effectiveness of SMBG has not been established.^7-11

Know when to recommend SMBG

With clinical interventions, we want to give priority to those that significantly improve patient outcomes. Checking blood glucose makes good sense for insulin-treated patients to monitor for and prevent asymptomatic hypoglycemia or hyperglycemia, especially when the risk for these complications is high. In a large database study of almost 27,000 children and adolescents with type 1 diabetes, increased daily frequency of SMBG, after adjustment for multiple confounders, was significantly associated with lower HbA1c levels (–0.2% per additional test per day, leveling off at 5 tests per day) and fewer acute complications.¹²

Although it has been suggested that more frequent SMBG improves long-term glycemic control among patients with insulin-treated type 1 and type 2 diabetes, the benefits are modest.¹³ The ADA recommends SMBG 3 or more times daily for patients using multiple insulin injections or insulin pump therapy.¹⁴

In patients with type 2 diabetes who are not taking insulin, the benefits of SMBG are less clear. A meta-analysis of SMBG in non-insulin-treated patients with type 2 diabetes showed that it was associated with a reduction of HbA1c of –0.4%.¹⁵ A Cochrane review added that SMBG leads to small but significant decreases after 6 months, but that these improvements are not sustained at 12 months. The same review noted no improvements in patient satisfaction or general health-related quality of life resulting from SMBG.⁶ But many of the studies in this analysis included other interventions, making it difficult to isolate the impact of SMBG on glycemic control. Other studies show that SMBG does not improve glycemic control at all.¹⁶

For patients using less-frequent insulin injections, non-insulin therapies, or medical nutrition therapy alone, the ADA suggests that SMBG may be useful as a guide to management. Continuous glucose monitoring for patients with type 2 diabetes might improve glycemic control, but the evidence for this is inconsistent.¹⁷

Why wouldn’t you want to recommend self-monitoring? Despite the fact that the benefits of SMBG are unclear in patients with type 2 diabetes not treated with insulin, it’s hard to imagine why this practice could be harmful to patients. After all, it’s natural to assume that more knowledge must be a good thing. Unfortunately, it is not that simple. Even in newly diagnosed patients with type 2 diabetes not taking insulin, self-monitoring does not improve glycemic control and may increase depression.¹⁶

It is also important to remember that self-monitoring comes at considerable cost, monetarily for the health care system and in impaired quality of life for patients.¹⁸ While there is scant evidence in the empiric literature about patient attitudes toward self-monitoring, the available evidence suggests that patients are ambivalent about it. One qualitative study concluded that patients tended not to act on the results of self-monitoring, in part because of a lack of education about the appropriate response to readings.¹⁹ With better knowledge, it is possible that patients might find more value in SMBG.

Self-management programs: Not all are created equal

The driving principle in patient-centered care is engaging patients to be active participants in the management of their chronic conditions. At face value, this would seem to be a good thing. But although individual trials of self-management are promising, the balance of evidence for self-management is limited and inconclusive. In a systematic review of 72 randomized trials of DSME in patients ≥18 years with type 2 diabetes, short-term improvements in diabetes knowledge, frequency and accuracy of glucose self-monitoring, self-reported dietary habits, and better glycemic control were possible, but long-term clinical effectiveness was not shown. In this analysis, there was no significant effect on cardiovascular events or mortality.²⁰ In another systematic review and critique of the literature on self-management, investigators again found small to moderate effects, but with significant evidence of publication bias in the included trials.²¹

The uncertainty about self-management exists because not all self-management interventions have equal impact on patient outcomes. Motivational interviewing, collaborative problem solving, and negotiating individualized goals for each patient, for example, may have longer-standing benefit than those focused on education alone.²²

A 2009 meta-analysis of DSME and its efficacy differentiated teaching, behavioral, psychological, and “mixed” or combination approaches. Most of the interventions were behaviorally oriented, sometimes combined with one other format. Psychological interventions targeting negative or self-defeating moods and social and emotional coping skills yielded moderate effects on metabolic control and self-care behaviors.²³

Clinic-based self-management. One randomized prospective study compared intensive clinic-based education on complications of diabetes with standard care. After 4 years, patients exhibited significant reductions in HbA1c, blood pressure, and low-density lipoprotein cholesterol levels.²⁴

A large meta-analysis examining a range of self-management programs for multiple chronic conditions showed a statistically and clinically significant improvement in glycemic control equivalent to a 0.81% reduction in HbA1c. Features of self-management addressed in this meta-analysis included various forms of nurse- and provider-driven education about medications, diet and exercise, motivational interviewing, and biofeedback.²⁵

Nurse-led DSME has been associated with improvements in HbA1c and cardiovascular risk factors.²⁶ Dietician-led DSME has been associated improvements in HbA1c when compared with routine care.²⁶

Cognitive behavioral therapy. Overall, the most frequently reported and most widely used psychosocial intervention is cognitive behavioral therapy (CBT); it is often short term and skills based, targeting unhelpful negative thinking and increasing positive behavior, including problem solving and relaxation, which have been shown to be effective in treating depression.²⁷ An older randomized control trial (RCT) specifically focused on type 2 diabetes explored the impact of CBT on both diabetes and depression among patients with diabetes and comorbid major depressive disorder (MDD). Improvements in depression seen at the end of the intervention were still evident 6 months later. And while there was no difference in HbA1c levels immediately following the intervention, after 6 months the mean HbA1c level was significantly better in the CBT group than in the control group (9.5% vs 10.9%; P=.03). There was no statistically significant difference in SMBG between the groups.²⁸

Group-based vs individual training. The evidence comparing group-based and individual self-management support is inconsistent. In one RCT focused on personalized action-oriented goals for healthy eating, SMBG, taking medications, problem solving, risk reduction, healthy coping, and physical activity, individual education led to reductions in HbA1c levels (–0.51%) after 6 months that were not observed in the group-based education and usual care groups.¹⁰ On the other hand, a Cochrane review of trials comparing group-based and individual routine care suggested greater benefits overall in group-based approaches, but with the caveat that many of the included trials had methodological limitations.²⁹

Mobile phone and online interventions? Stay tuned
The jury is still out on interventions like peer advising and telephone, telemedicine, and online support. In a systematic review of 22 trials evaluating mobile phone interventions for self-management (eg, text messaging, phone reminders, and coaching interventions), investigators observed a 0.5% decrease in HbA1c levels over a median followup period of 6 months.³⁰ Various telephone interventions have shown modest and short-term improvements in HbA1c levels, but none of these interventions has improved clinical outcomes.^31-33 Combinations of telephone and online self-management are beginning to show promise, but so far the evidence shows only short-term benefit, and clinical outcomes have not been studied.^34,35

CASE Based on the available evidence, a number of ways to support Ms. M’s efforts at self-management would be justified. Eliciting her perspective on the options would be well worth the effort. She is not taking insulin, so we would not recommend daily SMBG, but we’d support her if she expressed a strong preference for self-monitoring. Once insulin treatment enters the picture, however, we would strongly recommend daily SMBG to promote patient engagement and safety. And although there is limited evidence to support referral to self-management programs, if a particular program fit Ms. M’s lifestyle, we would refer her nonetheless.

CORRESPONDENCE 
Michael Mendoza, MD, MPH, Highland Family Medicine, 777 S. Clinton Avenue, Rochester, NY 14620; [email protected]

CASE Donna M is a 53-year-old woman with type 2 diabetes mellitus, who maintains fair glycemic control with metformin and glipizide. Her HbA1c level is 8.7%, but she has mixed feelings about initiating insulin treatment. Many of her family members also struggle with diabetes, and they frequently accompany Ms. M on her office visits. Ms. M is motivated to do whatever she can—in addition to taking her medications—to improve her diabetes. Her family asks if there is anything they can do to help. If you were Ms. M’s physician, what would you recommend?

The Centers for Disease Control and Prevention (CDC) estimates that diabetes affects 25.8 million people (or 8.3% of the population) in the United States, and that 7 million of them are undiagnosed.¹ Based on the known prevalence of prediabetes, the CDC estimates that 79 million Americans ≥20 years of age are at risk for diabetes. Approximately 5.7 million people with diabetes take insulin, with or without oral medications.²

As the spotlight shines brighter on efforts to promote patient-centeredness in health care—especially with respect to chronic illness—attention to the role of self-management has also grown. And family physicians have begun to reconsider how best to engage and motivate patients to manage their illness.

In this article, we review “what else” patients can do—and perhaps need not do—based on the evidence.

What is self-management anyway?

The concept of self-management is not foreign to most family physicians, yet they and their patients probably do not share a common understanding of what it entails. The American Diabetes Association (ADA) defines diabetes self-management as “the ongoing process of facilitating the knowledge, skill, and ability necessary for diabetes self-care. Self-management should incorporate the needs, goals, and life experiences of the person with diabetes and should be guided by evidence-based standards. The overall objectives of DSME (diabetes self-management education) are to support informed decision-making, self-care behaviors, problem solving, and active collaboration with the health care team and improve clinical outcomes, health status, and quality of life.”³

Few family physicians would disagree that self-management is a good thing for patients, but many would be surprised to find that the evidence for self-management is not as convincing as one might expect. The CDC reports that 57.4% of patients with diabetes have attended a self-management class for diabetes, and 63.6% perform daily self-monitoring of blood glucose (SMBG).⁴ Yet, there is only indirect evidence that self-management programs are associated with modest improvements in HbA1c.⁵ SMBG has long been considered a mainstay of diabetes self-care, yet a growing body of evidence has shown that this practice is not universally beneficial.⁶ Although self-management education may reduce HbA1c levels in the short term, the long-term clinical effectiveness of SMBG has not been established.^7-11

Know when to recommend SMBG

With clinical interventions, we want to give priority to those that significantly improve patient outcomes. Checking blood glucose makes good sense for insulin-treated patients to monitor for and prevent asymptomatic hypoglycemia or hyperglycemia, especially when the risk for these complications is high. In a large database study of almost 27,000 children and adolescents with type 1 diabetes, increased daily frequency of SMBG, after adjustment for multiple confounders, was significantly associated with lower HbA1c levels (–0.2% per additional test per day, leveling off at 5 tests per day) and fewer acute complications.¹²

Although it has been suggested that more frequent SMBG improves long-term glycemic control among patients with insulin-treated type 1 and type 2 diabetes, the benefits are modest.¹³ The ADA recommends SMBG 3 or more times daily for patients using multiple insulin injections or insulin pump therapy.¹⁴

In patients with type 2 diabetes who are not taking insulin, the benefits of SMBG are less clear. A meta-analysis of SMBG in non-insulin-treated patients with type 2 diabetes showed that it was associated with a reduction of HbA1c of –0.4%.¹⁵ A Cochrane review added that SMBG leads to small but significant decreases after 6 months, but that these improvements are not sustained at 12 months. The same review noted no improvements in patient satisfaction or general health-related quality of life resulting from SMBG.⁶ But many of the studies in this analysis included other interventions, making it difficult to isolate the impact of SMBG on glycemic control. Other studies show that SMBG does not improve glycemic control at all.¹⁶

For patients using less-frequent insulin injections, non-insulin therapies, or medical nutrition therapy alone, the ADA suggests that SMBG may be useful as a guide to management. Continuous glucose monitoring for patients with type 2 diabetes might improve glycemic control, but the evidence for this is inconsistent.¹⁷

Why wouldn’t you want to recommend self-monitoring? Despite the fact that the benefits of SMBG are unclear in patients with type 2 diabetes not treated with insulin, it’s hard to imagine why this practice could be harmful to patients. After all, it’s natural to assume that more knowledge must be a good thing. Unfortunately, it is not that simple. Even in newly diagnosed patients with type 2 diabetes not taking insulin, self-monitoring does not improve glycemic control and may increase depression.¹⁶

It is also important to remember that self-monitoring comes at considerable cost, monetarily for the health care system and in impaired quality of life for patients.¹⁸ While there is scant evidence in the empiric literature about patient attitudes toward self-monitoring, the available evidence suggests that patients are ambivalent about it. One qualitative study concluded that patients tended not to act on the results of self-monitoring, in part because of a lack of education about the appropriate response to readings.¹⁹ With better knowledge, it is possible that patients might find more value in SMBG.

Self-management programs: Not all are created equal

The driving principle in patient-centered care is engaging patients to be active participants in the management of their chronic conditions. At face value, this would seem to be a good thing. But although individual trials of self-management are promising, the balance of evidence for self-management is limited and inconclusive. In a systematic review of 72 randomized trials of DSME in patients ≥18 years with type 2 diabetes, short-term improvements in diabetes knowledge, frequency and accuracy of glucose self-monitoring, self-reported dietary habits, and better glycemic control were possible, but long-term clinical effectiveness was not shown. In this analysis, there was no significant effect on cardiovascular events or mortality.²⁰ In another systematic review and critique of the literature on self-management, investigators again found small to moderate effects, but with significant evidence of publication bias in the included trials.²¹

The uncertainty about self-management exists because not all self-management interventions have equal impact on patient outcomes. Motivational interviewing, collaborative problem solving, and negotiating individualized goals for each patient, for example, may have longer-standing benefit than those focused on education alone.²²

A 2009 meta-analysis of DSME and its efficacy differentiated teaching, behavioral, psychological, and “mixed” or combination approaches. Most of the interventions were behaviorally oriented, sometimes combined with one other format. Psychological interventions targeting negative or self-defeating moods and social and emotional coping skills yielded moderate effects on metabolic control and self-care behaviors.²³

Clinic-based self-management. One randomized prospective study compared intensive clinic-based education on complications of diabetes with standard care. After 4 years, patients exhibited significant reductions in HbA1c, blood pressure, and low-density lipoprotein cholesterol levels.²⁴

A large meta-analysis examining a range of self-management programs for multiple chronic conditions showed a statistically and clinically significant improvement in glycemic control equivalent to a 0.81% reduction in HbA1c. Features of self-management addressed in this meta-analysis included various forms of nurse- and provider-driven education about medications, diet and exercise, motivational interviewing, and biofeedback.²⁵

Nurse-led DSME has been associated with improvements in HbA1c and cardiovascular risk factors.²⁶ Dietician-led DSME has been associated improvements in HbA1c when compared with routine care.²⁶

Cognitive behavioral therapy. Overall, the most frequently reported and most widely used psychosocial intervention is cognitive behavioral therapy (CBT); it is often short term and skills based, targeting unhelpful negative thinking and increasing positive behavior, including problem solving and relaxation, which have been shown to be effective in treating depression.²⁷ An older randomized control trial (RCT) specifically focused on type 2 diabetes explored the impact of CBT on both diabetes and depression among patients with diabetes and comorbid major depressive disorder (MDD). Improvements in depression seen at the end of the intervention were still evident 6 months later. And while there was no difference in HbA1c levels immediately following the intervention, after 6 months the mean HbA1c level was significantly better in the CBT group than in the control group (9.5% vs 10.9%; P=.03). There was no statistically significant difference in SMBG between the groups.²⁸

Group-based vs individual training. The evidence comparing group-based and individual self-management support is inconsistent. In one RCT focused on personalized action-oriented goals for healthy eating, SMBG, taking medications, problem solving, risk reduction, healthy coping, and physical activity, individual education led to reductions in HbA1c levels (–0.51%) after 6 months that were not observed in the group-based education and usual care groups.¹⁰ On the other hand, a Cochrane review of trials comparing group-based and individual routine care suggested greater benefits overall in group-based approaches, but with the caveat that many of the included trials had methodological limitations.²⁹

Mobile phone and online interventions? Stay tuned
The jury is still out on interventions like peer advising and telephone, telemedicine, and online support. In a systematic review of 22 trials evaluating mobile phone interventions for self-management (eg, text messaging, phone reminders, and coaching interventions), investigators observed a 0.5% decrease in HbA1c levels over a median followup period of 6 months.³⁰ Various telephone interventions have shown modest and short-term improvements in HbA1c levels, but none of these interventions has improved clinical outcomes.^31-33 Combinations of telephone and online self-management are beginning to show promise, but so far the evidence shows only short-term benefit, and clinical outcomes have not been studied.^34,35

CASE Based on the available evidence, a number of ways to support Ms. M’s efforts at self-management would be justified. Eliciting her perspective on the options would be well worth the effort. She is not taking insulin, so we would not recommend daily SMBG, but we’d support her if she expressed a strong preference for self-monitoring. Once insulin treatment enters the picture, however, we would strongly recommend daily SMBG to promote patient engagement and safety. And although there is limited evidence to support referral to self-management programs, if a particular program fit Ms. M’s lifestyle, we would refer her nonetheless.

CORRESPONDENCE 
Michael Mendoza, MD, MPH, Highland Family Medicine, 777 S. Clinton Avenue, Rochester, NY 14620; [email protected]

Most studies of heart failure (HF)—the most common cause of hospitalization in patients older than 65 years¹—have focused on patients with reduced ejection fraction (EF). Yet half of those hospitalized for acute decompensated HF have a normal left ventricular EF.² For these patients, contractility is not the problem—impaired relaxation during diastole is.

Commonly called diastolic HF, heart failure with preserved ejection fraction (HFPEF) is a more precise name for this condition. Patients are usually older than those with a reduced EF.³ Thus, as the US population ages, the prevalence of HFPEF increases, as well.⁴

Diagnostic criteria have been developed for HFPEF, but there are few large, high-quality studies to guide its treatment. Yet family physicians need to be familiar with HFPEF and know how best to treat it. With extrapolation from studies of patients with reduced EF, as well as expert consensus and our own experience, we offer an evidence-based approach to the management of both stable and acute decompensated HFPEF.

A closer look at diastolic dysfunction

Defined as an abnormality of diastolic compliance, filling, or relaxation of the ventricle, diastolic dysfunction can occur whether EF is normal or abnormal.³ Ventricular diastole includes isovolumic relaxation, early passive filling after mitral valve opening, and active filling during atrial contraction. Transmission of high ventricular pressure to the pulmonary circulation leads to pulmonary edema, dyspnea, and other symptoms of HF. Factors other than abnormal diastolic physiology, such as chronic volume overload, ventricular coupling dyssynchrony, increased autonomic tone leading to reduced venous capacitance, and chronotropic intolerance, may also be involved.⁵

Patient history: What to look for
A variety of conditions, including ischemia, tachycardia, impaired myocardial relaxation, and age-related loss of myocardial compliance, can contribute to abnormal diastolic function, but the major causes of HFPEF are chronic hypertension, hypertrophic cardiomyopathy, and coronary artery disease (CAD).³ Rarely, infiltrative or restrictive cardiomyopathy (eg, amyloidosis or sarcoidosis) is implicated.⁶ Noncardiovascular comorbidities such as diabetes, renal impairment, anemia, and chronic lung disease are more prevalent among those with HFPEF, and more women are affected than men.¹

Mortality risk. In a study of more than 100,000 hospitalizations for acute decompensated HF, patients with preserved EF had lower in-hospital mortality (3% vs 4% for those with reduced EF).² Patients with both diabetes and CAD commonly develop HFPEF,⁷ and the presence of these comorbidities are an independent predictor of 5-year mortality.⁸

Population studies suggest that 5-year mortality rates for African Americans with HFPEF are higher than for Caucasians with this condition.⁹ Other predictors of mortality include older age, male sex, lower left ventricular EF, ischemic disease, impaired renal function, and peripheral arterial disease.^10-12

Diagnosing HFPEF: What you’ll see, when to test

The presentation of patients with HFPEF is similar to that of individuals with reduced EF. In an outpatient setting, both groups will have reduced exercise capacity; increased neuroendocrine activation, which may cause chronic fluid retention, vasoconstriction, and tachycardia; and a reduced quality of life.⁵

Neither the American College of Cardiology/American Heart Association (ACC/AHA) nor the Heart Failure Society of America (HFSA)^13,14 recommends screening for asymptomatic left ventricular dysfunction. For those with signs and symptoms of HF, however, echocardiography is a key component of the initial evaluation. Echocardiography provides information about left ventricular systolic function, including EF, regional wall motion abnormalities, and wall thickness. Echocardiographic evidence of diastolic abnormalities is found for some patients with HFPEF, while others have no demonstrable diastolic dysfunction.³

While an electrocardiogram (EKG) cannot distinguish between HF with reduced EF and HFPEF, common findings might include signs of ventricular hypertrophy or tachycardia during acute exacerbations. An EKG should be obtained in patients with suspected HF to screen for antecedent causes such as hypertrophy, atrial fibrillation, and ischemia.¹⁵

What Doppler echocardiography and the E/A ratio reveal
Doppler echocardiography is used to further evaluate the characteristics of blood flow, showing the relationship among left ventricular (LV) relaxation, atrial pressure, atrial contraction, and blood flow velocity across the mitral valve during diastole. The peak velocity of blood flow during early diastole (called the “E wave”) and late diastole (the atrial contraction, or “A wave”) is measured and the E/A ratio (reflecting the transmitral blood flow pattern) is calculated (FIGURE).³

FIGURE

The E/A ratio* and what it reveals

A, atrial contraction; E, early passive filling; MVC, mitral valve closes; MVO, mitral valve opens.
*E/A ratio represents the relationship between the peak velocity of blood flow during early diastole (E wave) and late diastole (A wave).
Adapted from: Aurigemma GP, Gaasch WH. N Engl J Med. 2004.³

Normally, transmitral flow velocity is greater during early diastole than during atrial contraction, and the E/A ratio is approximately 1.5 (E>A). With early diastolic dysfunction, impaired relaxation prevents blood from flowing passively into the LV during early diastole. This causes reversal of the E/A ratio, which drops to <1 (E<A). As diastolic function worsens, atrial contraction is impaired, and left atrial pressure rises. The result: A reduction in the A wave amplitude and proportionally more blood flow during early diastole and a “pseudonormal” (E>A) ratio, with a greater difference between the E and A than is normally observed. This finding is an independent predictor of all-cause mortality in patients with asymptomatic HF.¹⁶

Cardiac catheterization. Invasive measurement of LV filling pressures is the gold standard for diagnosing HFPEF. If echocardiography does not lead to a clear diagnosis, cardiac catheterization can provide information about concomitant pulmonary hypertension and mechanical asynchrony that may contribute to symptomatic HF.¹ When the diagnosis is uncertain, additional testing—eg, plasma brain natriuretic peptide (BNP), chest x-ray, or exercise testing—may be necessary to establish a diagnosis of symptomatic HF.

The diagnostic criteria developed by HFSA include clinical evidence of HF and:

• echocardiographic evidence of LV hypertrophy or left atrial enlargement (without atrial fibrillation) or
• evidence of diastolic dysfunction on Doppler echocardiography or cardiac catheterization.¹⁴

It is important to note that the diagnostic criteria have not been validated, and the sensitivity and specificity of the various clinical findings are not known.

CASE Carrie W, a 76-year-old woman referred to you by a colleague, presents for follow-up after being hospitalized for HF. She recalls feeling fatigue, chest pain, and out of breath with even minimal exertion before being admitted to the hospital.

You obtain her hospital records, which show that echocardiography found impaired LV relaxation based on a reversed E/A ratio and an EF of 65%. In addition, BNP was elevated, and a chest x-ray showed pulmonary vascular congestion. You note that her blood pressure was 175/103 mm Hg on admission and an EKG showed LV hypertrophy and sinus tachycardia, but no ischemia.

Before being hospitalized, Ms. W was taking extended-release metoprolol, aspirin, and lisinopril. The hospitalist added lovastatin and increased the daily dose of extended-release metoprolol from 25 to 100 mg.

What changes, if any, would you make in her medication regimen?

Diastolic dysfunction as chronic disease
Often asymptomatic, diastolic dysfunction should be thought of as a chronic progressive disease characterized by complex physiologic adaptations that vary over time (See “Staging heart failure: The clinical course of HFPEF”.¹³) Patients with HFPEF have a difficult time tolerating hemodynamic stress and any perturbation of afterload, heart rate, or ventricular function can precipitate an acute exacerbation.² Clinical factors that precipitate acute decompensation of HFPEF—which we’ll discuss a bit later—include uncontrolled hypertension; atrial fibrillation; and noncardiovascular comorbidities such as lung disease, renal impairment, or sepsis.²

The Acute Decompensated HEart failure national REgistry (ADHERE), in which the records of well over 80,000 Medicare patients were reviewed, found that more than 60% of those hospitalized with HFPEF had uncontrolled hypertension, with a systolic pressure >140 mm Hg; 21% had atrial fibrillation.² These findings emphasize the importance of aggressive blood pressure (BP) and heart rate control.

Management of HFPEF is goal directed

The aim of pharmacologic treatment of HFPEF is to maintain fluid balance, prevent tachycardia, treat and prevent ischemia, and control hypertension (TABLE).^14,17-30 While the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers, among other pharmacologic agents, is well studied for patients with reduced EF, there is limited evidence to guide the treatment of those with HFPEF. Although no single agent or drug class has been shown to be superior for such patients, there are a number of pharmacologic treatments to consider.

TABLE
Management of heart failure with preserved ejection fraction—matching treatment and goals^14,17-30

Inhibition of the renin-angiotensin-aldosterone system
Pathologic activation of the renin-angiotensin-aldosterone system (RAAS) contributes to elevated systolic and diastolic pressure, LV hypertrophy, and LV fibrosis. Inhibition of this system is a promising treatment modality for HFPEF.³¹

ACE inhibitors. Experimental studies suggest that ACE inhibitors benefit the diastolic properties of the heart, in both short- and long-term use. The PEP-CHF trial found that for older patients with diastolic dysfunction, perindopril led to significant improvements in functional class and exercise capacity but failed to show a statistically significant reduction in all-cause mortality or hospitalization for acute decompensated HF.¹⁷

ARBs. There is no evidence to show that ARB therapy improves morbidity or mortality in HFPEF. Using surrogate end points, ARBs have been associated with regression of LV hypertrophy, and losartan was found to improve exercise tolerance and quality of life, compared with hydrochlorothiazide.^18,19 In the CHARM-Preserved trial, candesartan showed an insignificant reduction in cardiovascular mortality and hospitalization for HF.

These results must be viewed with caution, however, because adverse effects led to high rates of medication discontinuation.³² In the I-PRESERVE trial, irbesartan conferred no benefit with respect to mortality, hospitalization, or quality of life on patients with HFPEF.³³

ACE inhibitor or ARB—not both. ACE inhibitors and ARBs are good choices for BP control in patients with HFPEF, especially if LV hypertrophy is present, but periodic testing of renal function and potassium levels is needed. ACE inhibitors and ARBs should not be used concurrently, as the combination increases the risk of acute renal failure and has no benefit in clinical outcomes.³⁴

BP and rate control
In small trials, beta-blockers have been found to improve diastolic function as seen on echocardiography, but data on morbidity and mortality are lacking.²⁰ A secondary analysis of the OPTIMIZE-HF registry found that beta-blocker therapy was associated with reduced mortality and readmission in patients with reduced EF, but not in those with normal EF.²¹

Findings from the SENIORS trial were more promising: Treatment with nebivolol reduced both mortality and readmission rates for elderly patients with HF, with similar benefits for those with reduced and preserved EF.²² Overall, beta-blockers appear to be a reasonable choice for heart rate and/or BP control in patients who have HFPEF and atrial fibrillation or hypertension. Carvedilol, long-acting metoprolol, and bisoprolol have been shown to reduce mortality in HF with reduced EF, and it is reasonable to choose one of these agents for patients with preserved EF, as well.²³

Calcium channel blockers (CCBs) may be useful in treating patients with HFPEF for both BP and heart rate control, as well. Theoretically, CCBs may also improve the process of relaxation by altering intracellular calcium cycling during the contractile cycle in myocytes. This contrasts with the management of HF patients with reduced EF, for whom the use of nonselective CCBs such as diltiazem and verapamil may adversely affect contractility.

In small RCTs, verapamil has been found to improve HF symptoms and exercise tolerance in patients with HFPEF,²⁴ but no evidence of improved outcomes or mortality rates with CCB use has been found.

Other pharmacologic options to consider
Aldosterone antagonist therapy is an important component of treatment for patients with HF with reduced EF. Data supporting the use of spironolactone use from the RALES trial and eplerenone in the EPHESUS and EMPHASIS-HF trials suggest a reduction in mortality in patients with low (<35%) LVEF.^25-27 For patients with preserved EF, however, spironolactone is not generally recommended.

A large National Institutes of Health-sponsored trial is underway to determine if the drug is beneficial for patients with preserved LVEF, and will build on a small study in which 30 patients with HFPEF showed improved myocardial function after treatment with spironolactone.³⁵ Until more data become available, the risks of using aldosterone antagonists outweigh the evidence to support their use in this patient population.

Diuretics are an important component of treatment for all patients with HF and fluid overload. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) showed a reduced incidence of symptomatic HFPEF in patients taking diuretics.²⁸ As is the case with patients with reduced EF, those with preserved EF should be treated with diuretics if they have symptoms of fluid overload.

Statins. Intensive lipid lowering with statin therapy has been shown in observational studies to benefit patients with HFPEF with respect to mortality, independent of baseline low-density lipoprotein cholesterol.²⁹ RCTs are needed to confirm these observations, but statin therapy is recommended for the secondary prevention of cardiovascular disease, independent of the presence of diastolic dysfunction or HFPEF.

Guard against hypotension. Patients with diastolic dysfunction are susceptible to hypotension if there is a rapid reduction in preload with diuretics, nonselective CCBs, or nitrates, so it is important that doses be titrated slowly.

Nonpharmacologic measures are important, too

In addition to optimizing treatment of comorbid conditions, patients with HFPEF should be advised that lifestyle modifications such as weight loss, smoking cessation, and dietary changes can do much to reduce the risk. You can help by providing an exercise “prescription” (with a specified intensity, frequency, and duration) and dietary guidelines, with emphasis on the importance of a low-sodium diet to prevent fluid overload.^14,30 Recommend local programs for patients with HF, which many hospitals and health systems offer as part of their efforts to reduce readmission rates.

Consider cardioversion
Tachycardia shortens the time for filling during diastole; thus, it is poorly tolerated in patients with diastolic dysfunction and could trigger acute decompensation. To avoid the risk, restoration of sinus rhythm should be considered for patients with HFPEF and atrial fibrillation. Patients with known paroxysmal or permanent atrial fibrillation and preserved EF should be seen by a cardiologist to determine whether direct current cardioversion or ablation with a permanent pacemaker is appropriate.¹¹ When cardioversion is contraindicated, a beta-blocker is needed to control heart rate and improve hemodynamics.

Patients with stable angina and HFPEF should be evaluated for revascularization when medical therapy alone is not sufficient for symptom relief.¹⁰ Here, too, a cardiology consult is indicated for any patient who has HF and an abnormal noninvasive stress test or persistent symptoms despite optimal drug therapy.

Recognizing and responding to acute decompensated HFPEF

The initial response to acute decompensated HFPEF, like that of HF with reduced EF, should be focused on restoring volume status and providing oxygenation, ventilation, and vasodilator therapy in some cases.¹¹ Unlike those with acute decompensated HF with reduced EF, however, patients with HFPEF can safely tolerate the initiation of beta-blockers in the acute phase, especially when rate control is needed.³ Inotropic agents like digoxin and dobutamine, however, are contraindicated.³

Guidelines recommend hospitalization for patients with abnormal vital signs, arrhythmia, and suspected acute coronary syndromes, and consideration of hospitalization for those with associated comorbid conditions, new HF, or progressive fluid overload.¹³

CASE Because Ms. W has a normal BP and heart rate and is feeling well, you decline to alter her medication regimen. You do, however, recommend that she begin an exercise program, adopt a low-sodium diet, and maintain regular contact with your office so you can evaluate any changes in status.

You introduce Ms. W to the nurse case manager in your office. The nurse works with the patient to develop an action plan that includes daily tracking of her weight and sodium intake; a progressive walking program, starting with 2-minute sessions and progressing to 15 to 30 minutes 3 to 5 times a week; weekly telephone checkins; and immediate calls to report any weight increase or symptoms of HF.

At follow-up 6 months later, Ms. W has improved BP and reports that she enjoys her new exercise routine. She has more energy and denies any edema or breathing difficulties.

Most studies of heart failure (HF)—the most common cause of hospitalization in patients older than 65 years¹—have focused on patients with reduced ejection fraction (EF). Yet half of those hospitalized for acute decompensated HF have a normal left ventricular EF.² For these patients, contractility is not the problem—impaired relaxation during diastole is.

Commonly called diastolic HF, heart failure with preserved ejection fraction (HFPEF) is a more precise name for this condition. Patients are usually older than those with a reduced EF.³ Thus, as the US population ages, the prevalence of HFPEF increases, as well.⁴

Diagnostic criteria have been developed for HFPEF, but there are few large, high-quality studies to guide its treatment. Yet family physicians need to be familiar with HFPEF and know how best to treat it. With extrapolation from studies of patients with reduced EF, as well as expert consensus and our own experience, we offer an evidence-based approach to the management of both stable and acute decompensated HFPEF.

A closer look at diastolic dysfunction

Defined as an abnormality of diastolic compliance, filling, or relaxation of the ventricle, diastolic dysfunction can occur whether EF is normal or abnormal.³ Ventricular diastole includes isovolumic relaxation, early passive filling after mitral valve opening, and active filling during atrial contraction. Transmission of high ventricular pressure to the pulmonary circulation leads to pulmonary edema, dyspnea, and other symptoms of HF. Factors other than abnormal diastolic physiology, such as chronic volume overload, ventricular coupling dyssynchrony, increased autonomic tone leading to reduced venous capacitance, and chronotropic intolerance, may also be involved.⁵

Patient history: What to look for
A variety of conditions, including ischemia, tachycardia, impaired myocardial relaxation, and age-related loss of myocardial compliance, can contribute to abnormal diastolic function, but the major causes of HFPEF are chronic hypertension, hypertrophic cardiomyopathy, and coronary artery disease (CAD).³ Rarely, infiltrative or restrictive cardiomyopathy (eg, amyloidosis or sarcoidosis) is implicated.⁶ Noncardiovascular comorbidities such as diabetes, renal impairment, anemia, and chronic lung disease are more prevalent among those with HFPEF, and more women are affected than men.¹

Mortality risk. In a study of more than 100,000 hospitalizations for acute decompensated HF, patients with preserved EF had lower in-hospital mortality (3% vs 4% for those with reduced EF).² Patients with both diabetes and CAD commonly develop HFPEF,⁷ and the presence of these comorbidities are an independent predictor of 5-year mortality.⁸

Population studies suggest that 5-year mortality rates for African Americans with HFPEF are higher than for Caucasians with this condition.⁹ Other predictors of mortality include older age, male sex, lower left ventricular EF, ischemic disease, impaired renal function, and peripheral arterial disease.^10-12

Diagnosing HFPEF: What you’ll see, when to test

The presentation of patients with HFPEF is similar to that of individuals with reduced EF. In an outpatient setting, both groups will have reduced exercise capacity; increased neuroendocrine activation, which may cause chronic fluid retention, vasoconstriction, and tachycardia; and a reduced quality of life.⁵

Neither the American College of Cardiology/American Heart Association (ACC/AHA) nor the Heart Failure Society of America (HFSA)^13,14 recommends screening for asymptomatic left ventricular dysfunction. For those with signs and symptoms of HF, however, echocardiography is a key component of the initial evaluation. Echocardiography provides information about left ventricular systolic function, including EF, regional wall motion abnormalities, and wall thickness. Echocardiographic evidence of diastolic abnormalities is found for some patients with HFPEF, while others have no demonstrable diastolic dysfunction.³

While an electrocardiogram (EKG) cannot distinguish between HF with reduced EF and HFPEF, common findings might include signs of ventricular hypertrophy or tachycardia during acute exacerbations. An EKG should be obtained in patients with suspected HF to screen for antecedent causes such as hypertrophy, atrial fibrillation, and ischemia.¹⁵

What Doppler echocardiography and the E/A ratio reveal
Doppler echocardiography is used to further evaluate the characteristics of blood flow, showing the relationship among left ventricular (LV) relaxation, atrial pressure, atrial contraction, and blood flow velocity across the mitral valve during diastole. The peak velocity of blood flow during early diastole (called the “E wave”) and late diastole (the atrial contraction, or “A wave”) is measured and the E/A ratio (reflecting the transmitral blood flow pattern) is calculated (FIGURE).³

FIGURE

The E/A ratio* and what it reveals

A, atrial contraction; E, early passive filling; MVC, mitral valve closes; MVO, mitral valve opens.
*E/A ratio represents the relationship between the peak velocity of blood flow during early diastole (E wave) and late diastole (A wave).
Adapted from: Aurigemma GP, Gaasch WH. N Engl J Med. 2004.³

Normally, transmitral flow velocity is greater during early diastole than during atrial contraction, and the E/A ratio is approximately 1.5 (E>A). With early diastolic dysfunction, impaired relaxation prevents blood from flowing passively into the LV during early diastole. This causes reversal of the E/A ratio, which drops to <1 (E<A). As diastolic function worsens, atrial contraction is impaired, and left atrial pressure rises. The result: A reduction in the A wave amplitude and proportionally more blood flow during early diastole and a “pseudonormal” (E>A) ratio, with a greater difference between the E and A than is normally observed. This finding is an independent predictor of all-cause mortality in patients with asymptomatic HF.¹⁶

Cardiac catheterization. Invasive measurement of LV filling pressures is the gold standard for diagnosing HFPEF. If echocardiography does not lead to a clear diagnosis, cardiac catheterization can provide information about concomitant pulmonary hypertension and mechanical asynchrony that may contribute to symptomatic HF.¹ When the diagnosis is uncertain, additional testing—eg, plasma brain natriuretic peptide (BNP), chest x-ray, or exercise testing—may be necessary to establish a diagnosis of symptomatic HF.

The diagnostic criteria developed by HFSA include clinical evidence of HF and:

• echocardiographic evidence of LV hypertrophy or left atrial enlargement (without atrial fibrillation) or
• evidence of diastolic dysfunction on Doppler echocardiography or cardiac catheterization.¹⁴

It is important to note that the diagnostic criteria have not been validated, and the sensitivity and specificity of the various clinical findings are not known.

CASE Carrie W, a 76-year-old woman referred to you by a colleague, presents for follow-up after being hospitalized for HF. She recalls feeling fatigue, chest pain, and out of breath with even minimal exertion before being admitted to the hospital.

You obtain her hospital records, which show that echocardiography found impaired LV relaxation based on a reversed E/A ratio and an EF of 65%. In addition, BNP was elevated, and a chest x-ray showed pulmonary vascular congestion. You note that her blood pressure was 175/103 mm Hg on admission and an EKG showed LV hypertrophy and sinus tachycardia, but no ischemia.

Before being hospitalized, Ms. W was taking extended-release metoprolol, aspirin, and lisinopril. The hospitalist added lovastatin and increased the daily dose of extended-release metoprolol from 25 to 100 mg.

What changes, if any, would you make in her medication regimen?

Diastolic dysfunction as chronic disease
Often asymptomatic, diastolic dysfunction should be thought of as a chronic progressive disease characterized by complex physiologic adaptations that vary over time (See “Staging heart failure: The clinical course of HFPEF”.¹³) Patients with HFPEF have a difficult time tolerating hemodynamic stress and any perturbation of afterload, heart rate, or ventricular function can precipitate an acute exacerbation.² Clinical factors that precipitate acute decompensation of HFPEF—which we’ll discuss a bit later—include uncontrolled hypertension; atrial fibrillation; and noncardiovascular comorbidities such as lung disease, renal impairment, or sepsis.²

The Acute Decompensated HEart failure national REgistry (ADHERE), in which the records of well over 80,000 Medicare patients were reviewed, found that more than 60% of those hospitalized with HFPEF had uncontrolled hypertension, with a systolic pressure >140 mm Hg; 21% had atrial fibrillation.² These findings emphasize the importance of aggressive blood pressure (BP) and heart rate control.

Management of HFPEF is goal directed

The aim of pharmacologic treatment of HFPEF is to maintain fluid balance, prevent tachycardia, treat and prevent ischemia, and control hypertension (TABLE).^14,17-30 While the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers, among other pharmacologic agents, is well studied for patients with reduced EF, there is limited evidence to guide the treatment of those with HFPEF. Although no single agent or drug class has been shown to be superior for such patients, there are a number of pharmacologic treatments to consider.

TABLE
Management of heart failure with preserved ejection fraction—matching treatment and goals^14,17-30

Inhibition of the renin-angiotensin-aldosterone system
Pathologic activation of the renin-angiotensin-aldosterone system (RAAS) contributes to elevated systolic and diastolic pressure, LV hypertrophy, and LV fibrosis. Inhibition of this system is a promising treatment modality for HFPEF.³¹

ACE inhibitors. Experimental studies suggest that ACE inhibitors benefit the diastolic properties of the heart, in both short- and long-term use. The PEP-CHF trial found that for older patients with diastolic dysfunction, perindopril led to significant improvements in functional class and exercise capacity but failed to show a statistically significant reduction in all-cause mortality or hospitalization for acute decompensated HF.¹⁷

ARBs. There is no evidence to show that ARB therapy improves morbidity or mortality in HFPEF. Using surrogate end points, ARBs have been associated with regression of LV hypertrophy, and losartan was found to improve exercise tolerance and quality of life, compared with hydrochlorothiazide.^18,19 In the CHARM-Preserved trial, candesartan showed an insignificant reduction in cardiovascular mortality and hospitalization for HF.

These results must be viewed with caution, however, because adverse effects led to high rates of medication discontinuation.³² In the I-PRESERVE trial, irbesartan conferred no benefit with respect to mortality, hospitalization, or quality of life on patients with HFPEF.³³

ACE inhibitor or ARB—not both. ACE inhibitors and ARBs are good choices for BP control in patients with HFPEF, especially if LV hypertrophy is present, but periodic testing of renal function and potassium levels is needed. ACE inhibitors and ARBs should not be used concurrently, as the combination increases the risk of acute renal failure and has no benefit in clinical outcomes.³⁴

BP and rate control
In small trials, beta-blockers have been found to improve diastolic function as seen on echocardiography, but data on morbidity and mortality are lacking.²⁰ A secondary analysis of the OPTIMIZE-HF registry found that beta-blocker therapy was associated with reduced mortality and readmission in patients with reduced EF, but not in those with normal EF.²¹

Findings from the SENIORS trial were more promising: Treatment with nebivolol reduced both mortality and readmission rates for elderly patients with HF, with similar benefits for those with reduced and preserved EF.²² Overall, beta-blockers appear to be a reasonable choice for heart rate and/or BP control in patients who have HFPEF and atrial fibrillation or hypertension. Carvedilol, long-acting metoprolol, and bisoprolol have been shown to reduce mortality in HF with reduced EF, and it is reasonable to choose one of these agents for patients with preserved EF, as well.²³

Calcium channel blockers (CCBs) may be useful in treating patients with HFPEF for both BP and heart rate control, as well. Theoretically, CCBs may also improve the process of relaxation by altering intracellular calcium cycling during the contractile cycle in myocytes. This contrasts with the management of HF patients with reduced EF, for whom the use of nonselective CCBs such as diltiazem and verapamil may adversely affect contractility.

In small RCTs, verapamil has been found to improve HF symptoms and exercise tolerance in patients with HFPEF,²⁴ but no evidence of improved outcomes or mortality rates with CCB use has been found.

Other pharmacologic options to consider
Aldosterone antagonist therapy is an important component of treatment for patients with HF with reduced EF. Data supporting the use of spironolactone use from the RALES trial and eplerenone in the EPHESUS and EMPHASIS-HF trials suggest a reduction in mortality in patients with low (<35%) LVEF.^25-27 For patients with preserved EF, however, spironolactone is not generally recommended.

A large National Institutes of Health-sponsored trial is underway to determine if the drug is beneficial for patients with preserved LVEF, and will build on a small study in which 30 patients with HFPEF showed improved myocardial function after treatment with spironolactone.³⁵ Until more data become available, the risks of using aldosterone antagonists outweigh the evidence to support their use in this patient population.

Diuretics are an important component of treatment for all patients with HF and fluid overload. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) showed a reduced incidence of symptomatic HFPEF in patients taking diuretics.²⁸ As is the case with patients with reduced EF, those with preserved EF should be treated with diuretics if they have symptoms of fluid overload.

Statins. Intensive lipid lowering with statin therapy has been shown in observational studies to benefit patients with HFPEF with respect to mortality, independent of baseline low-density lipoprotein cholesterol.²⁹ RCTs are needed to confirm these observations, but statin therapy is recommended for the secondary prevention of cardiovascular disease, independent of the presence of diastolic dysfunction or HFPEF.

Guard against hypotension. Patients with diastolic dysfunction are susceptible to hypotension if there is a rapid reduction in preload with diuretics, nonselective CCBs, or nitrates, so it is important that doses be titrated slowly.

Nonpharmacologic measures are important, too

In addition to optimizing treatment of comorbid conditions, patients with HFPEF should be advised that lifestyle modifications such as weight loss, smoking cessation, and dietary changes can do much to reduce the risk. You can help by providing an exercise “prescription” (with a specified intensity, frequency, and duration) and dietary guidelines, with emphasis on the importance of a low-sodium diet to prevent fluid overload.^14,30 Recommend local programs for patients with HF, which many hospitals and health systems offer as part of their efforts to reduce readmission rates.

Consider cardioversion
Tachycardia shortens the time for filling during diastole; thus, it is poorly tolerated in patients with diastolic dysfunction and could trigger acute decompensation. To avoid the risk, restoration of sinus rhythm should be considered for patients with HFPEF and atrial fibrillation. Patients with known paroxysmal or permanent atrial fibrillation and preserved EF should be seen by a cardiologist to determine whether direct current cardioversion or ablation with a permanent pacemaker is appropriate.¹¹ When cardioversion is contraindicated, a beta-blocker is needed to control heart rate and improve hemodynamics.

Patients with stable angina and HFPEF should be evaluated for revascularization when medical therapy alone is not sufficient for symptom relief.¹⁰ Here, too, a cardiology consult is indicated for any patient who has HF and an abnormal noninvasive stress test or persistent symptoms despite optimal drug therapy.

Recognizing and responding to acute decompensated HFPEF

The initial response to acute decompensated HFPEF, like that of HF with reduced EF, should be focused on restoring volume status and providing oxygenation, ventilation, and vasodilator therapy in some cases.¹¹ Unlike those with acute decompensated HF with reduced EF, however, patients with HFPEF can safely tolerate the initiation of beta-blockers in the acute phase, especially when rate control is needed.³ Inotropic agents like digoxin and dobutamine, however, are contraindicated.³

Guidelines recommend hospitalization for patients with abnormal vital signs, arrhythmia, and suspected acute coronary syndromes, and consideration of hospitalization for those with associated comorbid conditions, new HF, or progressive fluid overload.¹³

CASE Because Ms. W has a normal BP and heart rate and is feeling well, you decline to alter her medication regimen. You do, however, recommend that she begin an exercise program, adopt a low-sodium diet, and maintain regular contact with your office so you can evaluate any changes in status.

You introduce Ms. W to the nurse case manager in your office. The nurse works with the patient to develop an action plan that includes daily tracking of her weight and sodium intake; a progressive walking program, starting with 2-minute sessions and progressing to 15 to 30 minutes 3 to 5 times a week; weekly telephone checkins; and immediate calls to report any weight increase or symptoms of HF.

At follow-up 6 months later, Ms. W has improved BP and reports that she enjoys her new exercise routine. She has more energy and denies any edema or breathing difficulties.

Most studies of heart failure (HF)—the most common cause of hospitalization in patients older than 65 years¹—have focused on patients with reduced ejection fraction (EF). Yet half of those hospitalized for acute decompensated HF have a normal left ventricular EF.² For these patients, contractility is not the problem—impaired relaxation during diastole is.

Commonly called diastolic HF, heart failure with preserved ejection fraction (HFPEF) is a more precise name for this condition. Patients are usually older than those with a reduced EF.³ Thus, as the US population ages, the prevalence of HFPEF increases, as well.⁴

Diagnostic criteria have been developed for HFPEF, but there are few large, high-quality studies to guide its treatment. Yet family physicians need to be familiar with HFPEF and know how best to treat it. With extrapolation from studies of patients with reduced EF, as well as expert consensus and our own experience, we offer an evidence-based approach to the management of both stable and acute decompensated HFPEF.

A closer look at diastolic dysfunction

Defined as an abnormality of diastolic compliance, filling, or relaxation of the ventricle, diastolic dysfunction can occur whether EF is normal or abnormal.³ Ventricular diastole includes isovolumic relaxation, early passive filling after mitral valve opening, and active filling during atrial contraction. Transmission of high ventricular pressure to the pulmonary circulation leads to pulmonary edema, dyspnea, and other symptoms of HF. Factors other than abnormal diastolic physiology, such as chronic volume overload, ventricular coupling dyssynchrony, increased autonomic tone leading to reduced venous capacitance, and chronotropic intolerance, may also be involved.⁵

Patient history: What to look for
A variety of conditions, including ischemia, tachycardia, impaired myocardial relaxation, and age-related loss of myocardial compliance, can contribute to abnormal diastolic function, but the major causes of HFPEF are chronic hypertension, hypertrophic cardiomyopathy, and coronary artery disease (CAD).³ Rarely, infiltrative or restrictive cardiomyopathy (eg, amyloidosis or sarcoidosis) is implicated.⁶ Noncardiovascular comorbidities such as diabetes, renal impairment, anemia, and chronic lung disease are more prevalent among those with HFPEF, and more women are affected than men.¹

Mortality risk. In a study of more than 100,000 hospitalizations for acute decompensated HF, patients with preserved EF had lower in-hospital mortality (3% vs 4% for those with reduced EF).² Patients with both diabetes and CAD commonly develop HFPEF,⁷ and the presence of these comorbidities are an independent predictor of 5-year mortality.⁸

Population studies suggest that 5-year mortality rates for African Americans with HFPEF are higher than for Caucasians with this condition.⁹ Other predictors of mortality include older age, male sex, lower left ventricular EF, ischemic disease, impaired renal function, and peripheral arterial disease.^10-12

Diagnosing HFPEF: What you’ll see, when to test

The presentation of patients with HFPEF is similar to that of individuals with reduced EF. In an outpatient setting, both groups will have reduced exercise capacity; increased neuroendocrine activation, which may cause chronic fluid retention, vasoconstriction, and tachycardia; and a reduced quality of life.⁵

Neither the American College of Cardiology/American Heart Association (ACC/AHA) nor the Heart Failure Society of America (HFSA)^13,14 recommends screening for asymptomatic left ventricular dysfunction. For those with signs and symptoms of HF, however, echocardiography is a key component of the initial evaluation. Echocardiography provides information about left ventricular systolic function, including EF, regional wall motion abnormalities, and wall thickness. Echocardiographic evidence of diastolic abnormalities is found for some patients with HFPEF, while others have no demonstrable diastolic dysfunction.³

While an electrocardiogram (EKG) cannot distinguish between HF with reduced EF and HFPEF, common findings might include signs of ventricular hypertrophy or tachycardia during acute exacerbations. An EKG should be obtained in patients with suspected HF to screen for antecedent causes such as hypertrophy, atrial fibrillation, and ischemia.¹⁵

What Doppler echocardiography and the E/A ratio reveal
Doppler echocardiography is used to further evaluate the characteristics of blood flow, showing the relationship among left ventricular (LV) relaxation, atrial pressure, atrial contraction, and blood flow velocity across the mitral valve during diastole. The peak velocity of blood flow during early diastole (called the “E wave”) and late diastole (the atrial contraction, or “A wave”) is measured and the E/A ratio (reflecting the transmitral blood flow pattern) is calculated (FIGURE).³

FIGURE

The E/A ratio* and what it reveals

A, atrial contraction; E, early passive filling; MVC, mitral valve closes; MVO, mitral valve opens.
*E/A ratio represents the relationship between the peak velocity of blood flow during early diastole (E wave) and late diastole (A wave).
Adapted from: Aurigemma GP, Gaasch WH. N Engl J Med. 2004.³

Normally, transmitral flow velocity is greater during early diastole than during atrial contraction, and the E/A ratio is approximately 1.5 (E>A). With early diastolic dysfunction, impaired relaxation prevents blood from flowing passively into the LV during early diastole. This causes reversal of the E/A ratio, which drops to <1 (E<A). As diastolic function worsens, atrial contraction is impaired, and left atrial pressure rises. The result: A reduction in the A wave amplitude and proportionally more blood flow during early diastole and a “pseudonormal” (E>A) ratio, with a greater difference between the E and A than is normally observed. This finding is an independent predictor of all-cause mortality in patients with asymptomatic HF.¹⁶

Cardiac catheterization. Invasive measurement of LV filling pressures is the gold standard for diagnosing HFPEF. If echocardiography does not lead to a clear diagnosis, cardiac catheterization can provide information about concomitant pulmonary hypertension and mechanical asynchrony that may contribute to symptomatic HF.¹ When the diagnosis is uncertain, additional testing—eg, plasma brain natriuretic peptide (BNP), chest x-ray, or exercise testing—may be necessary to establish a diagnosis of symptomatic HF.

The diagnostic criteria developed by HFSA include clinical evidence of HF and:

• echocardiographic evidence of LV hypertrophy or left atrial enlargement (without atrial fibrillation) or
• evidence of diastolic dysfunction on Doppler echocardiography or cardiac catheterization.¹⁴

It is important to note that the diagnostic criteria have not been validated, and the sensitivity and specificity of the various clinical findings are not known.

CASE Carrie W, a 76-year-old woman referred to you by a colleague, presents for follow-up after being hospitalized for HF. She recalls feeling fatigue, chest pain, and out of breath with even minimal exertion before being admitted to the hospital.

You obtain her hospital records, which show that echocardiography found impaired LV relaxation based on a reversed E/A ratio and an EF of 65%. In addition, BNP was elevated, and a chest x-ray showed pulmonary vascular congestion. You note that her blood pressure was 175/103 mm Hg on admission and an EKG showed LV hypertrophy and sinus tachycardia, but no ischemia.

Before being hospitalized, Ms. W was taking extended-release metoprolol, aspirin, and lisinopril. The hospitalist added lovastatin and increased the daily dose of extended-release metoprolol from 25 to 100 mg.

What changes, if any, would you make in her medication regimen?

Diastolic dysfunction as chronic disease
Often asymptomatic, diastolic dysfunction should be thought of as a chronic progressive disease characterized by complex physiologic adaptations that vary over time (See “Staging heart failure: The clinical course of HFPEF”.¹³) Patients with HFPEF have a difficult time tolerating hemodynamic stress and any perturbation of afterload, heart rate, or ventricular function can precipitate an acute exacerbation.² Clinical factors that precipitate acute decompensation of HFPEF—which we’ll discuss a bit later—include uncontrolled hypertension; atrial fibrillation; and noncardiovascular comorbidities such as lung disease, renal impairment, or sepsis.²

The Acute Decompensated HEart failure national REgistry (ADHERE), in which the records of well over 80,000 Medicare patients were reviewed, found that more than 60% of those hospitalized with HFPEF had uncontrolled hypertension, with a systolic pressure >140 mm Hg; 21% had atrial fibrillation.² These findings emphasize the importance of aggressive blood pressure (BP) and heart rate control.

Management of HFPEF is goal directed

The aim of pharmacologic treatment of HFPEF is to maintain fluid balance, prevent tachycardia, treat and prevent ischemia, and control hypertension (TABLE).^14,17-30 While the use of angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and beta-blockers, among other pharmacologic agents, is well studied for patients with reduced EF, there is limited evidence to guide the treatment of those with HFPEF. Although no single agent or drug class has been shown to be superior for such patients, there are a number of pharmacologic treatments to consider.

TABLE
Management of heart failure with preserved ejection fraction—matching treatment and goals^14,17-30

Inhibition of the renin-angiotensin-aldosterone system
Pathologic activation of the renin-angiotensin-aldosterone system (RAAS) contributes to elevated systolic and diastolic pressure, LV hypertrophy, and LV fibrosis. Inhibition of this system is a promising treatment modality for HFPEF.³¹

ACE inhibitors. Experimental studies suggest that ACE inhibitors benefit the diastolic properties of the heart, in both short- and long-term use. The PEP-CHF trial found that for older patients with diastolic dysfunction, perindopril led to significant improvements in functional class and exercise capacity but failed to show a statistically significant reduction in all-cause mortality or hospitalization for acute decompensated HF.¹⁷

ARBs. There is no evidence to show that ARB therapy improves morbidity or mortality in HFPEF. Using surrogate end points, ARBs have been associated with regression of LV hypertrophy, and losartan was found to improve exercise tolerance and quality of life, compared with hydrochlorothiazide.^18,19 In the CHARM-Preserved trial, candesartan showed an insignificant reduction in cardiovascular mortality and hospitalization for HF.

These results must be viewed with caution, however, because adverse effects led to high rates of medication discontinuation.³² In the I-PRESERVE trial, irbesartan conferred no benefit with respect to mortality, hospitalization, or quality of life on patients with HFPEF.³³

ACE inhibitor or ARB—not both. ACE inhibitors and ARBs are good choices for BP control in patients with HFPEF, especially if LV hypertrophy is present, but periodic testing of renal function and potassium levels is needed. ACE inhibitors and ARBs should not be used concurrently, as the combination increases the risk of acute renal failure and has no benefit in clinical outcomes.³⁴

BP and rate control
In small trials, beta-blockers have been found to improve diastolic function as seen on echocardiography, but data on morbidity and mortality are lacking.²⁰ A secondary analysis of the OPTIMIZE-HF registry found that beta-blocker therapy was associated with reduced mortality and readmission in patients with reduced EF, but not in those with normal EF.²¹

Findings from the SENIORS trial were more promising: Treatment with nebivolol reduced both mortality and readmission rates for elderly patients with HF, with similar benefits for those with reduced and preserved EF.²² Overall, beta-blockers appear to be a reasonable choice for heart rate and/or BP control in patients who have HFPEF and atrial fibrillation or hypertension. Carvedilol, long-acting metoprolol, and bisoprolol have been shown to reduce mortality in HF with reduced EF, and it is reasonable to choose one of these agents for patients with preserved EF, as well.²³

Calcium channel blockers (CCBs) may be useful in treating patients with HFPEF for both BP and heart rate control, as well. Theoretically, CCBs may also improve the process of relaxation by altering intracellular calcium cycling during the contractile cycle in myocytes. This contrasts with the management of HF patients with reduced EF, for whom the use of nonselective CCBs such as diltiazem and verapamil may adversely affect contractility.

In small RCTs, verapamil has been found to improve HF symptoms and exercise tolerance in patients with HFPEF,²⁴ but no evidence of improved outcomes or mortality rates with CCB use has been found.

Other pharmacologic options to consider
Aldosterone antagonist therapy is an important component of treatment for patients with HF with reduced EF. Data supporting the use of spironolactone use from the RALES trial and eplerenone in the EPHESUS and EMPHASIS-HF trials suggest a reduction in mortality in patients with low (<35%) LVEF.^25-27 For patients with preserved EF, however, spironolactone is not generally recommended.

A large National Institutes of Health-sponsored trial is underway to determine if the drug is beneficial for patients with preserved LVEF, and will build on a small study in which 30 patients with HFPEF showed improved myocardial function after treatment with spironolactone.³⁵ Until more data become available, the risks of using aldosterone antagonists outweigh the evidence to support their use in this patient population.

Diuretics are an important component of treatment for all patients with HF and fluid overload. The Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT) showed a reduced incidence of symptomatic HFPEF in patients taking diuretics.²⁸ As is the case with patients with reduced EF, those with preserved EF should be treated with diuretics if they have symptoms of fluid overload.

Statins. Intensive lipid lowering with statin therapy has been shown in observational studies to benefit patients with HFPEF with respect to mortality, independent of baseline low-density lipoprotein cholesterol.²⁹ RCTs are needed to confirm these observations, but statin therapy is recommended for the secondary prevention of cardiovascular disease, independent of the presence of diastolic dysfunction or HFPEF.

Guard against hypotension. Patients with diastolic dysfunction are susceptible to hypotension if there is a rapid reduction in preload with diuretics, nonselective CCBs, or nitrates, so it is important that doses be titrated slowly.

Nonpharmacologic measures are important, too

In addition to optimizing treatment of comorbid conditions, patients with HFPEF should be advised that lifestyle modifications such as weight loss, smoking cessation, and dietary changes can do much to reduce the risk. You can help by providing an exercise “prescription” (with a specified intensity, frequency, and duration) and dietary guidelines, with emphasis on the importance of a low-sodium diet to prevent fluid overload.^14,30 Recommend local programs for patients with HF, which many hospitals and health systems offer as part of their efforts to reduce readmission rates.

Consider cardioversion
Tachycardia shortens the time for filling during diastole; thus, it is poorly tolerated in patients with diastolic dysfunction and could trigger acute decompensation. To avoid the risk, restoration of sinus rhythm should be considered for patients with HFPEF and atrial fibrillation. Patients with known paroxysmal or permanent atrial fibrillation and preserved EF should be seen by a cardiologist to determine whether direct current cardioversion or ablation with a permanent pacemaker is appropriate.¹¹ When cardioversion is contraindicated, a beta-blocker is needed to control heart rate and improve hemodynamics.

Patients with stable angina and HFPEF should be evaluated for revascularization when medical therapy alone is not sufficient for symptom relief.¹⁰ Here, too, a cardiology consult is indicated for any patient who has HF and an abnormal noninvasive stress test or persistent symptoms despite optimal drug therapy.

Recognizing and responding to acute decompensated HFPEF

The initial response to acute decompensated HFPEF, like that of HF with reduced EF, should be focused on restoring volume status and providing oxygenation, ventilation, and vasodilator therapy in some cases.¹¹ Unlike those with acute decompensated HF with reduced EF, however, patients with HFPEF can safely tolerate the initiation of beta-blockers in the acute phase, especially when rate control is needed.³ Inotropic agents like digoxin and dobutamine, however, are contraindicated.³

Guidelines recommend hospitalization for patients with abnormal vital signs, arrhythmia, and suspected acute coronary syndromes, and consideration of hospitalization for those with associated comorbid conditions, new HF, or progressive fluid overload.¹³

CASE Because Ms. W has a normal BP and heart rate and is feeling well, you decline to alter her medication regimen. You do, however, recommend that she begin an exercise program, adopt a low-sodium diet, and maintain regular contact with your office so you can evaluate any changes in status.

You introduce Ms. W to the nurse case manager in your office. The nurse works with the patient to develop an action plan that includes daily tracking of her weight and sodium intake; a progressive walking program, starting with 2-minute sessions and progressing to 15 to 30 minutes 3 to 5 times a week; weekly telephone checkins; and immediate calls to report any weight increase or symptoms of HF.

At follow-up 6 months later, Ms. W has improved BP and reports that she enjoys her new exercise routine. She has more energy and denies any edema or breathing difficulties.

Keloids are an ongoing clinical challenge. Despite the availability of multiple treatments, choosing an effective therapeutic regimen for these fibroproliferative scars can be vexing, as keloids usually recur.

This review provides a guide to determining which regimen is best for your patient. But first, a word about the causes of these claw-like growths and which patients are at highest risk of developing them.

Even superficial injuries can cause keloids

Keloids arise after a disruption of skin integrity following superficial or deep injuries (FIGURES 1A-C). Causes include physical trauma such as cuts, scratches, and insect bites; iatrogenic trauma as in vaccinations or surgical procedures; thermal or chemical burns; and skin eruptions such as chicken pox.

FIGURE 1
Keloids induced by scratches (A), ear piercing (B), and thermal burns (C)

Common sites of keloid development include the ears, jaw, neck, clavicle and sternum, and shoulders. Less commonly, keloids occur on the back, abdomen, and extremities. Rarely, keloids develop on the palms and soles, face, or mucous membranes.¹

A minor keloid is smaller than 0.5 cm, while a major keloid is larger. No upper growth limit has been identified, as keloids seem to enlarge indefinitely.² Keloid scars have a firm and inflexible texture, a shiny appearance, and are elevated above skin level. They are usually flesh-colored, but may be erythematous or hyperpigmented.¹ (A similar aberrant wound healing condition often confused with keloids is hypertrophic scarring. See “Differentiating keloids from hypertrophic scars”).

Although keloids have an aggressive growth pattern, they are considered benign tumors, because the development of malignant cells in a keloid is rare.¹ Most patients seek medical attention for cosmetic concerns. However, tissue bulk can cause functional problems, and some keloids are symptomatic with pruritus (27%) or pain (19%).^1,3

Who is affected?
The most consistent risk factor for keloid development is a previous keloid. Individuals with deeply pigmented skin appear to be at higher risk, with an estimated prevalence of 4% to 16% among individuals of African, Asian, and Hispanic ancestry.³ Although the rate of keloid occurrence among Caucasians has not been established, keloids have been reported in individuals of nearly every skin color, except albinos.³ Keloids occur in both sexes with similar frequency, and are most likely to develop during puberty and early adulthood—between the ages of 10 and 30 years—but can occur at any age.^1,3

Although no clear familial inheritance pattern has been identified, keloids are associated with blood type A and human leukocyte antigens (HLA)-B14, -B21, -BW35, -DR5, -DRB1, -DQA1, -DQB1, and -DQW3.^3,4 Emerging research indicates that mutations of the CDC2L1 gene—which encodes a protein kinase essential to cell cycle control—correlate with keloid formation.⁴

Wound healing gone awry

Normal wound healing involves an overlapping series of processes, including hemostasis, inflammation, and granulation and remodeling. Various mechanisms have been identified for keloid pathology, although no single definitive trigger is known.

Hemostasis. In normal hemostasis, platelets aggregate around a fibrin clot in a wound, stimulating the release of growth factors,³ which precipitate the migration of fibroblasts to the granulation-tissue scaffolding for wound healing. Keloids have increased fibroblast proliferation, with up to 20-fold increased production of Type 1 collagen.¹

Inflammation. During the inflammation phase, cytokine cascades stimulate cell proliferation from inflammatory, endothelial, epithelial, and fibroblast cell lines. Keloids have altered levels of many cytokines, resulting in increased inflammatory activity, such as histamine release by mast cells.³

Granulation and remodeling. During normal granulation and remodeling, fibroblasts aggregate and produce extracellular matrix components. The keloid fibroblasts produce higher levels of collagen, elastin, fibronectin, and proteoglycans, but lower levels of hyaluronic acid.^3,5 Keloid fibroblasts also make lower levels of tissue plasminogen activator inhibitor (TPA-I), with inferior breakdown of scaffold structures and collagens. While collagen bundles run parallel to the epithelial surface in normal skin, keloid collagen fibers are larger, thicker, and randomly oriented in dense sheets, swirls, or nodules.¹

In normal tissue, wound healing stops after the wound has been fully epithelialized by keratinocytes, after which the scar tissue contracts to minimal size. However, keloid growth can continue for years.¹

Numerous studies have inspired various hypotheses for keloid formation. Studies demonstrating that keloids contain an increased level of immunoglobulins suggest that they may be produced by an abnormal immune reaction. Microscopic examinations of keloids have shown that overabundant endothelial cells occlude microvessels, suggesting that keloids may occur in the context of wound hypoxia. In vitro studies showing that fibroblasts proliferate when cultured with keloidal keratinocytes suggest that keloids may be a result of abnormal epithelial–mesenchymal interactions.^6,7 A hypothesis based on the body sites where keloids are observed is that mechanical stretch and tension across a wound may overstimulate collagen production, possibly as a result of mechanoreceptor damage or disorders.⁸

Treatment: Weighing the options

Due to the complex mechanisms of pathogenesis, many modalities are available for managing keloids, yet no definitive treatment protocols exist. Intradermal, extradermal, or systemic therapies may be used singly, although combination regimens are the most effective in treating keloids and preventing recurrences.⁵ The TABLE^1,3,5,9-14 provides an overview of monotherapeutic treatment options, including efficacy and risks.

TABLE
Treatment options for keloids

Offer symptomatic therapy routinely
Some patients find symptomatic relief through hygienic measures, such as regular washing and drying. Antihistamines can relieve symptoms of burning or pruritus,⁹ but are not expected to reduce keloid size.

Use corticosteroids for first-line treatment
Corticosteroids are the most widely used therapy for keloids.³ They decrease keloid bulking by inhibiting collagen synthesis¹ and stimulate tissue collagenases and collagen degradation.⁵ Commonly used in the office setting are intralesional injections of triamcinolone acetonide, a potent anti-inflammatory and highly atrophogenic agent.

Administer injections every 4 to 8 weeks until clinical improvement (usually requiring several months) or prohibitive adverse effects occur. A general dosing guideline is about 0.1 to 0.2 mL of corticosteroid for every square centimeter of keloid tissue. Injecting higher doses can lead to accretions or deposits beneath the skin that might need to be unroofed. Additionally, excess corticosteroid can cause an atrophic contour deformity in the adjacent subcutaneous tissue. FIGURE 2 details steroid injection procedures and follow-up based on the author’s (SPD) experience.

FIGURE 2
A 5-step procedure for injecting keloids with corticosteroids*

*Based on the author’s (SPD) experience.

Contraindications to injections include local or systemic infection and known allergy or anaphylactic reaction to corticosteroids. Although injecting keloids can be difficult initially, the tissue tends to soften and become easier to inject with each successive treatment. Some clinicians advocate cryotherapy to soften the keloid before giving injections. Large trials, in which more than 80% of patients had moderate to marked keloid regression,¹⁰ have demonstrated the efficacy of this technique in reducing keloid size and itching.

Surgery alone is ineffective
The oldest remedy, simple scalpel excision of keloidal tissue, invariably results in regrowth, because the aberrant wound healing process is not remedied.¹¹ Although surgical excision is a poor monotherapy, it may be useful in combination with other modalities. Repairs using meticulous atraumatic surgical techniques with minimal wound tension can lessen the risk of keloid recurrence. Absorbable monofilament sutures with a subcuticular stitch help to minimize further epidermal damage.⁶

Pressure is useful in certain cases
Applying pressure is a noninvasive method that produces initial tissue thinning and pliability, with 60% to 80% of patients reporting at least partial improvement.³ Pressure reduces keloids by decreasing tissue metabolism, so long-term therapy is required, with application of pressure 23 to 24 hours daily over several months.¹² Pressure of 25 to 40 mm Hg is needed to exceed capillary pressure without damaging peripheral circulation.³

Custom pressure garments for burn patients have been used in specialized cases involving limbs and torso, face and neck, and hands and feet. For earlobe keloids, clip-on earring devices are the only practical solution. Compliance tends to wane after months of therapy, and cessation may be followed by rebound hypertrophy. The therapeutic effect of regular pressure massage has been poorly studied. Because pressure has minimal adverse effects, it is likely most useful as an adjunct therapy where practical.

Radiation has variable effectiveness
Radiation damages fibroblasts, inhibits proliferation, and may improve local oxygenation.¹³ Low megavolt electron beam radiation is used to limit depth of penetration, usually with a total dose of 10 to 20 Gy fractionated over several weeks.⁵ A dose-response effect is likely.³ Response rates vary from 10% to 94%,³ and keloid recurrence is common, making radiation a poor choice for primary treatment except in cases of a large-volume unresectable keloid (eg, post-burn keloids).¹³

Adverse effects can include nodule formation, hyperpigmentation, ulceration, pruritus, paresthesia, and wound dehiscence. Theoretical risks of malignancy with radiation treatment of keloids have not been borne out in large studies, which have shown a zero percent malignancy rate despite rare anecdotal reports.¹⁵ Nevertheless, radiation therapy for benign disease is not recommended for children or pregnant women, or in breast, thyroid, or other cancer-prone body sites.⁵

Occlusive dressings require patient compliance
An innovation in keloid treatment is the use of occlusive dressings, which started in 1981 and gained popularity in the 1990s.¹⁶ Gel, fluid, or rubbery sheeting, usually made from silicone, is applied topically for 12 to 24 hours daily for up to 18 months.^1,12,14 Gel may be practical along creases or in areas of motion where silicone sheets are obtrusive. Because long-term therapy is recommended, occlusive dressings require active patient participation. Occlusive dressings can decrease pruritic symptoms by decreasing mast cell activity,¹² and may do so by warmth, hydration, or occlusion effects.³

Although study methodology has been suboptimal and further research is required, some practitioners have reported efficacy of 86% for texture reduction, 84% improvement in color, and 68% in diminishing height of scars.¹⁴ However, silicone gel and sheeting may be most successful when applied to a wound before a keloid has formed, as a preventive measure for keloid-prone patients.¹⁴ Occlusive dressings are a relatively benign treatment because silicone rubber is inert, but adverse effects may include skin breakdown, rash, or pruritus that may require discontinuation of therapy for a few days or more.

Combination regimens may be most effective
If a keloid remains unresponsive to first-line therapies, combined therapies may reduce keloid size and prevent recurrence. Select regimens according to keloid characteristics and patient preferences.¹⁷ Corticosteroids used after surgical excision can produce cure rates exceeding 80%, making this a consistently successful management regimen for keloids and the standard of care in many primary care practices.³

Surgery and pressure are the preferred combination for earlobe keloids, as adverse effects are minimal and compliant patients may achieve response rates exceeding 80%.^3,5

Surgery followed by immediate radiation reportedly has a response rate of 65% or higher.¹⁸ This regimen may be most successful in low-tension body areas, like the neck or lower limbs, where keloids are less likely to recur.¹⁸

A combination of surgery and occlusive dressings is also promising. Early studies have had recurrence-free rates of more than 80% when patients applied the dressings for up to 24 hours daily over 4 to 6 months.⁶

Emerging therapies that require further testing

Many promising treatments lack sufficiently rigorous evidence of efficacy.

• Intralesional calcium channel blockers, which depolymerize actin¹⁹ and inhibit protein synthesis,⁵ have shown promising results in nonrandomized early clinical trials.¹⁹
• Ultraviolet light is a potentially successful noninvasive method.
• Topical retinoids (vitamin A derivatives) may be effective but must be applied twice daily for several months to reduce collagen metabolism by fibroblasts⁵; they may also cause photosensitivity and skin irritation.⁷
• Intralesional fluorouracil (5-FU) (as an antimetabolite) successfully reduced keloid size after one year of treatment in a few small trials.^5,20
• Oral lathyrogen, such as penicillamine with colchicine, can interfere with collagen cross-linking; in a small case series there was no keloid recurrence after treatment.⁵
• Topical imiquimod (Aldara) cream, an immune response modifier, showed promise in a few case reports.^5,21
• Laser procedures are less likely than scalpel procedures to produce keloid scars and have been reported to successfully improve scar color, size, and texture, although the risk of hyperpigmentation ranges from 1% to 24%.^2,3,22 (Lasers induce ischemia through blood vessel destruction and cause decreased fibroblast production and histamine release.^23,24) Red flat scars (which triamcinolone injections may cause) can be lightened with yellow light laser, which has been used in the treatment of capillary malformations.²⁵

Other methods may produce suboptimal results. Cryotherapy causes ischemic damage that reduces tumor bulk at least temporarily, but is inappropriate for darker skin due to a high risk of persistent hypopigmentation.^1,26,27 Intralesional antifibrotic cytokines, such as interferon, reduce collagen synthesis in vitro,¹ but lead to considerable systemic adverse effects including headache, myalgias, and influenza-like symptoms.^3,5 Skin grafting is inappropriate as it may lead to keloid wave formation at the graft edges.

CORRESPONDENCE 
Stephen P. Daane, MD, 2186 Geary Boulevard #212, San Francisco, CA 94115; [email protected]

Keloids are an ongoing clinical challenge. Despite the availability of multiple treatments, choosing an effective therapeutic regimen for these fibroproliferative scars can be vexing, as keloids usually recur.

This review provides a guide to determining which regimen is best for your patient. But first, a word about the causes of these claw-like growths and which patients are at highest risk of developing them.

Even superficial injuries can cause keloids

Keloids arise after a disruption of skin integrity following superficial or deep injuries (FIGURES 1A-C). Causes include physical trauma such as cuts, scratches, and insect bites; iatrogenic trauma as in vaccinations or surgical procedures; thermal or chemical burns; and skin eruptions such as chicken pox.

FIGURE 1
Keloids induced by scratches (A), ear piercing (B), and thermal burns (C)

Common sites of keloid development include the ears, jaw, neck, clavicle and sternum, and shoulders. Less commonly, keloids occur on the back, abdomen, and extremities. Rarely, keloids develop on the palms and soles, face, or mucous membranes.¹

A minor keloid is smaller than 0.5 cm, while a major keloid is larger. No upper growth limit has been identified, as keloids seem to enlarge indefinitely.² Keloid scars have a firm and inflexible texture, a shiny appearance, and are elevated above skin level. They are usually flesh-colored, but may be erythematous or hyperpigmented.¹ (A similar aberrant wound healing condition often confused with keloids is hypertrophic scarring. See “Differentiating keloids from hypertrophic scars”).

Although keloids have an aggressive growth pattern, they are considered benign tumors, because the development of malignant cells in a keloid is rare.¹ Most patients seek medical attention for cosmetic concerns. However, tissue bulk can cause functional problems, and some keloids are symptomatic with pruritus (27%) or pain (19%).^1,3

Who is affected?
The most consistent risk factor for keloid development is a previous keloid. Individuals with deeply pigmented skin appear to be at higher risk, with an estimated prevalence of 4% to 16% among individuals of African, Asian, and Hispanic ancestry.³ Although the rate of keloid occurrence among Caucasians has not been established, keloids have been reported in individuals of nearly every skin color, except albinos.³ Keloids occur in both sexes with similar frequency, and are most likely to develop during puberty and early adulthood—between the ages of 10 and 30 years—but can occur at any age.^1,3

Although no clear familial inheritance pattern has been identified, keloids are associated with blood type A and human leukocyte antigens (HLA)-B14, -B21, -BW35, -DR5, -DRB1, -DQA1, -DQB1, and -DQW3.^3,4 Emerging research indicates that mutations of the CDC2L1 gene—which encodes a protein kinase essential to cell cycle control—correlate with keloid formation.⁴

Wound healing gone awry

Normal wound healing involves an overlapping series of processes, including hemostasis, inflammation, and granulation and remodeling. Various mechanisms have been identified for keloid pathology, although no single definitive trigger is known.

Hemostasis. In normal hemostasis, platelets aggregate around a fibrin clot in a wound, stimulating the release of growth factors,³ which precipitate the migration of fibroblasts to the granulation-tissue scaffolding for wound healing. Keloids have increased fibroblast proliferation, with up to 20-fold increased production of Type 1 collagen.¹

Inflammation. During the inflammation phase, cytokine cascades stimulate cell proliferation from inflammatory, endothelial, epithelial, and fibroblast cell lines. Keloids have altered levels of many cytokines, resulting in increased inflammatory activity, such as histamine release by mast cells.³

Granulation and remodeling. During normal granulation and remodeling, fibroblasts aggregate and produce extracellular matrix components. The keloid fibroblasts produce higher levels of collagen, elastin, fibronectin, and proteoglycans, but lower levels of hyaluronic acid.^3,5 Keloid fibroblasts also make lower levels of tissue plasminogen activator inhibitor (TPA-I), with inferior breakdown of scaffold structures and collagens. While collagen bundles run parallel to the epithelial surface in normal skin, keloid collagen fibers are larger, thicker, and randomly oriented in dense sheets, swirls, or nodules.¹

In normal tissue, wound healing stops after the wound has been fully epithelialized by keratinocytes, after which the scar tissue contracts to minimal size. However, keloid growth can continue for years.¹

Numerous studies have inspired various hypotheses for keloid formation. Studies demonstrating that keloids contain an increased level of immunoglobulins suggest that they may be produced by an abnormal immune reaction. Microscopic examinations of keloids have shown that overabundant endothelial cells occlude microvessels, suggesting that keloids may occur in the context of wound hypoxia. In vitro studies showing that fibroblasts proliferate when cultured with keloidal keratinocytes suggest that keloids may be a result of abnormal epithelial–mesenchymal interactions.^6,7 A hypothesis based on the body sites where keloids are observed is that mechanical stretch and tension across a wound may overstimulate collagen production, possibly as a result of mechanoreceptor damage or disorders.⁸

Treatment: Weighing the options

Due to the complex mechanisms of pathogenesis, many modalities are available for managing keloids, yet no definitive treatment protocols exist. Intradermal, extradermal, or systemic therapies may be used singly, although combination regimens are the most effective in treating keloids and preventing recurrences.⁵ The TABLE^1,3,5,9-14 provides an overview of monotherapeutic treatment options, including efficacy and risks.

TABLE
Treatment options for keloids

Offer symptomatic therapy routinely
Some patients find symptomatic relief through hygienic measures, such as regular washing and drying. Antihistamines can relieve symptoms of burning or pruritus,⁹ but are not expected to reduce keloid size.

Use corticosteroids for first-line treatment
Corticosteroids are the most widely used therapy for keloids.³ They decrease keloid bulking by inhibiting collagen synthesis¹ and stimulate tissue collagenases and collagen degradation.⁵ Commonly used in the office setting are intralesional injections of triamcinolone acetonide, a potent anti-inflammatory and highly atrophogenic agent.

Administer injections every 4 to 8 weeks until clinical improvement (usually requiring several months) or prohibitive adverse effects occur. A general dosing guideline is about 0.1 to 0.2 mL of corticosteroid for every square centimeter of keloid tissue. Injecting higher doses can lead to accretions or deposits beneath the skin that might need to be unroofed. Additionally, excess corticosteroid can cause an atrophic contour deformity in the adjacent subcutaneous tissue. FIGURE 2 details steroid injection procedures and follow-up based on the author’s (SPD) experience.

FIGURE 2
A 5-step procedure for injecting keloids with corticosteroids*

*Based on the author’s (SPD) experience.

Contraindications to injections include local or systemic infection and known allergy or anaphylactic reaction to corticosteroids. Although injecting keloids can be difficult initially, the tissue tends to soften and become easier to inject with each successive treatment. Some clinicians advocate cryotherapy to soften the keloid before giving injections. Large trials, in which more than 80% of patients had moderate to marked keloid regression,¹⁰ have demonstrated the efficacy of this technique in reducing keloid size and itching.

Surgery alone is ineffective
The oldest remedy, simple scalpel excision of keloidal tissue, invariably results in regrowth, because the aberrant wound healing process is not remedied.¹¹ Although surgical excision is a poor monotherapy, it may be useful in combination with other modalities. Repairs using meticulous atraumatic surgical techniques with minimal wound tension can lessen the risk of keloid recurrence. Absorbable monofilament sutures with a subcuticular stitch help to minimize further epidermal damage.⁶

Pressure is useful in certain cases
Applying pressure is a noninvasive method that produces initial tissue thinning and pliability, with 60% to 80% of patients reporting at least partial improvement.³ Pressure reduces keloids by decreasing tissue metabolism, so long-term therapy is required, with application of pressure 23 to 24 hours daily over several months.¹² Pressure of 25 to 40 mm Hg is needed to exceed capillary pressure without damaging peripheral circulation.³

Custom pressure garments for burn patients have been used in specialized cases involving limbs and torso, face and neck, and hands and feet. For earlobe keloids, clip-on earring devices are the only practical solution. Compliance tends to wane after months of therapy, and cessation may be followed by rebound hypertrophy. The therapeutic effect of regular pressure massage has been poorly studied. Because pressure has minimal adverse effects, it is likely most useful as an adjunct therapy where practical.

Radiation has variable effectiveness
Radiation damages fibroblasts, inhibits proliferation, and may improve local oxygenation.¹³ Low megavolt electron beam radiation is used to limit depth of penetration, usually with a total dose of 10 to 20 Gy fractionated over several weeks.⁵ A dose-response effect is likely.³ Response rates vary from 10% to 94%,³ and keloid recurrence is common, making radiation a poor choice for primary treatment except in cases of a large-volume unresectable keloid (eg, post-burn keloids).¹³

Adverse effects can include nodule formation, hyperpigmentation, ulceration, pruritus, paresthesia, and wound dehiscence. Theoretical risks of malignancy with radiation treatment of keloids have not been borne out in large studies, which have shown a zero percent malignancy rate despite rare anecdotal reports.¹⁵ Nevertheless, radiation therapy for benign disease is not recommended for children or pregnant women, or in breast, thyroid, or other cancer-prone body sites.⁵

Occlusive dressings require patient compliance
An innovation in keloid treatment is the use of occlusive dressings, which started in 1981 and gained popularity in the 1990s.¹⁶ Gel, fluid, or rubbery sheeting, usually made from silicone, is applied topically for 12 to 24 hours daily for up to 18 months.^1,12,14 Gel may be practical along creases or in areas of motion where silicone sheets are obtrusive. Because long-term therapy is recommended, occlusive dressings require active patient participation. Occlusive dressings can decrease pruritic symptoms by decreasing mast cell activity,¹² and may do so by warmth, hydration, or occlusion effects.³

Although study methodology has been suboptimal and further research is required, some practitioners have reported efficacy of 86% for texture reduction, 84% improvement in color, and 68% in diminishing height of scars.¹⁴ However, silicone gel and sheeting may be most successful when applied to a wound before a keloid has formed, as a preventive measure for keloid-prone patients.¹⁴ Occlusive dressings are a relatively benign treatment because silicone rubber is inert, but adverse effects may include skin breakdown, rash, or pruritus that may require discontinuation of therapy for a few days or more.

Combination regimens may be most effective
If a keloid remains unresponsive to first-line therapies, combined therapies may reduce keloid size and prevent recurrence. Select regimens according to keloid characteristics and patient preferences.¹⁷ Corticosteroids used after surgical excision can produce cure rates exceeding 80%, making this a consistently successful management regimen for keloids and the standard of care in many primary care practices.³

Surgery and pressure are the preferred combination for earlobe keloids, as adverse effects are minimal and compliant patients may achieve response rates exceeding 80%.^3,5

Surgery followed by immediate radiation reportedly has a response rate of 65% or higher.¹⁸ This regimen may be most successful in low-tension body areas, like the neck or lower limbs, where keloids are less likely to recur.¹⁸

A combination of surgery and occlusive dressings is also promising. Early studies have had recurrence-free rates of more than 80% when patients applied the dressings for up to 24 hours daily over 4 to 6 months.⁶

Emerging therapies that require further testing

Many promising treatments lack sufficiently rigorous evidence of efficacy.

• Intralesional calcium channel blockers, which depolymerize actin¹⁹ and inhibit protein synthesis,⁵ have shown promising results in nonrandomized early clinical trials.¹⁹
• Ultraviolet light is a potentially successful noninvasive method.
• Topical retinoids (vitamin A derivatives) may be effective but must be applied twice daily for several months to reduce collagen metabolism by fibroblasts⁵; they may also cause photosensitivity and skin irritation.⁷
• Intralesional fluorouracil (5-FU) (as an antimetabolite) successfully reduced keloid size after one year of treatment in a few small trials.^5,20
• Oral lathyrogen, such as penicillamine with colchicine, can interfere with collagen cross-linking; in a small case series there was no keloid recurrence after treatment.⁵
• Topical imiquimod (Aldara) cream, an immune response modifier, showed promise in a few case reports.^5,21
• Laser procedures are less likely than scalpel procedures to produce keloid scars and have been reported to successfully improve scar color, size, and texture, although the risk of hyperpigmentation ranges from 1% to 24%.^2,3,22 (Lasers induce ischemia through blood vessel destruction and cause decreased fibroblast production and histamine release.^23,24) Red flat scars (which triamcinolone injections may cause) can be lightened with yellow light laser, which has been used in the treatment of capillary malformations.²⁵

Other methods may produce suboptimal results. Cryotherapy causes ischemic damage that reduces tumor bulk at least temporarily, but is inappropriate for darker skin due to a high risk of persistent hypopigmentation.^1,26,27 Intralesional antifibrotic cytokines, such as interferon, reduce collagen synthesis in vitro,¹ but lead to considerable systemic adverse effects including headache, myalgias, and influenza-like symptoms.^3,5 Skin grafting is inappropriate as it may lead to keloid wave formation at the graft edges.

CORRESPONDENCE 
Stephen P. Daane, MD, 2186 Geary Boulevard #212, San Francisco, CA 94115; [email protected]

Keloids are an ongoing clinical challenge. Despite the availability of multiple treatments, choosing an effective therapeutic regimen for these fibroproliferative scars can be vexing, as keloids usually recur.

This review provides a guide to determining which regimen is best for your patient. But first, a word about the causes of these claw-like growths and which patients are at highest risk of developing them.

Even superficial injuries can cause keloids

Keloids arise after a disruption of skin integrity following superficial or deep injuries (FIGURES 1A-C). Causes include physical trauma such as cuts, scratches, and insect bites; iatrogenic trauma as in vaccinations or surgical procedures; thermal or chemical burns; and skin eruptions such as chicken pox.

FIGURE 1
Keloids induced by scratches (A), ear piercing (B), and thermal burns (C)

Common sites of keloid development include the ears, jaw, neck, clavicle and sternum, and shoulders. Less commonly, keloids occur on the back, abdomen, and extremities. Rarely, keloids develop on the palms and soles, face, or mucous membranes.¹

A minor keloid is smaller than 0.5 cm, while a major keloid is larger. No upper growth limit has been identified, as keloids seem to enlarge indefinitely.² Keloid scars have a firm and inflexible texture, a shiny appearance, and are elevated above skin level. They are usually flesh-colored, but may be erythematous or hyperpigmented.¹ (A similar aberrant wound healing condition often confused with keloids is hypertrophic scarring. See “Differentiating keloids from hypertrophic scars”).

Although keloids have an aggressive growth pattern, they are considered benign tumors, because the development of malignant cells in a keloid is rare.¹ Most patients seek medical attention for cosmetic concerns. However, tissue bulk can cause functional problems, and some keloids are symptomatic with pruritus (27%) or pain (19%).^1,3

Who is affected?
The most consistent risk factor for keloid development is a previous keloid. Individuals with deeply pigmented skin appear to be at higher risk, with an estimated prevalence of 4% to 16% among individuals of African, Asian, and Hispanic ancestry.³ Although the rate of keloid occurrence among Caucasians has not been established, keloids have been reported in individuals of nearly every skin color, except albinos.³ Keloids occur in both sexes with similar frequency, and are most likely to develop during puberty and early adulthood—between the ages of 10 and 30 years—but can occur at any age.^1,3

Although no clear familial inheritance pattern has been identified, keloids are associated with blood type A and human leukocyte antigens (HLA)-B14, -B21, -BW35, -DR5, -DRB1, -DQA1, -DQB1, and -DQW3.^3,4 Emerging research indicates that mutations of the CDC2L1 gene—which encodes a protein kinase essential to cell cycle control—correlate with keloid formation.⁴

Wound healing gone awry

Normal wound healing involves an overlapping series of processes, including hemostasis, inflammation, and granulation and remodeling. Various mechanisms have been identified for keloid pathology, although no single definitive trigger is known.

Hemostasis. In normal hemostasis, platelets aggregate around a fibrin clot in a wound, stimulating the release of growth factors,³ which precipitate the migration of fibroblasts to the granulation-tissue scaffolding for wound healing. Keloids have increased fibroblast proliferation, with up to 20-fold increased production of Type 1 collagen.¹

Inflammation. During the inflammation phase, cytokine cascades stimulate cell proliferation from inflammatory, endothelial, epithelial, and fibroblast cell lines. Keloids have altered levels of many cytokines, resulting in increased inflammatory activity, such as histamine release by mast cells.³

Granulation and remodeling. During normal granulation and remodeling, fibroblasts aggregate and produce extracellular matrix components. The keloid fibroblasts produce higher levels of collagen, elastin, fibronectin, and proteoglycans, but lower levels of hyaluronic acid.^3,5 Keloid fibroblasts also make lower levels of tissue plasminogen activator inhibitor (TPA-I), with inferior breakdown of scaffold structures and collagens. While collagen bundles run parallel to the epithelial surface in normal skin, keloid collagen fibers are larger, thicker, and randomly oriented in dense sheets, swirls, or nodules.¹

In normal tissue, wound healing stops after the wound has been fully epithelialized by keratinocytes, after which the scar tissue contracts to minimal size. However, keloid growth can continue for years.¹

Numerous studies have inspired various hypotheses for keloid formation. Studies demonstrating that keloids contain an increased level of immunoglobulins suggest that they may be produced by an abnormal immune reaction. Microscopic examinations of keloids have shown that overabundant endothelial cells occlude microvessels, suggesting that keloids may occur in the context of wound hypoxia. In vitro studies showing that fibroblasts proliferate when cultured with keloidal keratinocytes suggest that keloids may be a result of abnormal epithelial–mesenchymal interactions.^6,7 A hypothesis based on the body sites where keloids are observed is that mechanical stretch and tension across a wound may overstimulate collagen production, possibly as a result of mechanoreceptor damage or disorders.⁸

Treatment: Weighing the options

Due to the complex mechanisms of pathogenesis, many modalities are available for managing keloids, yet no definitive treatment protocols exist. Intradermal, extradermal, or systemic therapies may be used singly, although combination regimens are the most effective in treating keloids and preventing recurrences.⁵ The TABLE^1,3,5,9-14 provides an overview of monotherapeutic treatment options, including efficacy and risks.

TABLE
Treatment options for keloids

Offer symptomatic therapy routinely
Some patients find symptomatic relief through hygienic measures, such as regular washing and drying. Antihistamines can relieve symptoms of burning or pruritus,⁹ but are not expected to reduce keloid size.

Use corticosteroids for first-line treatment
Corticosteroids are the most widely used therapy for keloids.³ They decrease keloid bulking by inhibiting collagen synthesis¹ and stimulate tissue collagenases and collagen degradation.⁵ Commonly used in the office setting are intralesional injections of triamcinolone acetonide, a potent anti-inflammatory and highly atrophogenic agent.

Administer injections every 4 to 8 weeks until clinical improvement (usually requiring several months) or prohibitive adverse effects occur. A general dosing guideline is about 0.1 to 0.2 mL of corticosteroid for every square centimeter of keloid tissue. Injecting higher doses can lead to accretions or deposits beneath the skin that might need to be unroofed. Additionally, excess corticosteroid can cause an atrophic contour deformity in the adjacent subcutaneous tissue. FIGURE 2 details steroid injection procedures and follow-up based on the author’s (SPD) experience.

FIGURE 2
A 5-step procedure for injecting keloids with corticosteroids*

*Based on the author’s (SPD) experience.

Contraindications to injections include local or systemic infection and known allergy or anaphylactic reaction to corticosteroids. Although injecting keloids can be difficult initially, the tissue tends to soften and become easier to inject with each successive treatment. Some clinicians advocate cryotherapy to soften the keloid before giving injections. Large trials, in which more than 80% of patients had moderate to marked keloid regression,¹⁰ have demonstrated the efficacy of this technique in reducing keloid size and itching.

Surgery alone is ineffective
The oldest remedy, simple scalpel excision of keloidal tissue, invariably results in regrowth, because the aberrant wound healing process is not remedied.¹¹ Although surgical excision is a poor monotherapy, it may be useful in combination with other modalities. Repairs using meticulous atraumatic surgical techniques with minimal wound tension can lessen the risk of keloid recurrence. Absorbable monofilament sutures with a subcuticular stitch help to minimize further epidermal damage.⁶

Pressure is useful in certain cases
Applying pressure is a noninvasive method that produces initial tissue thinning and pliability, with 60% to 80% of patients reporting at least partial improvement.³ Pressure reduces keloids by decreasing tissue metabolism, so long-term therapy is required, with application of pressure 23 to 24 hours daily over several months.¹² Pressure of 25 to 40 mm Hg is needed to exceed capillary pressure without damaging peripheral circulation.³

Custom pressure garments for burn patients have been used in specialized cases involving limbs and torso, face and neck, and hands and feet. For earlobe keloids, clip-on earring devices are the only practical solution. Compliance tends to wane after months of therapy, and cessation may be followed by rebound hypertrophy. The therapeutic effect of regular pressure massage has been poorly studied. Because pressure has minimal adverse effects, it is likely most useful as an adjunct therapy where practical.

Radiation has variable effectiveness
Radiation damages fibroblasts, inhibits proliferation, and may improve local oxygenation.¹³ Low megavolt electron beam radiation is used to limit depth of penetration, usually with a total dose of 10 to 20 Gy fractionated over several weeks.⁵ A dose-response effect is likely.³ Response rates vary from 10% to 94%,³ and keloid recurrence is common, making radiation a poor choice for primary treatment except in cases of a large-volume unresectable keloid (eg, post-burn keloids).¹³

Adverse effects can include nodule formation, hyperpigmentation, ulceration, pruritus, paresthesia, and wound dehiscence. Theoretical risks of malignancy with radiation treatment of keloids have not been borne out in large studies, which have shown a zero percent malignancy rate despite rare anecdotal reports.¹⁵ Nevertheless, radiation therapy for benign disease is not recommended for children or pregnant women, or in breast, thyroid, or other cancer-prone body sites.⁵

Occlusive dressings require patient compliance
An innovation in keloid treatment is the use of occlusive dressings, which started in 1981 and gained popularity in the 1990s.¹⁶ Gel, fluid, or rubbery sheeting, usually made from silicone, is applied topically for 12 to 24 hours daily for up to 18 months.^1,12,14 Gel may be practical along creases or in areas of motion where silicone sheets are obtrusive. Because long-term therapy is recommended, occlusive dressings require active patient participation. Occlusive dressings can decrease pruritic symptoms by decreasing mast cell activity,¹² and may do so by warmth, hydration, or occlusion effects.³

Although study methodology has been suboptimal and further research is required, some practitioners have reported efficacy of 86% for texture reduction, 84% improvement in color, and 68% in diminishing height of scars.¹⁴ However, silicone gel and sheeting may be most successful when applied to a wound before a keloid has formed, as a preventive measure for keloid-prone patients.¹⁴ Occlusive dressings are a relatively benign treatment because silicone rubber is inert, but adverse effects may include skin breakdown, rash, or pruritus that may require discontinuation of therapy for a few days or more.

Combination regimens may be most effective
If a keloid remains unresponsive to first-line therapies, combined therapies may reduce keloid size and prevent recurrence. Select regimens according to keloid characteristics and patient preferences.¹⁷ Corticosteroids used after surgical excision can produce cure rates exceeding 80%, making this a consistently successful management regimen for keloids and the standard of care in many primary care practices.³

Surgery and pressure are the preferred combination for earlobe keloids, as adverse effects are minimal and compliant patients may achieve response rates exceeding 80%.^3,5

Surgery followed by immediate radiation reportedly has a response rate of 65% or higher.¹⁸ This regimen may be most successful in low-tension body areas, like the neck or lower limbs, where keloids are less likely to recur.¹⁸

A combination of surgery and occlusive dressings is also promising. Early studies have had recurrence-free rates of more than 80% when patients applied the dressings for up to 24 hours daily over 4 to 6 months.⁶

Emerging therapies that require further testing

Many promising treatments lack sufficiently rigorous evidence of efficacy.

• Intralesional calcium channel blockers, which depolymerize actin¹⁹ and inhibit protein synthesis,⁵ have shown promising results in nonrandomized early clinical trials.¹⁹
• Ultraviolet light is a potentially successful noninvasive method.
• Topical retinoids (vitamin A derivatives) may be effective but must be applied twice daily for several months to reduce collagen metabolism by fibroblasts⁵; they may also cause photosensitivity and skin irritation.⁷
• Intralesional fluorouracil (5-FU) (as an antimetabolite) successfully reduced keloid size after one year of treatment in a few small trials.^5,20
• Oral lathyrogen, such as penicillamine with colchicine, can interfere with collagen cross-linking; in a small case series there was no keloid recurrence after treatment.⁵
• Topical imiquimod (Aldara) cream, an immune response modifier, showed promise in a few case reports.^5,21
• Laser procedures are less likely than scalpel procedures to produce keloid scars and have been reported to successfully improve scar color, size, and texture, although the risk of hyperpigmentation ranges from 1% to 24%.^2,3,22 (Lasers induce ischemia through blood vessel destruction and cause decreased fibroblast production and histamine release.^23,24) Red flat scars (which triamcinolone injections may cause) can be lightened with yellow light laser, which has been used in the treatment of capillary malformations.²⁵

Other methods may produce suboptimal results. Cryotherapy causes ischemic damage that reduces tumor bulk at least temporarily, but is inappropriate for darker skin due to a high risk of persistent hypopigmentation.^1,26,27 Intralesional antifibrotic cytokines, such as interferon, reduce collagen synthesis in vitro,¹ but lead to considerable systemic adverse effects including headache, myalgias, and influenza-like symptoms.^3,5 Skin grafting is inappropriate as it may lead to keloid wave formation at the graft edges.

CORRESPONDENCE 
Stephen P. Daane, MD, 2186 Geary Boulevard #212, San Francisco, CA 94115; [email protected]

CASE Laura M delivers her third baby at 35 weeks 4 days after an uneventful spontaneous labor. Julia, 5 lb 1 oz, has Apgar scores of 8 and 9. You see them on the mother-baby unit Friday afternoon, 36 hours after the delivery.

Ms. M has successfully breastfed her other 2 children and is planning to breastfeed Julia as well. She says the infant is nursing well today but seemed sleepy yesterday. The nursing notes say that Julia went to the nursery overnight because her mother was tired, and the infant spit up after receiving a formula bottle. Ms. M is asking you to discharge her because tomorrow is her son’s birthday. After considering this and her experience with breastfeeding, you decide to discharge her with follow-up on Monday instead of checking her out to your partner for the weekend.

Ms. M returns to your office on Monday with Julia, whose weight is down 10% and is “glowing yellow.” The baby is not latching well at the breast and is spitting up when Ms. M tries to supplement with formula. After examining Julia and checking lab work (bilirubin, 20 mg/dL), you decide to readmit her for feeding difficulties and hyperbilirubinemia.

Complications are common with late preterm infants, which refers to babies born between 34 weeks 0 days and 36 weeks 6 days of pregnancy. Between 1990 and 2006, there was a dramatic (25%) increase in the rate of late preterm infants in the United States, although more recently this number has leveled off.¹

Several factors have been linked to increased late preterm births: maternal obesity, increased maternal age, and the increasing rate of multiple gestation pregnancies that have resulted from the expanded use of reproductive technology.² Similarly, treatment of severe preeclampsia and premature rupture of membranes often includes delivery after 34 weeks of gestation,³ further contributing to the problem. Finally, higher rates of antenatal screening have contributed to more inductions and cesarean sections at earlier gestational ages. One study even found a correlation between higher malpractice premiums and more frequent late preterm inductions.⁴

Don’t let their appearance fool you

At first appearance, late preterm infants are similar to term infants in terms of Apgar scores,⁵ size, and weight.² However, the care of these infants can be complex. They are often placed in well-infant nurseries under the same protocols as term infants and discharged before an adequate observation period. These infants have both increased short- and long-term morbidity and mortality and use a significant amount of health care resources.⁵ Morbidity in these infants decreases with each week of gestation from 34 weeks to a nadir at 39 weeks and can be unrelated to maternal and pregnancy complications.⁶

The following are some important issues to keep in mind when caring for these infants.

Hypothermia and hypoglycemia
Late preterm infants experience increased cold stress because of their limited fat stores, reduced brown fat, an immature epidermal barrier, and increased surface area to body mass ratio.² Hypothermia increases the metabolic demands on the neonate and can worsen hypoglycemia as well as respiratory distress.⁷

Ideally, clinicians should dry these infants with warm blankets, place them skin-to-skin with their mother, and cover them with a warm blanket and cap to avoid excess energy expenditure.⁸ If conditions necessitate, neonates can be placed in a radiant warmer. Infants’ temperature needs to be monitored within the first 30 minutes of life and frequently reassessed during the first 12 hours of life—the “transition period.”⁸ The infant’s axillary temperature should be maintained between 36.5°C and 37.4°C (97.7-99.3°F); the temperature should remain stable in an open crib for the 12 hours before discharge.²

Decreased glycogen stores, increased glucose utilization, and immature hepatic enzymes help to explain the fact that hypoglycemia is 3 times more common in late preterm infants compared with full-term neonates.⁷ In all newborns, glucose levels decrease to their nadir between 30 and 90 minutes of life and normally trigger the breakdown of glycogen if the infant does not eat.⁷ Hypoglycemia can manifest as a change in level of consciousness, apnea, cyanosis, tachypnea, hypothermia, and seizures.⁹ The evidence is limited and there is controversy as to what level of hypoglycemia and over what duration of time is harmful.⁹

Most experts agree that breastfeeding should be started in the delivery room, and plasma glucose checked at 60 minutes of life and any time an infant is symptomatic. A level less than 45 mg/dL during the transition period should prompt feeding.⁹ Glucose levels should be rechecked within an hour of feeding and every 3 hours thereafter. If the level remains low or the infant is not interested in feeding, give a bolus of D₁₀W and consider an infusion.^7,10 TABLE 1¹⁰ highlights one proposed method of glucose management.

TABLE 1
How best to manage glucose in a late preterm newborn¹⁰

Respiratory distress
At least 30% of late preterm infants will have some evidence of respiratory distress,⁵ which is defined as the need for oxygen supplementation due to tachypnea, grunting, nasal flaring, retractions, or cyanosis. Those at highest risk are white males born via cesarean section.¹¹ Transient tachypnea of the newborn (TTN) appears to be the cause of almost half the cases of respiratory distress in these young patients.¹² As this is a diagnosis by exclusion, consider other common causes: respiratory distress syndrome, neonatal pneumonia, meconium aspiration syndrome, and persistent pulmonary hypertension.¹² The need for ventilator support is a significant concern in this group and increases exponentially with decreasing gestational age.⁶

Hyperbilirubinemia
More than half of all late preterm infants will present with clinically significant jaundice.⁵ Late preterm infants have an increased bilirubin load, decreased uptake of bilirubin, and delayed conjugation. They are less able to bind bilirubin to albumin, which increases their predisposition to bilirubin-induced neurological dysfunction and kernicterus.¹³ They also have more difficulty with breastfeeding, which exacerbates their hyperbilirubinemia.¹⁴

Infants born at 36 weeks have an 8-fold increased risk of developing severe hyperbilirubinemia (total serum bilirubin >20 mg/dL) than those born at 41 weeks,¹³ which explains why they are disproportionately represented in the US Pilot Kernicterus Registry.¹⁴ These infants can develop neurological sequelae at lower levels of bilirubin than their term counterparts and have less chance of complete recovery once intensive therapy has been implemented.¹⁴

The 2 main risk factors for severe hyperbilirubinemia have to do with discharge time and breastfeeding. Discharge at less than 48 hours is a risk factor for both term and late preterm infants.^14,15 This is likely due to the fact that bilirubin peaks in late preterm infants between Days 5 and 7, and in term infants between Days 3 and 5.¹⁶ Difficulties with breastfeeding, the second risk factor,¹⁷ can be due to a combination of delayed maternal lactogenesis and ineffective milk removal on the part of the infant.¹⁸ When infants ingest smaller volumes of milk, bowel movements are infrequent and the bilirubin in the gut gets reabsorbed instead of excreted.

American Academy of Pediatrics (AAP) guidelines suggest measuring total serum bilirubin or transcutaneous bilirubin and plotting the value on an hour-specific, gestational-age-specific, risk-specific nomogram (FIGURE).¹⁹ Alternately, BiliTool (http://www.bilitool.org) can be used to individualize an infant’s risk.

FIGURE
Bilirubin levels and risk of significant hyperbilirubinemia¹⁹
Bilirubin levels should be plotted according to the infant’s hours of life and assessed according to risk factors on the appropriate risk line. If infants are 34 weeks 0 days to 34 weeks 6 days, they should be assessed on the high risk line.

• Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin.
• Risk factors include isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin <3.0 g/dL (if measured).
• For well infants 35-37 6/7 weeks, you can adjust the total serum bilirubin (TSB) levels for intervention around the medium risk line. It is an option to intervene at lower TSB levels for infants closer to 35 weeks and at higher TSB levels for those closer to 37 6/7 weeks.
• It is an option to provide conventional phototherapy in the hospital or at home at TSB levels of 2-3 mg/dL (35-50 mmol/L) below those shown, but home phototherapy should not be used in any infant with risk factors.

Reprinted with permission from: American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316. Copyright © 2004 by the American Academy of Pediatrics.

Feeding difficulties
The advantages of breast milk feeding for these babies are great. Unfortunately, it is breastfed infants who are more likely to have feeding difficulties and are at higher risk for readmission.¹⁷ Early feeding skills are complex and challenging. Because of their immaturity, late preterm infants have less effective suck and swallow coordination. They can be sleepier and have less stamina.¹⁰ Infants require coordinated oral motor movements, breathing, and swallowing to avoid desaturation and aspiration.²⁰ It is also important to note that almost every reported case of kernicterus in the past 20 years has been in breastfed infants whose feeding was not well established.¹³ First-born infants are especially at risk, as it takes longer to establish an adequate supply of milk.

For late preterm infants, it is imperative to establish successful breastfeeding to avoid dehydration and jaundice. Lactation consultation, education, and close follow-up are essential to successful breastfeeding in this group.¹⁸ The AAP Committee on Fetus and Newborn recommends a formal breastfeeding evaluation by trained caregivers at least twice daily prior to discharge.²

Brain injury
Late gestation is a critical period of brain growth. The 34-week-old brain weighs 65% of the term brain and increases linearly with each week. Fifty percent of the increase in cortical volume happens after 34 weeks.²¹ The risk of intraventricular hemorrhage and periventricular leukomalacia, while common in earlier preemies, is rare in infants born after 34 weeks. However, there is evidence to suggest other complications. Late preterm infants are more likely to be diagnosed with developmental delay and require special resources in preschool and less likely to be ready for school.²²

Sepsis
While late preterm neonates do have a small but significant increase in culture-proven sepsis and pneumonia compared with term babies,⁶ the work-up for possible sepsis is 3 times more likely. When these infants have poor feeding, mild respiratory distress, or TTN, physicians become concerned about sepsis and initiate a work-up.⁵ Currently there are no management guidelines for sepsis evaluation in this subset of preterm infants.²³

Readmission is a distinct possibility

One study of healthy late preterm infants showed a readmission rate of 4.8%. The most common reasons for readmission were jaundice and infection.¹⁷ Risk factors for readmission were breastfeeding, primiparity, labor and delivery complications, public payer source at delivery, and a mother of Asian/Pacific Islander ethnicity.¹⁷ Another study showed that discharge at less than 48 hours significantly increased the likelihood of readmission, even more so if the infant was breastfeeding.¹⁵

Several recent studies have highlighted a relationship between decreasing gestational age and a wide range of long-term adverse outcomes. In the early years of childhood, there is an increased risk for developmental delay and decreased kindergarten readiness.²² There is also a significant risk for disability, including cerebral palsy, mental retardation, and behavioral disorders.

Late preterm infants are at greater risk for several complications and the mortality rate is high in this group, when compared with term infants. By initial appearance and even weight, they rival their term counterparts. However, while they may look much like term babies and not weigh much less, they need more intense monitoring and should meet stringent discharge criteria (TABLE 2²).

TABLE 2
Minimum discharge criteria for late preterm infants²
All criteria should be met prior to discharge.

Clearly, more studies need to be done to address the unique needs and specific treatment guidelines for these infants. In fact, hospitals may need to consider introducing neonatal observation nurseries with protocols specifically tailored for late preterm infants.

CASE Ms. M and Julia likely would have been better served with an extra day in the hospital to address feeding issues and monitor for hyperbilirubinemia. Julia received phototherapy, IV fluids, and intensive lactation support, which included pumped breast milk given through a supplemental nursing system.

Over the course of 48 hours, her bilirubin decreased to 14 mg/dL and she was able to feed for longer periods of time without tiring. While both Ms. M and Julia’s initial outcomes were good, an extra day of feeding support may have prevented a readmission, thousands of dollars in care, and unnecessary stress on both mother and baby.

CORRESPONDENCE 
Kimberly Stuckey-Schrock, MD, IU Health Goshen, Lincoln Avenue Family Medicine, 400 W Lincoln Avenue, Goshen, IN 46526; [email protected]

CASE Laura M delivers her third baby at 35 weeks 4 days after an uneventful spontaneous labor. Julia, 5 lb 1 oz, has Apgar scores of 8 and 9. You see them on the mother-baby unit Friday afternoon, 36 hours after the delivery.

Ms. M has successfully breastfed her other 2 children and is planning to breastfeed Julia as well. She says the infant is nursing well today but seemed sleepy yesterday. The nursing notes say that Julia went to the nursery overnight because her mother was tired, and the infant spit up after receiving a formula bottle. Ms. M is asking you to discharge her because tomorrow is her son’s birthday. After considering this and her experience with breastfeeding, you decide to discharge her with follow-up on Monday instead of checking her out to your partner for the weekend.

Ms. M returns to your office on Monday with Julia, whose weight is down 10% and is “glowing yellow.” The baby is not latching well at the breast and is spitting up when Ms. M tries to supplement with formula. After examining Julia and checking lab work (bilirubin, 20 mg/dL), you decide to readmit her for feeding difficulties and hyperbilirubinemia.

Complications are common with late preterm infants, which refers to babies born between 34 weeks 0 days and 36 weeks 6 days of pregnancy. Between 1990 and 2006, there was a dramatic (25%) increase in the rate of late preterm infants in the United States, although more recently this number has leveled off.¹

Several factors have been linked to increased late preterm births: maternal obesity, increased maternal age, and the increasing rate of multiple gestation pregnancies that have resulted from the expanded use of reproductive technology.² Similarly, treatment of severe preeclampsia and premature rupture of membranes often includes delivery after 34 weeks of gestation,³ further contributing to the problem. Finally, higher rates of antenatal screening have contributed to more inductions and cesarean sections at earlier gestational ages. One study even found a correlation between higher malpractice premiums and more frequent late preterm inductions.⁴

Don’t let their appearance fool you

At first appearance, late preterm infants are similar to term infants in terms of Apgar scores,⁵ size, and weight.² However, the care of these infants can be complex. They are often placed in well-infant nurseries under the same protocols as term infants and discharged before an adequate observation period. These infants have both increased short- and long-term morbidity and mortality and use a significant amount of health care resources.⁵ Morbidity in these infants decreases with each week of gestation from 34 weeks to a nadir at 39 weeks and can be unrelated to maternal and pregnancy complications.⁶

The following are some important issues to keep in mind when caring for these infants.

Hypothermia and hypoglycemia
Late preterm infants experience increased cold stress because of their limited fat stores, reduced brown fat, an immature epidermal barrier, and increased surface area to body mass ratio.² Hypothermia increases the metabolic demands on the neonate and can worsen hypoglycemia as well as respiratory distress.⁷

Ideally, clinicians should dry these infants with warm blankets, place them skin-to-skin with their mother, and cover them with a warm blanket and cap to avoid excess energy expenditure.⁸ If conditions necessitate, neonates can be placed in a radiant warmer. Infants’ temperature needs to be monitored within the first 30 minutes of life and frequently reassessed during the first 12 hours of life—the “transition period.”⁸ The infant’s axillary temperature should be maintained between 36.5°C and 37.4°C (97.7-99.3°F); the temperature should remain stable in an open crib for the 12 hours before discharge.²

Decreased glycogen stores, increased glucose utilization, and immature hepatic enzymes help to explain the fact that hypoglycemia is 3 times more common in late preterm infants compared with full-term neonates.⁷ In all newborns, glucose levels decrease to their nadir between 30 and 90 minutes of life and normally trigger the breakdown of glycogen if the infant does not eat.⁷ Hypoglycemia can manifest as a change in level of consciousness, apnea, cyanosis, tachypnea, hypothermia, and seizures.⁹ The evidence is limited and there is controversy as to what level of hypoglycemia and over what duration of time is harmful.⁹

Most experts agree that breastfeeding should be started in the delivery room, and plasma glucose checked at 60 minutes of life and any time an infant is symptomatic. A level less than 45 mg/dL during the transition period should prompt feeding.⁹ Glucose levels should be rechecked within an hour of feeding and every 3 hours thereafter. If the level remains low or the infant is not interested in feeding, give a bolus of D₁₀W and consider an infusion.^7,10 TABLE 1¹⁰ highlights one proposed method of glucose management.

TABLE 1
How best to manage glucose in a late preterm newborn¹⁰

Respiratory distress
At least 30% of late preterm infants will have some evidence of respiratory distress,⁵ which is defined as the need for oxygen supplementation due to tachypnea, grunting, nasal flaring, retractions, or cyanosis. Those at highest risk are white males born via cesarean section.¹¹ Transient tachypnea of the newborn (TTN) appears to be the cause of almost half the cases of respiratory distress in these young patients.¹² As this is a diagnosis by exclusion, consider other common causes: respiratory distress syndrome, neonatal pneumonia, meconium aspiration syndrome, and persistent pulmonary hypertension.¹² The need for ventilator support is a significant concern in this group and increases exponentially with decreasing gestational age.⁶

Hyperbilirubinemia
More than half of all late preterm infants will present with clinically significant jaundice.⁵ Late preterm infants have an increased bilirubin load, decreased uptake of bilirubin, and delayed conjugation. They are less able to bind bilirubin to albumin, which increases their predisposition to bilirubin-induced neurological dysfunction and kernicterus.¹³ They also have more difficulty with breastfeeding, which exacerbates their hyperbilirubinemia.¹⁴

Infants born at 36 weeks have an 8-fold increased risk of developing severe hyperbilirubinemia (total serum bilirubin >20 mg/dL) than those born at 41 weeks,¹³ which explains why they are disproportionately represented in the US Pilot Kernicterus Registry.¹⁴ These infants can develop neurological sequelae at lower levels of bilirubin than their term counterparts and have less chance of complete recovery once intensive therapy has been implemented.¹⁴

The 2 main risk factors for severe hyperbilirubinemia have to do with discharge time and breastfeeding. Discharge at less than 48 hours is a risk factor for both term and late preterm infants.^14,15 This is likely due to the fact that bilirubin peaks in late preterm infants between Days 5 and 7, and in term infants between Days 3 and 5.¹⁶ Difficulties with breastfeeding, the second risk factor,¹⁷ can be due to a combination of delayed maternal lactogenesis and ineffective milk removal on the part of the infant.¹⁸ When infants ingest smaller volumes of milk, bowel movements are infrequent and the bilirubin in the gut gets reabsorbed instead of excreted.

American Academy of Pediatrics (AAP) guidelines suggest measuring total serum bilirubin or transcutaneous bilirubin and plotting the value on an hour-specific, gestational-age-specific, risk-specific nomogram (FIGURE).¹⁹ Alternately, BiliTool (http://www.bilitool.org) can be used to individualize an infant’s risk.

FIGURE
Bilirubin levels and risk of significant hyperbilirubinemia¹⁹
Bilirubin levels should be plotted according to the infant’s hours of life and assessed according to risk factors on the appropriate risk line. If infants are 34 weeks 0 days to 34 weeks 6 days, they should be assessed on the high risk line.

• Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin.
• Risk factors include isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin <3.0 g/dL (if measured).
• For well infants 35-37 6/7 weeks, you can adjust the total serum bilirubin (TSB) levels for intervention around the medium risk line. It is an option to intervene at lower TSB levels for infants closer to 35 weeks and at higher TSB levels for those closer to 37 6/7 weeks.
• It is an option to provide conventional phototherapy in the hospital or at home at TSB levels of 2-3 mg/dL (35-50 mmol/L) below those shown, but home phototherapy should not be used in any infant with risk factors.

Reprinted with permission from: American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316. Copyright © 2004 by the American Academy of Pediatrics.

Feeding difficulties
The advantages of breast milk feeding for these babies are great. Unfortunately, it is breastfed infants who are more likely to have feeding difficulties and are at higher risk for readmission.¹⁷ Early feeding skills are complex and challenging. Because of their immaturity, late preterm infants have less effective suck and swallow coordination. They can be sleepier and have less stamina.¹⁰ Infants require coordinated oral motor movements, breathing, and swallowing to avoid desaturation and aspiration.²⁰ It is also important to note that almost every reported case of kernicterus in the past 20 years has been in breastfed infants whose feeding was not well established.¹³ First-born infants are especially at risk, as it takes longer to establish an adequate supply of milk.

For late preterm infants, it is imperative to establish successful breastfeeding to avoid dehydration and jaundice. Lactation consultation, education, and close follow-up are essential to successful breastfeeding in this group.¹⁸ The AAP Committee on Fetus and Newborn recommends a formal breastfeeding evaluation by trained caregivers at least twice daily prior to discharge.²

Brain injury
Late gestation is a critical period of brain growth. The 34-week-old brain weighs 65% of the term brain and increases linearly with each week. Fifty percent of the increase in cortical volume happens after 34 weeks.²¹ The risk of intraventricular hemorrhage and periventricular leukomalacia, while common in earlier preemies, is rare in infants born after 34 weeks. However, there is evidence to suggest other complications. Late preterm infants are more likely to be diagnosed with developmental delay and require special resources in preschool and less likely to be ready for school.²²

Sepsis
While late preterm neonates do have a small but significant increase in culture-proven sepsis and pneumonia compared with term babies,⁶ the work-up for possible sepsis is 3 times more likely. When these infants have poor feeding, mild respiratory distress, or TTN, physicians become concerned about sepsis and initiate a work-up.⁵ Currently there are no management guidelines for sepsis evaluation in this subset of preterm infants.²³

Readmission is a distinct possibility

One study of healthy late preterm infants showed a readmission rate of 4.8%. The most common reasons for readmission were jaundice and infection.¹⁷ Risk factors for readmission were breastfeeding, primiparity, labor and delivery complications, public payer source at delivery, and a mother of Asian/Pacific Islander ethnicity.¹⁷ Another study showed that discharge at less than 48 hours significantly increased the likelihood of readmission, even more so if the infant was breastfeeding.¹⁵

Several recent studies have highlighted a relationship between decreasing gestational age and a wide range of long-term adverse outcomes. In the early years of childhood, there is an increased risk for developmental delay and decreased kindergarten readiness.²² There is also a significant risk for disability, including cerebral palsy, mental retardation, and behavioral disorders.

Late preterm infants are at greater risk for several complications and the mortality rate is high in this group, when compared with term infants. By initial appearance and even weight, they rival their term counterparts. However, while they may look much like term babies and not weigh much less, they need more intense monitoring and should meet stringent discharge criteria (TABLE 2²).

TABLE 2
Minimum discharge criteria for late preterm infants²
All criteria should be met prior to discharge.

Clearly, more studies need to be done to address the unique needs and specific treatment guidelines for these infants. In fact, hospitals may need to consider introducing neonatal observation nurseries with protocols specifically tailored for late preterm infants.

CASE Ms. M and Julia likely would have been better served with an extra day in the hospital to address feeding issues and monitor for hyperbilirubinemia. Julia received phototherapy, IV fluids, and intensive lactation support, which included pumped breast milk given through a supplemental nursing system.

Over the course of 48 hours, her bilirubin decreased to 14 mg/dL and she was able to feed for longer periods of time without tiring. While both Ms. M and Julia’s initial outcomes were good, an extra day of feeding support may have prevented a readmission, thousands of dollars in care, and unnecessary stress on both mother and baby.

CORRESPONDENCE 
Kimberly Stuckey-Schrock, MD, IU Health Goshen, Lincoln Avenue Family Medicine, 400 W Lincoln Avenue, Goshen, IN 46526; [email protected]

CASE Laura M delivers her third baby at 35 weeks 4 days after an uneventful spontaneous labor. Julia, 5 lb 1 oz, has Apgar scores of 8 and 9. You see them on the mother-baby unit Friday afternoon, 36 hours after the delivery.

Ms. M has successfully breastfed her other 2 children and is planning to breastfeed Julia as well. She says the infant is nursing well today but seemed sleepy yesterday. The nursing notes say that Julia went to the nursery overnight because her mother was tired, and the infant spit up after receiving a formula bottle. Ms. M is asking you to discharge her because tomorrow is her son’s birthday. After considering this and her experience with breastfeeding, you decide to discharge her with follow-up on Monday instead of checking her out to your partner for the weekend.

Ms. M returns to your office on Monday with Julia, whose weight is down 10% and is “glowing yellow.” The baby is not latching well at the breast and is spitting up when Ms. M tries to supplement with formula. After examining Julia and checking lab work (bilirubin, 20 mg/dL), you decide to readmit her for feeding difficulties and hyperbilirubinemia.

Complications are common with late preterm infants, which refers to babies born between 34 weeks 0 days and 36 weeks 6 days of pregnancy. Between 1990 and 2006, there was a dramatic (25%) increase in the rate of late preterm infants in the United States, although more recently this number has leveled off.¹

Several factors have been linked to increased late preterm births: maternal obesity, increased maternal age, and the increasing rate of multiple gestation pregnancies that have resulted from the expanded use of reproductive technology.² Similarly, treatment of severe preeclampsia and premature rupture of membranes often includes delivery after 34 weeks of gestation,³ further contributing to the problem. Finally, higher rates of antenatal screening have contributed to more inductions and cesarean sections at earlier gestational ages. One study even found a correlation between higher malpractice premiums and more frequent late preterm inductions.⁴

Don’t let their appearance fool you

At first appearance, late preterm infants are similar to term infants in terms of Apgar scores,⁵ size, and weight.² However, the care of these infants can be complex. They are often placed in well-infant nurseries under the same protocols as term infants and discharged before an adequate observation period. These infants have both increased short- and long-term morbidity and mortality and use a significant amount of health care resources.⁵ Morbidity in these infants decreases with each week of gestation from 34 weeks to a nadir at 39 weeks and can be unrelated to maternal and pregnancy complications.⁶

The following are some important issues to keep in mind when caring for these infants.

Hypothermia and hypoglycemia
Late preterm infants experience increased cold stress because of their limited fat stores, reduced brown fat, an immature epidermal barrier, and increased surface area to body mass ratio.² Hypothermia increases the metabolic demands on the neonate and can worsen hypoglycemia as well as respiratory distress.⁷

Ideally, clinicians should dry these infants with warm blankets, place them skin-to-skin with their mother, and cover them with a warm blanket and cap to avoid excess energy expenditure.⁸ If conditions necessitate, neonates can be placed in a radiant warmer. Infants’ temperature needs to be monitored within the first 30 minutes of life and frequently reassessed during the first 12 hours of life—the “transition period.”⁸ The infant’s axillary temperature should be maintained between 36.5°C and 37.4°C (97.7-99.3°F); the temperature should remain stable in an open crib for the 12 hours before discharge.²

Decreased glycogen stores, increased glucose utilization, and immature hepatic enzymes help to explain the fact that hypoglycemia is 3 times more common in late preterm infants compared with full-term neonates.⁷ In all newborns, glucose levels decrease to their nadir between 30 and 90 minutes of life and normally trigger the breakdown of glycogen if the infant does not eat.⁷ Hypoglycemia can manifest as a change in level of consciousness, apnea, cyanosis, tachypnea, hypothermia, and seizures.⁹ The evidence is limited and there is controversy as to what level of hypoglycemia and over what duration of time is harmful.⁹

Most experts agree that breastfeeding should be started in the delivery room, and plasma glucose checked at 60 minutes of life and any time an infant is symptomatic. A level less than 45 mg/dL during the transition period should prompt feeding.⁹ Glucose levels should be rechecked within an hour of feeding and every 3 hours thereafter. If the level remains low or the infant is not interested in feeding, give a bolus of D₁₀W and consider an infusion.^7,10 TABLE 1¹⁰ highlights one proposed method of glucose management.

TABLE 1
How best to manage glucose in a late preterm newborn¹⁰

Respiratory distress
At least 30% of late preterm infants will have some evidence of respiratory distress,⁵ which is defined as the need for oxygen supplementation due to tachypnea, grunting, nasal flaring, retractions, or cyanosis. Those at highest risk are white males born via cesarean section.¹¹ Transient tachypnea of the newborn (TTN) appears to be the cause of almost half the cases of respiratory distress in these young patients.¹² As this is a diagnosis by exclusion, consider other common causes: respiratory distress syndrome, neonatal pneumonia, meconium aspiration syndrome, and persistent pulmonary hypertension.¹² The need for ventilator support is a significant concern in this group and increases exponentially with decreasing gestational age.⁶

Hyperbilirubinemia
More than half of all late preterm infants will present with clinically significant jaundice.⁵ Late preterm infants have an increased bilirubin load, decreased uptake of bilirubin, and delayed conjugation. They are less able to bind bilirubin to albumin, which increases their predisposition to bilirubin-induced neurological dysfunction and kernicterus.¹³ They also have more difficulty with breastfeeding, which exacerbates their hyperbilirubinemia.¹⁴

Infants born at 36 weeks have an 8-fold increased risk of developing severe hyperbilirubinemia (total serum bilirubin >20 mg/dL) than those born at 41 weeks,¹³ which explains why they are disproportionately represented in the US Pilot Kernicterus Registry.¹⁴ These infants can develop neurological sequelae at lower levels of bilirubin than their term counterparts and have less chance of complete recovery once intensive therapy has been implemented.¹⁴

The 2 main risk factors for severe hyperbilirubinemia have to do with discharge time and breastfeeding. Discharge at less than 48 hours is a risk factor for both term and late preterm infants.^14,15 This is likely due to the fact that bilirubin peaks in late preterm infants between Days 5 and 7, and in term infants between Days 3 and 5.¹⁶ Difficulties with breastfeeding, the second risk factor,¹⁷ can be due to a combination of delayed maternal lactogenesis and ineffective milk removal on the part of the infant.¹⁸ When infants ingest smaller volumes of milk, bowel movements are infrequent and the bilirubin in the gut gets reabsorbed instead of excreted.

American Academy of Pediatrics (AAP) guidelines suggest measuring total serum bilirubin or transcutaneous bilirubin and plotting the value on an hour-specific, gestational-age-specific, risk-specific nomogram (FIGURE).¹⁹ Alternately, BiliTool (http://www.bilitool.org) can be used to individualize an infant’s risk.

FIGURE
Bilirubin levels and risk of significant hyperbilirubinemia¹⁹
Bilirubin levels should be plotted according to the infant’s hours of life and assessed according to risk factors on the appropriate risk line. If infants are 34 weeks 0 days to 34 weeks 6 days, they should be assessed on the high risk line.

• Use total bilirubin. Do not subtract direct reacting or conjugated bilirubin.
• Risk factors include isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin <3.0 g/dL (if measured).
• For well infants 35-37 6/7 weeks, you can adjust the total serum bilirubin (TSB) levels for intervention around the medium risk line. It is an option to intervene at lower TSB levels for infants closer to 35 weeks and at higher TSB levels for those closer to 37 6/7 weeks.
• It is an option to provide conventional phototherapy in the hospital or at home at TSB levels of 2-3 mg/dL (35-50 mmol/L) below those shown, but home phototherapy should not be used in any infant with risk factors.

Reprinted with permission from: American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114:297-316. Copyright © 2004 by the American Academy of Pediatrics.

Feeding difficulties
The advantages of breast milk feeding for these babies are great. Unfortunately, it is breastfed infants who are more likely to have feeding difficulties and are at higher risk for readmission.¹⁷ Early feeding skills are complex and challenging. Because of their immaturity, late preterm infants have less effective suck and swallow coordination. They can be sleepier and have less stamina.¹⁰ Infants require coordinated oral motor movements, breathing, and swallowing to avoid desaturation and aspiration.²⁰ It is also important to note that almost every reported case of kernicterus in the past 20 years has been in breastfed infants whose feeding was not well established.¹³ First-born infants are especially at risk, as it takes longer to establish an adequate supply of milk.

For late preterm infants, it is imperative to establish successful breastfeeding to avoid dehydration and jaundice. Lactation consultation, education, and close follow-up are essential to successful breastfeeding in this group.¹⁸ The AAP Committee on Fetus and Newborn recommends a formal breastfeeding evaluation by trained caregivers at least twice daily prior to discharge.²

Brain injury
Late gestation is a critical period of brain growth. The 34-week-old brain weighs 65% of the term brain and increases linearly with each week. Fifty percent of the increase in cortical volume happens after 34 weeks.²¹ The risk of intraventricular hemorrhage and periventricular leukomalacia, while common in earlier preemies, is rare in infants born after 34 weeks. However, there is evidence to suggest other complications. Late preterm infants are more likely to be diagnosed with developmental delay and require special resources in preschool and less likely to be ready for school.²²

Sepsis
While late preterm neonates do have a small but significant increase in culture-proven sepsis and pneumonia compared with term babies,⁶ the work-up for possible sepsis is 3 times more likely. When these infants have poor feeding, mild respiratory distress, or TTN, physicians become concerned about sepsis and initiate a work-up.⁵ Currently there are no management guidelines for sepsis evaluation in this subset of preterm infants.²³

Readmission is a distinct possibility

One study of healthy late preterm infants showed a readmission rate of 4.8%. The most common reasons for readmission were jaundice and infection.¹⁷ Risk factors for readmission were breastfeeding, primiparity, labor and delivery complications, public payer source at delivery, and a mother of Asian/Pacific Islander ethnicity.¹⁷ Another study showed that discharge at less than 48 hours significantly increased the likelihood of readmission, even more so if the infant was breastfeeding.¹⁵

Several recent studies have highlighted a relationship between decreasing gestational age and a wide range of long-term adverse outcomes. In the early years of childhood, there is an increased risk for developmental delay and decreased kindergarten readiness.²² There is also a significant risk for disability, including cerebral palsy, mental retardation, and behavioral disorders.

Late preterm infants are at greater risk for several complications and the mortality rate is high in this group, when compared with term infants. By initial appearance and even weight, they rival their term counterparts. However, while they may look much like term babies and not weigh much less, they need more intense monitoring and should meet stringent discharge criteria (TABLE 2²).

TABLE 2
Minimum discharge criteria for late preterm infants²
All criteria should be met prior to discharge.

Clearly, more studies need to be done to address the unique needs and specific treatment guidelines for these infants. In fact, hospitals may need to consider introducing neonatal observation nurseries with protocols specifically tailored for late preterm infants.

CASE Ms. M and Julia likely would have been better served with an extra day in the hospital to address feeding issues and monitor for hyperbilirubinemia. Julia received phototherapy, IV fluids, and intensive lactation support, which included pumped breast milk given through a supplemental nursing system.

Over the course of 48 hours, her bilirubin decreased to 14 mg/dL and she was able to feed for longer periods of time without tiring. While both Ms. M and Julia’s initial outcomes were good, an extra day of feeding support may have prevented a readmission, thousands of dollars in care, and unnecessary stress on both mother and baby.

CORRESPONDENCE 
Kimberly Stuckey-Schrock, MD, IU Health Goshen, Lincoln Avenue Family Medicine, 400 W Lincoln Avenue, Goshen, IN 46526; [email protected]

CASE A 44-year-old Korean woman who was receiving pegylated interferon (IFN) and ribavirin for chronic hepatitis C infection came into our facility with complaints of gradual onset of fatigue, unintentional weight loss of 15 pounds within a month, palpitations, and heat intolerance. She said her symptoms had worsened a week earlier, after she’d undergone an abdominal computed tomography scan with intravenous contrast.

Her physical exam revealed a blood pressure of 90/60 mm Hg, heart rate of 120 beats per minute, body mass index (BMI) of 17 kg/m², and visibly symmetric thyroid enlargement without any nodules, tenderness, or bruits. Despite her low systolic reading, she was asymptomatic and not septic or in thyroid storm. Laboratory data showed pancytopenia with a white blood cell count of 700/mcL (absolute neutrophil count, 189), hemoglobin of 9.6 g/L, platelet count of 96,000 cell/mcL, elevated free thyroxine (T4) of 5.7 ng/dL (normal, 0.6-1.6 ng/dL), total triiodothyronine (T3) of 301 ng/dL (normal, 90-180 ng/dL), and suppressed thyroid-stimulating hormone (TSH) of 0.01 mcU/mL (normal, 0.27-4.20 mcU/mL). The thyroid peroxidase antibody level was elevated at 9420 U/mL (normal, <35 U/mL), with a normal level of thyroid-stimulating immunoglobulin. Neither of these latter tests was obtained before IFN treatment. The patient had no history of thyroid dysfunction.

We discontinued the patient’s pegylated IFN and ribavirin. Antithyroid medication and beta-blockade were contraindicated due to pancytopenia and hypotension, respectively. Given her recent iodine exposure from contrast media, radioactive iodine treatment would be ineffective. We started the patient on cholestyramine 4 g orally 3 times a day and she improved rapidly. Her thyroid function normalized after 2.5 weeks of treatment.

After 6 weeks, when her TSH increased to 13 mcU/mL, we discontinued cholestyramine. Two weeks later, her TSH was >50 mcU/mL and we started the patient on levothyroxine replacement.

Discussion

The association between IFN-alpha and thyroid disease was recognized as early as 1985.¹ Between 5% and 10% of patients receiving IFN-alpha therapy may develop clinical thyroid disease, including painless thyroiditis, Hashimoto’s thyroiditis, and Graves’ disease,² although a recent prospective study in Australia showed a thyroid disease prevalence of just 1% up to 6 months after treatment with IFN-alpha and ribavirin.³

The cause of our patient’s thyrotoxicosis. IFN-alpha therapy likely caused our patient’s thyrotoxicosis, but iodide-induced hyperthyroidism may occur after use of iodinated contrast media.⁴ Prompt treatment of thyrotoxicosis with beta-blockers, anti-thyroid drugs, or radioiodine is necessary to reduce morbidity and the risk of developing thyroid storm, a condition associated with significant mortality.^2,5

Cholestyramine, a bile salt sequestrant, has been used chiefly to lower cholesterol since the 1960s.^6,7 However, studies also found that cholestyramine’s ionic exchange properties could decrease excessive thyroid hormone levels by enhancing hormone clearance from the enterohepatic circulation and thereby increase hormone fecal excretion.^6,7 In one study, radioactive iodine was given to patients simultaneously receiving levothyroxine for thyroid hormone deficiency and cholestyramine for hyperlipidemia.⁶ Results included increased stool radioactivity, decreased urine radioactivity, and decreased thyroid uptake consistent with enhanced clearance of thyroid hormones.⁶ The study also showed that 50 mg of cholestyramine can bind about 3000 mcg of T4.⁶

Cholestyramine as adjunctive therapy has rapidly decreased thyroid hormone levels compared with standard therapy alone, maintaining its effect for about 4 weeks.^2,5,8,9 Complete normalization of free T4 and free T3 levels and notable symptom improvement have occurred within one week of instituting cholestyramine therapy.⁵ The optimal dosage is 4 g cholestyramine orally, 2 to 4 times daily for 4 weeks.^2,5,8,9 Primary adverse effects of cholestyramine are constipation and abdominal discomfort. In contrast to methimazole or propylthiouracil, which only treat conditions of excess thyroid hormone production, cholestyramine is effective for any condition with excessive thyroid hormone levels—eg, subacute thyroiditis, Jod-Basdow phenomenon, and factitious thyroid hormone disorder.

Resolution. In our patient, the clinical picture was consistent with an autoimmune form of thyrotoxicosis induced by IFN therapy and possibly exacerbated by iodine exposure. In the absence of a thyroid scan at the time of thyrotoxicosis, we cannot exclude destructive thyroiditis; in fact, the ensuing hypothyroidism strengthens this possibility. Nevertheless, we believe that the oral administration of cholestyramine as monotherapy contributed to the resolution of our patient’s thyrotoxic symptoms when first-line medications were contraindicated.

CORRESPONDENCE 
Dagmar Lin, MD, Jackson Memorial Hospital, University of Miami, 1611 NW 12th Avenue, MICU, Central Room 455, Miami, FL 33136; [email protected]

CASE A 44-year-old Korean woman who was receiving pegylated interferon (IFN) and ribavirin for chronic hepatitis C infection came into our facility with complaints of gradual onset of fatigue, unintentional weight loss of 15 pounds within a month, palpitations, and heat intolerance. She said her symptoms had worsened a week earlier, after she’d undergone an abdominal computed tomography scan with intravenous contrast.

Her physical exam revealed a blood pressure of 90/60 mm Hg, heart rate of 120 beats per minute, body mass index (BMI) of 17 kg/m², and visibly symmetric thyroid enlargement without any nodules, tenderness, or bruits. Despite her low systolic reading, she was asymptomatic and not septic or in thyroid storm. Laboratory data showed pancytopenia with a white blood cell count of 700/mcL (absolute neutrophil count, 189), hemoglobin of 9.6 g/L, platelet count of 96,000 cell/mcL, elevated free thyroxine (T4) of 5.7 ng/dL (normal, 0.6-1.6 ng/dL), total triiodothyronine (T3) of 301 ng/dL (normal, 90-180 ng/dL), and suppressed thyroid-stimulating hormone (TSH) of 0.01 mcU/mL (normal, 0.27-4.20 mcU/mL). The thyroid peroxidase antibody level was elevated at 9420 U/mL (normal, <35 U/mL), with a normal level of thyroid-stimulating immunoglobulin. Neither of these latter tests was obtained before IFN treatment. The patient had no history of thyroid dysfunction.

We discontinued the patient’s pegylated IFN and ribavirin. Antithyroid medication and beta-blockade were contraindicated due to pancytopenia and hypotension, respectively. Given her recent iodine exposure from contrast media, radioactive iodine treatment would be ineffective. We started the patient on cholestyramine 4 g orally 3 times a day and she improved rapidly. Her thyroid function normalized after 2.5 weeks of treatment.

After 6 weeks, when her TSH increased to 13 mcU/mL, we discontinued cholestyramine. Two weeks later, her TSH was >50 mcU/mL and we started the patient on levothyroxine replacement.

Discussion

The association between IFN-alpha and thyroid disease was recognized as early as 1985.¹ Between 5% and 10% of patients receiving IFN-alpha therapy may develop clinical thyroid disease, including painless thyroiditis, Hashimoto’s thyroiditis, and Graves’ disease,² although a recent prospective study in Australia showed a thyroid disease prevalence of just 1% up to 6 months after treatment with IFN-alpha and ribavirin.³

The cause of our patient’s thyrotoxicosis. IFN-alpha therapy likely caused our patient’s thyrotoxicosis, but iodide-induced hyperthyroidism may occur after use of iodinated contrast media.⁴ Prompt treatment of thyrotoxicosis with beta-blockers, anti-thyroid drugs, or radioiodine is necessary to reduce morbidity and the risk of developing thyroid storm, a condition associated with significant mortality.^2,5

Cholestyramine, a bile salt sequestrant, has been used chiefly to lower cholesterol since the 1960s.^6,7 However, studies also found that cholestyramine’s ionic exchange properties could decrease excessive thyroid hormone levels by enhancing hormone clearance from the enterohepatic circulation and thereby increase hormone fecal excretion.^6,7 In one study, radioactive iodine was given to patients simultaneously receiving levothyroxine for thyroid hormone deficiency and cholestyramine for hyperlipidemia.⁶ Results included increased stool radioactivity, decreased urine radioactivity, and decreased thyroid uptake consistent with enhanced clearance of thyroid hormones.⁶ The study also showed that 50 mg of cholestyramine can bind about 3000 mcg of T4.⁶

Cholestyramine as adjunctive therapy has rapidly decreased thyroid hormone levels compared with standard therapy alone, maintaining its effect for about 4 weeks.^2,5,8,9 Complete normalization of free T4 and free T3 levels and notable symptom improvement have occurred within one week of instituting cholestyramine therapy.⁵ The optimal dosage is 4 g cholestyramine orally, 2 to 4 times daily for 4 weeks.^2,5,8,9 Primary adverse effects of cholestyramine are constipation and abdominal discomfort. In contrast to methimazole or propylthiouracil, which only treat conditions of excess thyroid hormone production, cholestyramine is effective for any condition with excessive thyroid hormone levels—eg, subacute thyroiditis, Jod-Basdow phenomenon, and factitious thyroid hormone disorder.

Resolution. In our patient, the clinical picture was consistent with an autoimmune form of thyrotoxicosis induced by IFN therapy and possibly exacerbated by iodine exposure. In the absence of a thyroid scan at the time of thyrotoxicosis, we cannot exclude destructive thyroiditis; in fact, the ensuing hypothyroidism strengthens this possibility. Nevertheless, we believe that the oral administration of cholestyramine as monotherapy contributed to the resolution of our patient’s thyrotoxic symptoms when first-line medications were contraindicated.

CORRESPONDENCE 
Dagmar Lin, MD, Jackson Memorial Hospital, University of Miami, 1611 NW 12th Avenue, MICU, Central Room 455, Miami, FL 33136; [email protected]

CASE A 44-year-old Korean woman who was receiving pegylated interferon (IFN) and ribavirin for chronic hepatitis C infection came into our facility with complaints of gradual onset of fatigue, unintentional weight loss of 15 pounds within a month, palpitations, and heat intolerance. She said her symptoms had worsened a week earlier, after she’d undergone an abdominal computed tomography scan with intravenous contrast.

Her physical exam revealed a blood pressure of 90/60 mm Hg, heart rate of 120 beats per minute, body mass index (BMI) of 17 kg/m², and visibly symmetric thyroid enlargement without any nodules, tenderness, or bruits. Despite her low systolic reading, she was asymptomatic and not septic or in thyroid storm. Laboratory data showed pancytopenia with a white blood cell count of 700/mcL (absolute neutrophil count, 189), hemoglobin of 9.6 g/L, platelet count of 96,000 cell/mcL, elevated free thyroxine (T4) of 5.7 ng/dL (normal, 0.6-1.6 ng/dL), total triiodothyronine (T3) of 301 ng/dL (normal, 90-180 ng/dL), and suppressed thyroid-stimulating hormone (TSH) of 0.01 mcU/mL (normal, 0.27-4.20 mcU/mL). The thyroid peroxidase antibody level was elevated at 9420 U/mL (normal, <35 U/mL), with a normal level of thyroid-stimulating immunoglobulin. Neither of these latter tests was obtained before IFN treatment. The patient had no history of thyroid dysfunction.

We discontinued the patient’s pegylated IFN and ribavirin. Antithyroid medication and beta-blockade were contraindicated due to pancytopenia and hypotension, respectively. Given her recent iodine exposure from contrast media, radioactive iodine treatment would be ineffective. We started the patient on cholestyramine 4 g orally 3 times a day and she improved rapidly. Her thyroid function normalized after 2.5 weeks of treatment.

After 6 weeks, when her TSH increased to 13 mcU/mL, we discontinued cholestyramine. Two weeks later, her TSH was >50 mcU/mL and we started the patient on levothyroxine replacement.

Discussion

The association between IFN-alpha and thyroid disease was recognized as early as 1985.¹ Between 5% and 10% of patients receiving IFN-alpha therapy may develop clinical thyroid disease, including painless thyroiditis, Hashimoto’s thyroiditis, and Graves’ disease,² although a recent prospective study in Australia showed a thyroid disease prevalence of just 1% up to 6 months after treatment with IFN-alpha and ribavirin.³

The cause of our patient’s thyrotoxicosis. IFN-alpha therapy likely caused our patient’s thyrotoxicosis, but iodide-induced hyperthyroidism may occur after use of iodinated contrast media.⁴ Prompt treatment of thyrotoxicosis with beta-blockers, anti-thyroid drugs, or radioiodine is necessary to reduce morbidity and the risk of developing thyroid storm, a condition associated with significant mortality.^2,5

Cholestyramine, a bile salt sequestrant, has been used chiefly to lower cholesterol since the 1960s.^6,7 However, studies also found that cholestyramine’s ionic exchange properties could decrease excessive thyroid hormone levels by enhancing hormone clearance from the enterohepatic circulation and thereby increase hormone fecal excretion.^6,7 In one study, radioactive iodine was given to patients simultaneously receiving levothyroxine for thyroid hormone deficiency and cholestyramine for hyperlipidemia.⁶ Results included increased stool radioactivity, decreased urine radioactivity, and decreased thyroid uptake consistent with enhanced clearance of thyroid hormones.⁶ The study also showed that 50 mg of cholestyramine can bind about 3000 mcg of T4.⁶

Cholestyramine as adjunctive therapy has rapidly decreased thyroid hormone levels compared with standard therapy alone, maintaining its effect for about 4 weeks.^2,5,8,9 Complete normalization of free T4 and free T3 levels and notable symptom improvement have occurred within one week of instituting cholestyramine therapy.⁵ The optimal dosage is 4 g cholestyramine orally, 2 to 4 times daily for 4 weeks.^2,5,8,9 Primary adverse effects of cholestyramine are constipation and abdominal discomfort. In contrast to methimazole or propylthiouracil, which only treat conditions of excess thyroid hormone production, cholestyramine is effective for any condition with excessive thyroid hormone levels—eg, subacute thyroiditis, Jod-Basdow phenomenon, and factitious thyroid hormone disorder.

Resolution. In our patient, the clinical picture was consistent with an autoimmune form of thyrotoxicosis induced by IFN therapy and possibly exacerbated by iodine exposure. In the absence of a thyroid scan at the time of thyrotoxicosis, we cannot exclude destructive thyroiditis; in fact, the ensuing hypothyroidism strengthens this possibility. Nevertheless, we believe that the oral administration of cholestyramine as monotherapy contributed to the resolution of our patient’s thyrotoxic symptoms when first-line medications were contraindicated.

CORRESPONDENCE 
Dagmar Lin, MD, Jackson Memorial Hospital, University of Miami, 1611 NW 12th Avenue, MICU, Central Room 455, Miami, FL 33136; [email protected]