Skin infections in athletes: Treating the patient, protecting the team

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;
shahn@summahealth.org

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;
shahn@summahealth.org

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;
shahn@summahealth.org

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