Is PASH Syndrome a Biofilm Disease?: A Case Series and Review of the Literature

Introduction. When occurring together, pyoderma gangrenosum, severe acne, and hidradenitis suppurativa have been described as PASH syndrome. Due to the chronic autoinflammatory state existing in affected patients, PASH syndrome has been attributed to the dysregulation of wound healing. Case Reports. Two cases are presented that demonstrate the paradigmatic clinical features of PASH syndrome and its potential link as an expanding spectrum of bacterial biofilm disorder. Conclusions. As reported herein, based on biofilm’s clinical presentation and resistance to proper wound healing, it could serve as the common denominator and may redirect clinicians’ treatment pathways in the near future.

Biofilm is a dynamic, heterogeneous species with a continuously evolving morphology.¹ It has been associated with and found in a number of pathologies, including periodontal disease, tuberculosis, cystic fibrosis, and osteomyelitis, among others.^1,2 These infectious networks can essentially affect every organ system in the human body, including skin. The complex architecture of biofilms presents a major challenge to clinicians due to an intrinsic ability to resist antibiotic therapy. A meta-analysis conducted by Malone et al³ that 78.2% of chronic wound specimens contain biofilm. In contrast, acute wounds only comprised 6% of this infectious community.⁴ Biofilm-controlled host senescent tissue is characterized by elevated levels of proinflammatory cytokines, neutrophils, and matrix metalloproteinases.⁵ It should be noted that intrinsic host immune factors appear to be less effective against biofilms than their innate phagocytic response to planktonic bacteria.⁵ Chronic inflammation stimulated by biofilm, in conjunction with host cellular dysfunction, is sufficient to obstruct the wound healing cascade.⁵ However, this pathogenicity helps elucidate the recalcitrant behavior of chronic wounds.

Biofilm releases inflammatory cells that consume oxygen and other integral biochemical requisites for proper healing.⁶ This serves as a breeding ground for anaerobic species that are increasingly pathogenic and resistant to antibacterial treatments. In 2012, Braun-Falco et al⁷ proposed a series of distinct pathologies that represent a new disease entity within the spectrum of autoimmune and dermatologic conditions known as PASH, which is characterized by the association of pyoderma gangrenosum (PG), acne vulgaris (A), and hidradenitis suppurativa (HS). Histopathological features typically present with neutrophilic dermatosis consistent with bacterial superinfections.⁸ The coalescing pathogenic features of biofilm involvement in chronic wounds could serve as the missing link connecting the distinct entities within PASH syndrome.

Herein, 2 cases of PASH in young women with wounds on their lower extremities are presented that demonstrate the potential link of these distinct etiologies.

Case 1

A 30-year-old Caucasian woman presented to the wound care center with open wounds of the left lower leg that were present for more than 4 years. She stated that the wounds started out as “pimples.” Prior to her visit, she was prescribed an assortment of topical therapies, including silver sulfadiazine, triamcinolone acetonide, and MediHoney (Integra Life Sciences, Plainsboro, NJ). However, these treatment modalities were not effective in reducing the patient’s symptoms. She then was referred to an infectious disease specialist who had her on a multiplicity of antibiotics, including cephalexin, ciprofloxacin, and a collagen-based wound care dressing; these agents were unable to treat her condition. She noted the lesions grew in size over time. There had been previous outbreaks of pimples across her back and abdominal regions. Multiple abdominal HS pustules were noted, but all seemed to have healed prior to  presentation. The patient stated the wounds (pre-sharp debridement) were extremely painful, a Wong-Baker scale of 4/10 but at times 20/10. Preceding debridement therapy made her lesions worse, which resulted in a diagnosis of PG. Upon physical examination, hair distribution to the left lower extremity was sparse and the skin was dry and atrophic with mild edema. The patient presented with a wide spectrum of comorbidities that included chronic venous insufficiency, obesity, generalized severe acne, folliculitis, and hirsutism (Figure 1).

In January 2016, a wound measuring 3.5 cm x 3.0 cm was located on the left anteromedial aspect (middle third) of the left lower extremity (Figure 2A). The wound environment remained relatively unchanged. A mild violaceous ring was still present at both wounds. A culture was taken and revealed growth of methicillin-resistant Staphylococcus aureus (MRSA), and histopathologic studies revealed mixed neutrophilic dermatosis. Based on the clinical picture, lab data, previous history, increased size (secondary to pathergy), and pathology report, a diagnosis of PG was made.

It should be noted that the pathergy exhibited by the lesion merely contributed to the diagnosis, because 25% to 50% of patients with PG present with this secondary reaction.⁸ There was no evidence of vasculitis, vasculopathy, or any infectious process or malignancy. Initial treatments included a prescription of minocycline 50 mg taken twice daily (due to its anti-inflammatory effect at low doses), systemic antibiotic therapy (ciprofloxacin and cephalexin), and Silvercel Nonadherent Dressing (Acelity, San Antonio, TX) with 4x4 Kerlix Double-layered Compression (Covidien Ltd, Dublin, Ireland) (Table 1).

At 2-month follow-up (March 2016), the wound measured 2.4 cm x 1.2 cm and was filled with pink granulation tissue and mild violaceous borders. Hyperpigmentation was found around the periwound environment (Figure 2B). The wound bed was about 90% granulation tissue and 10% slough and had no signs of necrotic tissue formation. Erythema was noted around the periwound. Superficial debridement was implemented at this point with monitoring for pathergy at next visit.

The patient continued the treatment regimen with the following modifications: minocycline was replaced with doxycycline 100 mg taken twice daily, mupirocin ointment (22 g) for daily application to the affected area, continued with the same systemic antibiotic therapy, and a nonadherent antimicrobial alginate dressing with double-layered compression. By the 5-month follow-up visit (June 2016), the ulcer had healed completely (Figure 2C).

However, at the 6-month follow-up visit (July 2016), she presented to the clinic with superficial ulcer recurrence located in the same anatomical area as the previous ulcer. The patient noted that she was currently menstruating. Possible explanations for this recurrence could be attributed to either insidious trauma (pathergy), dramatic increase in hormones (menses), or a combination of both factors leading to re-ulceration, if in fact there is a connection between PG and HS (eFigure 3). However, 3 weeks later, she returned for a follow-up visit with an exponential growth of the ulcer measuring 9 cm x 9 cm x 1 cm. The ulcer presented with hyperpigmented violaceous borders. Her treatment was then modified to address the ulceration recurrence (Table 1).

She returned to clinic for follow-up and interestingly, her ulcer had greatly decreased in size to 1.4 cm x 1 cm x 0.5 cm. One week later, she returned to the clinic to receive dehydrated human amnion-chorion membrane graft therapy (EpiFix; Marietta, GA). At that visit, her wound measurements were 1.8 cm x 0.9 cm (lateral) and 1.3 cm x 0.5 cm (medial). The diagnosis of PASH was considered due to the patient’s history of HS and acne in conjunction with the insidious onset of the PG ulceration. This case further illustrates the potential correlation between neutrophilic dermatoses and its role in broad-spectrum autoinflammatory (PASH) syndrome, which makes treatment pathways challenging.

Case 2

A 30-year-old Caucasian woman presented to the clinic in January 2015 with 7 open ulcers: 5 on her left leg and 2 on the right (Figure 4). The most severe ulcer was located on the lower anterolateral aspect of left leg that measured 4.5 cm x 2.5 cm x 0.1 cm and had been present for 4 months. She reported a multiyear history of multiple similar ulcers located on her legs, arms, and back. The initial presentations were pustular in nature and would spontaneously break down and become large, open wounds. Pain was severe (10/10 on the Wong-Baker scale) and worsened with any contact with the wounds. Previous treatment consisted of antibiotics, most recently sulfamethoxazole/trimethoprim. The patient had an additional history of arthritis, with a possible diagnosis of rheumatoid arthritis, treated with 20 mg of prednisone daily over the past 4 years. Her arthritis symptoms consisted of severe and debilitating ankle and foot pain that limited her ability to walk. She also reported a history of HS, primarily axillary in location, with no previous treatment.

Initial visit revealed 7 ulcers covered with moderate black necrotic slough, rolled borders, and scant yellow drainage of her bilateral lower extremities (Figure 4A, 4C, 4E, 4G, 4I, 4K, 4M). Surrounding erythema and lower extremity edema was noted. The wound measurements varied from 0.5 cm x 0.5 cm to a maximum of 4.5 cm x 2.5 cm.

The patient was noted to have an elevated white blood cell count on recent laboratory evaluation. She also had a plain radiograph of her ankle that demonstrated soft tissue edema. A venous Doppler ultrasound of her lower extremities was ordered to rule out a deep vein thrombosis (DVT) due to significant lower extremity edema; that result was normal. An antinuclear antibodies (ANA), rheumatoid factor (RF), hepatitis panel, and thyroid stimulating hormone also were ordered.

The largest ulcer was cultured and biopsied. A hydrocolloid non-adhesive (MediHoney; Integra Life Sciences) dressing was placed on the wounds (Table 2). Medication treatment included doxycycline 100 mg twice daily and levofloxacin 500 mg daily. Due to clinical suspicion of PG, a prednisone taper starting at 60 mg daily was initiated.

The patient returned for evaluation 1 week after presentation. The final biopsy result was indefinite for PG. The report stated “benign skin accompanied by acute fibropurulent exudate, without evidence of vasculitis, most consistent with pyoderma.” The ANA and RF were negative. The wound culture was positive for MRSA sensitive to tetracycline. Venous Doppler was negative for DVT. At this time, the patient was continued on doxycycline 100 mg daily and the prednisone taper (10 mg orally before breakfast, 5 mg after lunch and after dinner, and 10 mg at bedtime). Compression therapy was initiated on the left lower extremity. Hydrofera Blue (Hydrofera, Manchester, CT) was applied to the ulcerations. She was referred to rheumatology due to high suspicion of PG and history of possible rheumatoid arthritis per patient history.

With wound 7 healed, continued improvement was noted on her next visit 3 days later. Again, she was continued on doxycycline 100 mg twice daily and with the previous prednisone taper; compression wrap was continued on the left leg and gentian violet/methylene blue foam dressing was placed on the ulcerations. Two weeks after presentation, it was noted on follow-up that she had increased drainage and her dressing was changed to Maxorb Ag (Medline Inc, Northfield, IL). She was evaluated at post presentation week 3 and wound 6 had healed. She continued with compression wrap and silver calcium alginate dressings to the wounds.

Rheumatology evaluation occurred 1 month post presentation. The diagnosis of PG was felt to be accurate, and extensive additional laboratory evaluations were obtained. Due to her extensive skin disease, the patient was referred to dermatology.

Dermatologic evaluation occurred 5 weeks after initial presentation. Two additional biopsies of the left lower extremity were performed at that time. Exam additionally revealed axillary nodules with drainage. The diagnosis of PASH was speculated due to the patient’s history of HS and acne in addition to the continued suspicion of PG. Biopsy results supported the diagnosis of PG, noting “the dermis displays an interstitial diffuse distribution of neutrophils. Some lymphocytes and activated fibroblasts are present in the background. Features of vasculitis are absent. These features may represent a component of pyoderma (including PG).” With the exception of wound 5, all wound measurements had improved (eFigure 5).

The patient was started on dapsone 100 mg orally once daily and her prednisone was tapered to 15 mg 8 weeks post presentation. Benzoyl peroxide to clean the wound and smoking cessation counseling for the HS were prescribed. The patient continued with weekly wound center follow-up. Her ulcers continued to be dressed with silver calcium alginate dressings and compression wrap to her left leg. All wounds were determined to be healed by 11 weeks post presentation. Additional treatment for her HS consisted of Aquacel Ag (Convatec, Bridgewater, NJ) for any drainage. The patient was discharged at the 11-week follow-up visit.

One recurrence of a painful left lower extremity (wound 4) occurred in July 2016. This was treated with doxycycline 100 mg twice daily, silver calcium alginate dressings to the ulceration, and a compression wrap. The ulcer healed in < 3 weeks.

The patient continued with follow-up evaluations with dermatology and rheumatology. She was felt to be weakly positive for rheumatoid arthritis and methotrexate was added to her treatment plan. She has continued on 15 mg of prednisone as she had not tolerated tapering from this dose. She was last evaluated in the wound center in January 2017 for an axillary abscess associated with HS.

Comparison

A PASH case comparison between the 2 aforementioned cases is reported in eTable 3.

Pyoderma gangrenosum

The etiology of PG is idiopathic and 50% of PG cases have been associated with other autoimmune pathologies.⁹ This condition can be greatly debilitating and cause a variety of complications, including very painful ulcerations typically found on the extremities. Pyoderma gangrenosum does not usually present with distinct pathognomonic markers to clearly diagnose this disease process; therefore, it is a diagnosis of exclusion and usually based upon clinical presentation. It should be noted that PG causes an aberrant T-cell response that results in the excess production of tumor necrosis factor alpha (TNF-α), among other proinflammatory cytokines.¹⁰ Evidence supports the idea that TNF-α plays a role in chronic inflammation and migration of neutrophils to these lesions.¹⁰ According to a retrospective chart review,¹¹ many clinicians misdiagnose PG as other conditions that overlap in symptoms. In a previous evaluation of 86 cases,⁹ wound growth and expansion secondary to insidious pathergic response was demonstrated to occur in about 25% to 50% of PG cases. The authors hypothesize that there also may be a connection between menstruation and pathergy, as demonstrated in case 1.

Patients with PG may present with recurrent ulcers that begin as pustules; depending on the severity of the disease state, the ulcer can exponentially increase size. Additional dermatological characteristics include irregular violaceous borders and minor yellowish slough, with isolated patches of necrotic tissue. There is thought to be a potential link between biofilm and fibrin slough formation.¹² Biofilm can stimulate a deleterious inflammatory response that induces perpetual vascular permeability; consequently, increasing the exudative byproducts creates a conducive environment for necrotic tissue and slough formation.¹² There have been reported cases where PG can transpire in the same anatomic sites that have been affected by HS.¹³ Both PG and HS have the predilection for insidious lesion growth.¹³ Some experts have opined that the aforementioned dysregulation of the microbiome in both PG and HS allows these bacterial communities to form robust biofilm colonies that ultimately impede the wound healing cascade.¹³

Acne vulgaris

Acne vulgaris is considered to be a polymorphic disease with a complex pathophysiology. This dermatologic condition can be attributed to the chronic obstruction of hair follicles.¹⁴ The pathognomonic feature of acne vulgaris is the formation of a microcomedone, or “plug-like,” mechanism.¹⁴ These robust plugs are driven by the excessive proliferation of keratinocytes, dead cell debris, and oily sebum infiltrates that permeate hair follicles.¹⁴Propionibacterium acnes is a central component in the pathogenesis of acne vulgaris.^14,15 It has been proposed that P acnes can reside and replicate within a biofilm community located in the follicular microcomedone.¹⁶ A study from 2009 demonstrated the ability of P acnes to form large clusters of biofilms within segmented macrocolonies located in the sebaceous follicles of acne lesions.¹⁶ This underscores the involvement of P acnes in the development and progression of acne vulgaris lesions. In addition, this multifaceted infectious process could potentially explain the chronic inflammatory state and its intrinsic resistance to antimicrobial agents.¹⁶ Physical cues may insinuate hormone-sensitive acne, including onset between ages 20 and 30 and worsening the week prior to a woman’s menstrual cycle, to trigger inflammatory/nodular acne lesions.¹⁷ Acne vulgaris is a primary inflammatory disease. However, biofilm could be an additional pathogenic factor that impedes healing and enhances the inflammatory state of acne lesion development.

Hidradenitis suppurativa

The cause of HS is not fully understood, but there are several factors that contribute to its progressive nature, including behavioral, genetic, infectious, hormonal, and/or host defense mechanism (eFigure 6).¹⁸ The female-to-male ratio of patients impacted with HS is about 3:1. Hidradenitis suppurativa typically manifests after puberty, and average age of onset occurs between ages 20 and 40.¹⁹ Acne vulgaris/conglobata has been previously associated with HS.¹⁹ Studies have demonstrated increased levels of cytokine proliferation such as TNF-α in patients with HS.¹⁸ An occlusive plug forms inside the hair follicle, causing further buildup of infiltrates, and this eventually results in the release of destructive proinflammatory cytokines into the surrounding skin, causing a severe inflammatory response.¹⁸

These impediments can initiate the formation of cysts, abscesses, and sinus tracts, which are classic features of HS.¹⁸ Lesions are typically found in intertriginous areas: the axilla, groin, and gluteal cleft.¹⁸ The Hurley Classification System is useful for the classification of 3 severity groups for HS.¹⁹ The Hurley system is based primarily on the extent and presence of scarring, sinuses, and fistula formation. It is important to emphasize that these symptoms may be aggravated with the onset of menstruation.²⁰ A recent investigation conducted by Ring and Emtestam²¹ found that 67% of chronic HS lesions contained biofilm. In addition, the majority of biofilm were found within sinus tracts, which could explain the increased inflammation and recalcitrant nature of HS.²¹ A hormonal imbalance also could be an intrinsic pathergic response in lesions that increase in size or the potential development of sinus tracts. Patients affected by HS often experience the characteristic symptoms of an infection, such as tenderness, pain, warmth, and purulent discharge.^18-21

Biofilm

Biofilm differs from planktonic microbial entities in terms of their gene expression, structure, and propensity to cause antibiotic resistance. They are comprised of extracellular polymeric substances (EPS) that incorporate bacterial DNA within a sophisticated polysaccharide glycocalyx.²² The EPS complex protects the bacterial organisms living within the biofilm from the host’s immune system.²² It has been found that only 10% to 20% of biofilm is made up of bacterial or fungal organisms, leaving 80% to 90% of the wound biofilm makeup to EPS.²³ Mechanisms of biofilm formation and proliferation include adhesion of bacteria to surface, aggregation and formation of microcolonies, and dispersion of bacteria from the mature biofilm (eFigure 7).²⁴

It should be noted that the bacterial microcolonization within biofilm eventually reaches a critical mass.²⁵ The incipient planktonic species then are released from the biofilm’s outermost layer, infiltrating nearby surfaces.²⁴ Once these bacteria start to attach, expand, and maturate, they transform into another biofilm community that behaves as a single entity. Biofilm’s phenotypic properties include a dual function mechanism, biofilm protective networks, and rapid (bacterial) microcolonization growth and replication.²⁴ The planktonic phenotype has been speculated to be triggered upon a propagative mechanism targeting new sites for biofilm regeneration.²⁴ Once critical mass has been reached, the proliferation and formation of biofilm can be attributed to an intercellular communication mechanism known as quorum sensing (QS).²⁴ This feedback system is utilized to detect and respond to changes in the environment. It is important to emphasize that QS kinetics induce changes in bacterial gene expression that bolsters survival and endurance.

Biofilm can be overlooked by traditional culture techniques and grow by contiguous dissemination of planktonic bacteria that eventually infiltrate surrounding surfaces. Wound cultures typically reveal planktonic bacteria and not the full bacterial makeup of the biofilm communities.²⁶ Molecular methods have been demonstrated to be a better way of surveying the species makeup of the biofilms.²⁶ Rhoads et al²⁷ conducted a study comparing bacterial culture and molecular identification using DNA-based technologies. Routine bacterial culture identified 17 different bacterial species; in contrast, 338 species were identified using molecular testing techniques.²⁷ Furthermore, Dowd et al²⁸ used pyrosequencing techniques that identified the major populations of bacteria present in chronic wounds. Staphylococcus and Pseudomonas were identified as dominant in the wounds studied. It should be noted that current molecular analytical technologies are not able to adequately demarcate between planktonic and biofilm bacteria that are responsible for delayed wound healing.

Biofilm’s ability to inhibit antibiotic therapy is attributed to an array of intrinsic protective mechanisms. The general mechanism of action of antibiotics consists of the inhibition of bacterial proliferation by targeting areas of high metabolic activity from these planktonic entities.²⁹ Biofilm responds to this imminent threat by creating a series of quiescent bacterial communities that impede antibiotic treatment pathways with 4 pathogenic mechanisms: (1) block or hinder antibiotic penetration by the biofilm EPS; (2) formation of persister cells; (3) continuous adaptive responses; and (4) nutrient and oxygen limitations to lower the metabolic activity of bacteria, making antibiotic therapy essentially ineffective.²⁴ Previous studies have demonstrated the lowest concentration needed to eliminate bacterial biofilm for many antibiotics actually exceeds maximum prescription levels.²⁴ Therefore, standard oral doses of antibiotic therapy have little or no antimicrobial effect against biofilms.²⁴ Phillips et al³⁰ conducted in vivo studies demonstrating that mature biofilms can be regenerated in 72 hours. Also, biofilms can swiftly form and maturate within a 24-hour period. The inability to treat these communities with antibiotics quickly allows the formation of countless colonies.³⁰

A biofilm component could serve as an associative factor between each disease entity within PASH syndrome. P acnes has been shown to cause acne vulgaris biofilm formation.¹⁶ The P acnes biofilm causes a surge in cytokine proliferation, which results in the production of proinflammatory interleukins (8, 12) and TNF-α.³¹ The repeated occurrence of acne in the general population has raised some doubts that PASH syndrome could in fact be a separate entity; however, the coalescing biochemical and pathogenic features of acne vulgaris correlate to the sequence of events that may be responsible for biofilm-induced wound chronicity (eFigure 7).

Hidradenitis suppurativa also has been connected with biofilm infiltration.³² Sinus tract development results in the accumulation of slough and nonviable tissue at the base of these sinus lesions (eFigure 7), consequently promoting the essential blueprint for biofilm formation and development. These adhesive properties help attract free-living “planktonic” species in the area to colonize and form a robust community. As biofilm formation increases in HS, bacteria is unable to access vital oxygen and nutrients, causing the bacterial metabolic rate to decrease and consequently making antibiotic therapy ineffective (as commonly seen in patients with HS).

Pyoderma gangrenosum is typically presented upon examination as a painful, erythematous, slough-forming, and necrotizing lesion. The presence of slough and exudate can pose a severe barrier to wound healing.³⁰ The intrinsic features of slough support the developmental mechanisms of biofilm. Inflammation instigated by biofilm causes an increase of vascular permeability, which results in the production of fibrin slough.⁶ Therefore, the presence of slough and devitalized tissue in PG may indicate biofilm existence. Biofilm should be considered as another potential pathognomonic feature in this expanding disease spectrum of PASH.

Current & potential treatment pathways

Research has demonstrated the efficacy of sharp (surgical or conservative) wound debridement and has endorsed this procedure as a means of effectively removing biofilm from an open wound surface.³³ It should be noted that the current debridement modalities do not eliminate or prevent biofilm regrowth. In patients such as the PASH cases described herein, with concern of pathergic response, avoidance of sharp debridement would be essential.⁹ Focusing on biofilm treatment that would not cause a worsening ulcer size is fundamental in such patients. There is a need for time-dependent topical antimicrobial therapy in conjunction with debridement (when possible) to adequately suppress biofilm reconstitution.

Future diagnostic processes include molecular DNA-based technologies that can identify the types and susceptibility of bacteria involved; the procedure promotes directed treatment pathways such as the application and utilization of personalized biocides and topical antibiotics that may improve wound healing.²⁴ However, current methods of molecular analyses cannot yet differentiate between planktonic versus biofilm bacteria in order to quantify efficacy of various topical treatments on biofilm reduction. A paradigm shift toward EPS-disrupting technology should be at the forefront of future studies in order to improve and accelerate the healing rates of wounds in which biofilm is the main culprit.²⁴ Technologies that disrupt EPS typically incorporate a multimodal approach to remove biofilm and prevent its reformation. This treatment pathway should cause physical and chemical disruption of the EPS matrix, disruption of synergies between different microbial species, disruption and prevention of microbial cell attachment, exposure of persister cells to treatment, and provide continuous bactericidal contact on the individual microbial cells making up the biofilm.²⁴

Biofilm awareness and research has evolved tremendously during the past decade. The ubiquitous influence of biofilm in chronic wounds is clear, however, much of its mechanisms and pathogenicity remains unknown. In the event biofilms are suspected in wounds, clinicians should keep in mind that there is no one-step solution for treatment. Holistic and evidence-based practices of wound bed preparation may be helpful in combating these infectious communities. Essential milestones of biofilm treatment should include reduction of biofilm burden and prevention of the biofilm reconstitution. The reconstitution of biofilm deposition involves multiple pathways (eFigure 7A). Consequently, a solid understanding of biofilm kinetics is a critical factor in the determination of treatments. The concomitant utilization of systemic and topical treatment modalities may facilitate the reduction of biofilm proliferation and reconstitution. Pyoderma gangrenosum, acne vulgaris, and hidradenitis suppurativa syndrome comprises a series of distinct pathologies that involve the overactivation of the innate immune system. However, based on their clinical presentation and their resistance to proper wound healing, biofilm could serve as the common denominator and may redirect clinicians’ treatment pathways in the near future. More research is needed to clarify the exact mechanism biofilm has on PASH syndrome.

Affiliations: Barry University School of Podiatric Medicine, Miami Shores, FL; and Healogics, Jacksonville, FL

Correspondence: Joey Karim Ead, BBA, MS, 1330 West Avenue, Apt. 708, Miami Beach, FL 33139; joeyead@gmail.com

Disclosure: The authors disclose no financial or other conflicts of interest.