Onychomycosis

Case study

By Steven Goldstein, DPM; Basem Halaka, DPM; David Vance, DPM; Jason Weslosky, DPM

History of Present Illness

The patient is a 62 year old male with a 2 year history of thickened, elongated, and yellow discolored nails of the hallux bilateral. The nails appear dystrophic with evidence of subungual debris. The patient does not recall any significant trauma to the nails but does admit to uncomfortable rubbing of the bilateral hallux nails in his shoes. The patient does not have any other contributing medical history.

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Differential Diagnosis

Diagnostic considerations in this case include onychomycosis, trauma, psoriasis, lichen planus, chronic paronychia, and dermatitis.

Work-up

The bilateral nails were debrided and multiple keratogenous samples were sent for analysis (histopathology and PCR). Care was taken to remove debri subungually as well as portions of the proximal nail plate.

Histopathology and Molecular Analysis

Identified in this study were histopathologic features of acute and chronic micro-trauma as well as onychomycosis. Fungal elements were demonstrated with both PAS and GMS stains. Fontana Masson staining was performed as well and was negative for melanin.   PCR testing was performed and was able to identify the organism, a saprophyte of the Fusarium genus.

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Discussion

The most prevalent risk factor for developing onychomycosis is advanced age. Other risk factors include warm climate, peripheral vascular disease, and diabetes mellitus. Immunocompromised conditions are also thought to be linked to the prevalence of onychomycosis, especially those caused by non-dermatophyte species. It should also be noted that onychomycosis and nail trauma often coexist, with nail trauma often being a predisposing factor for the development of onychomycosis.

While many onychomycosis cases are caused by dermatophytes, it is important to note that there are also cases involving yeasts and saprophytic species, thus proper identification is key to appropriate treatment .  In this case, the isolated pathogen was a saphrophyte of the Fusarium genus.  The most opportunistic of this species include F. solani complex, F. oxsporum complex and F. fujikorai complex.  Most commonly these species cause onychomycosis in tropical countries however they are also present in temperate and artic climates with recent reports of Fusarium as a common pathogen in central European countries.

Treatment

Multiple treatment options exist for onychomycosis. Medications exist in both oral and topical forms. Furthermore other options for treatment such as mechanical and chemical avulsion exist. Topical treatments are often reserved for superficial white onychomycosis or distal subungual onychomycosis affecting less than 50 percent of the nail surface. Tolnaftate and Ciclopirox are common topical therapies employed. Topical urea may be used in conjunction with topical therapies to act as a vehicle to increase penetration of the medication into the nail unit. Oral treatment options are often a better option for proximal subungual onychomycosis or onychomycosis that is involving more than 50% of the nail plate. Terbinafine, Itraconazole, Fluconazole are all oral medication options for treating this condition. Terbinafine is perhaps the most commonly prescribed and is useful against both dermatophyte and some non-dermatophyte species. Itraconazole has greater effect toward non-dermatophyte species however it must be used with caution as it is contraindicated in pregnancy. Fluconazole is another option however therapeutic treatment times remain longer when compared to other oral medications. Speciation of the organism may guide to the most effective oral therapy for the specific organism. Furthermore, both mechanical and chemical debridement remain as options for treating onychomycosis. Chemical debridement often consists of applying a compound containing urea to the nail. Depending on the exact formulation of the compound, this may be done under occlusion or without occlusion. It should be noted that chemical debridement alone is not effective and often has to be combined with other treatment modalities. Lastly, mechanical debridement or avulsion of the nail plate remains a viable option especially in cases where previously mentioned treatment modalities have failed. However care must be taken in patients with comorbidities such as peripheral vascular disease, diabetes, or infection.

Laboratory Testing Modalities for Onychomycosis

There are multiple tests that can be performed to evaluate for the presence of fungi in a tissue specimen.  Some of the commonly performed tests include the periodic acid-Schiff(PAS) reaction, Grocott methenamine silver(GMS) stain, Fontana-Masson stain, culture, and polymerase chain reaction(PCR) assay.  PAS is a periodic acid and Schiff reagent stain.  It is useful in detecting carbohydrates within the cell walls of living fungi. In PAS testing, the aldehyde groups in the fungal cell walls react with the stain to produce a magenta color.  The GMS stain is a chromic acid and bisulfite stain.  It is also useful in detecting fungal elements; however it is generally able to produce better staining contrast as well as improved detection of degenerated or dead fungi.  The Fontana-Masson stain highlights melanin pigment in certain fungal organisms along with melanin pigment deposition in various conditions.  Fontana-Masson has shown variable staining among different types of fungi; however, higher quantity staining within the fungal organisms favors dematiaceous fungi (pigmented saprophytic mold).  Fungal culture can be performed on fresh tissue but suffers from long turn-around time (28 days) and high false negative results.  PCR Assay detects the genetic material of fungi.  Advantages of PCR include rapid (1-2 day) turn-around, a minimum of 25% higher sensitivity than culture, and the ability to identify the specific fungal species.

References:

Werner B, Antunes A. Microscopic examination of normal nail clippings. Dermatol Pract Concept. 2013;3(3):9-14. Published 2013 Jul 31.

Ranawaka RR, Nagahawatte A, Gunasekara TA. Fusarium onychomycosis: prevalence, clinical presentations, response to itraconazole and terbinafine pulse therapy, and 1-year follow up in nine cases. Int J Dermatol. 2015;54(11):1275-1282.

Rammlmair A, Muhlethaler K, Haneke E. Fusarium onychomycoses in Switzerland-A mycological and histopathological study. Mycoses. 2019;62(10):928-931.

Gupta AK, Simpson FC. New therapeutic options for onychomycosis. Expert Opin Pharmacother. 2012;13:1131-1142.

Gupta AK, Kohli Y. In vitro susceptibility testing of ciclopirox,terbinafine, ketoconazole and itraconazole against dermatophytes and nondermatophytes, and in vitro evaluation of combination antifungalactivity. Br J Dermatol. 2003;149:296-305.

Figueiredo VT, de Assis Santos D, Resende MA, et al. Identificationand in vitro antifungal susceptibility testing of 200 clinical isolates of Candida spp. responsible for fingernail infections. Mycopathologia. 2007;164:27-33.

Emam, Sherin, and Osama El-salam. “Real-Time PCR: a Rapid and Sensitive Method for Diagnosis of Dermatophyte Induced Onychomycosis, a Comparative Study.” Alexandria Journal of Medicine, 29 Aug. 2015.

D’Hue, Zandra, et al. “GMS Is Superior to PAS for Diagnosis of Onychomycosis.” Journal of Cutaneous Pathology, 14 Aug. 2007.

West, Kelly, et al. “Fontana-Masson Stain in Fungal Infections.” Dermatopathology, Dec. 2017.




Web Space Dermatophytosis

By Adi Pajazetovic, DPM, Kalani Parker, DPM

Tinea pedis resistant to treatment may require systemic antifungals

History

A 67-year-old male with no known significant past medical history presented to clinic with an itchy dermatitis like lesion within his left fourth web space. Lesion has been present for an undefined length of time.

Physical Examination

Patient presented with an eczematous/tinea like lesion within the left fourth web space along with maceration to the area.

Diagnostic Testing

A shave biopsy was performed and a submission of a skin fragment measuring 0.3 x 0.3 x 0.1 cm was received to confirm diagnosis of tinea.

Histological Findings

The received specimen was sectioned, and the sections demonstrated scattered neutrophils within the stratum corneum. A periodic Acid Schiff (PAS) stain test was performed, which highlighted septated fungal hyphae, morphologically consistent with dermatophytes within the keratin layer. A PAS is commonly used stain in mycoses diagnosis as it highlights the carbohydrate rich cell wall of fungi1.

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Diagnosis

Dermatophytosis involving the volar or near volar skin of the foot (Tinea Pedis)

Discussion

Tinea pedis is one of the most common fungal pedal skin infections and is caused by a dermatophyte. It can present as an interdigital manifestation, moccasin patterned, or with inflammatory vesicles, and can often be associated with onychomycosis2. The condition generally affects an older population and can be as prevalent as 70% of the population .

The dermatophytes are filamentous fungi in the genera Trichophyton, Microsporum and Epidermophyton. They metabolize and subsist on keratin and infection typically is superficial involving the epidermis. The clinical features include interdigital, hyperkeratotic and vesiculobullous tinea pedis. The interdigital tinea pedis manifests as pruritic, erythematous erosions or scales between the toes, especially in the third and fourth digital interspaces3.  BakoDx now offers a web space DNA test that can help differentiate the cause of the interdigital infections. Infectious agents tested include fungi such as dermatophytes and specific bacterial agents as well. The sampling is a simple shave biopsy of the interdigital lesion. All that is needed is a visible sample of tissue. This easy procedure will aid in the treatment of the infection as it specifies the inciting organism.

Treatment

Tinea pedis rarely causes significant morbidity or mortality, but there is some evidence that it can act as a portal of entry for bacteria causing bacterial cellulitis. Topical antifungal treatment is generally adequate. For extensive infections and especially involving immunocompromised patients, oral therapy may be required. Relapse from inadequate therapy is common and reinfection can reoccur in 10% of cases. Tinea pedis resistant to treatment may require systemic antifungals such as terbinafine, fluconazole, or itraconazole. In cases involving both fungal and bacterial infections, a concomitant antibiotic therapy is justified.

Most superficial cutaneous dermatophyte infections are managed with topical therapy such as azoles, Nystatin, etc. Oral treatment with terbinafine, itraconazole, fluconazole, and griseofulvin is used for recalcitrant infections. The use of combination antifungal and corticosteroids is discouraged as it is unnecessary to achieve cure and increases the risk of steroid induced skin atrophy3.

References:

1: Wang, Michael Z (02/01/2017). “Correlation between histopathologic features and likelihood of identifying superficial dermatophytosis with periodic acid Schiff-diastase staining: a cohort study”. Journal of cutaneous pathology (0303-6987), 44 (2),   152.

2: Usatine, R. P., Smith, M. A., Mayeaux, E. J., & Chumley, H. S. (2019). The color atlas and synopsis of family medicine. New York: McGraw-Hill Education.

3: Goldstein AO, Goldstein BG. Dermatophyte (tinea) infections. UpToDate, 2019.




Molluscum Contagiosum

By Courtney McClurkin, DPM; Andrew Olson, DPM

Molluscum contagiosum can be confused with a variety of different skin pathologies

History

A 25 year old male with no known significant past medical history presents with a pigmented lesion to plantar aspect of his left foot present for an undetermined period of time.

Physical Examination

A raised red and black 3mm lesion is seen on the plantar aspect of left foot.

Diagnostic Testing

A 2mm punch biopsy was performed with clinical concern to rule out melanoma.

Histological Findings

Typical histological features of molluscum contagiosum were identified including molluscum bodies, which are intracytoplasmic eosinophilic structures contained within epidermal cells.  These molluscum bodies become basophilic in the upper part of the epidermis, and are found in high numbers in the horny layer.  There is also a dense polymorphonuclear infiltrate noted adjacent to the epithelium containing the molluscum bodies.

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Diagnosis

Molluscum contagiosum

Discussion

Molluscum contagiosum is a skin infection that is caused by a poxvirus.  Transmission of the molluscum contagiosum virus is through contact with an infected person or contaminated surface.  It is most commonly found in young children, but is also notorious for sexual transmission among adults and adolescents.  Transmission rates are generally similar for the immunocompromised.  However, the lesions can be more numerous, appear in atypical locations, and be more resistant to treatment.  The virus incubates for a period of 14 days to 6 months, followed by formation of slowly enlarging, single or multiple lesions.  The lesions most commonly appear as pearly, umbilicated papules.  They can become inflamed and erythematous, causing a “molluscum dermatitis”.  Most cases are self-limiting, though crops of lesions may come and go over the span of months.  There are, however, a plethora of treatment options ranging from physical destruction to systemic treatments.

Clinically, molluscum contagiosum can be confused with a variety of different skin pathologies, including but not limited to: verruca vulgaris, condyloma, nevocellular nevus, basal cell carcinoma, keratoacanthoma, lichen planus, eczema, foreign body granuloma, sarcoidosis, folliculitis, and true epidermal cyst.

Two histologic variants exist.  The pseudocystic variant is distinguished by invagination of colonized epithelium of dilated horn-filled infundibula bordered by a thick epidermis and are filled with compact, thick keratin.  In the polyploid variant, the dermis located beneath molluscum contagiosum has loose collagen fibers, dilated vessels, and inflammatory infiltrate.  Molluscum bodies are the most distinguishing  histologic feature.  These are large cells with cytoplasmic eosinophilic inclusions that contain viral particles.

Associated lesions with molluscum contagiosum are common, including true epidermal cysts, nevocellular nevus, Unna nevus, Clark nevus, soft fibromas, and Kaposi sarcoma.  Abscesses can be associated due to discharge of molluscum bodies to the dermis, followed by release of proinflammatory cytokines and activation of complement pathway.

Treatment

While molluscum contagiosum is typically self-limiting within 6 months, there are treatment options available.  Treatment is initiated in order to alleviate discomfort produced by itchy or painful lesions, for cosmetic reasons, to prevent spread of lesions, as well as to prevent trauma, scarring, and secondary infection of lesions.

Surgical treatments include: cryotherapy, curettage, punch biopsy, manual excision, electric cauterization, and laser therapy.

Topical treatments include: acidified nitrite, adapalene, Australian lemon myrtle oil, benzoyl peroxide, bromogeramine, cantharidin, cidofovir, diphencyprone, griseofulvin, honey, hydrogen peroxide, imiquimod, iodine, phenol, podophylotoxin (HIV patients), potassium hydroxide, salicylic acid, tea tree oil, and tretinoin.

Systemic treatments include cimetidine, griseofulvin, and cidofovir (in HIV-infected patients).

References:

Cribier, B., Y. Scrivener, and E. Grosshans. Molluscum contagiosum: histologic patterns and associated lesions. The American Journal of Dermatopathology 23(2): 99-103 (2001).

Mancini, A.J. and A. Shani-Adir. Other Viral Diseases. Dermatology 3rd ed. (2012): p. 1358-59.

Van der Wouden, J.C., et. al. Interventions for cutaneous molluscum contagiosum (review). Cochrane Database of Systematic Reviews Issue 5, Art. No.: CD004767 (2017).




Erythema Elevatum Diutinum

By Desiree Dalcherone, DPM; Laura Fernandez, DPM; Pooja Srivastava, DPM

Lesions are usually asymptomatic, but some cases might present with itching and pain

History

Patient is a 29 year old male with past medical history of Crohn’s disease, presenting with a one year history of progressively worsening, painful nodules to his bilateral legs and feet.

A punch biopsy of skin was taken from the nodule present to the patient’s plantar-medial left hallux.

Physical Examination

Multiple nodules were present on bilateral legs and feet.

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Histologic Findings

Sections show an intense neutrophilic infiltrate with associated nuclear dust and interstitial eosinophils at all levels of the reticular dermis. The deeper regions of the reticular dermis show significant fibrosis in association with the infiltrate present. Active neutrophilic vasculitis is felt to signify a late stage process.  Gomori methenamine silver stain fails to demonstrate fungal elements.  AFB stain fails to demonstrate mycobacterial organisms.

Diagnosis

Erythema Elevatum Diutinum (EED)

Discussion

Erythema elevatum diutinum is categorized as a chronic fibrosing leukocytoclastic vasculitis usually occurring in patients in their thirties to fifties, earlier in HIV. The lesions might present as orange to yellow plaques, or red to purple papules and nodules measuring approximately up to 1 cm. They are usually found in extensor surfaces in the back of the hands or fingers, wrists, elbows, knees, ankles, and toes. The lesions are usually asymptomatic, but some cases might present with itching and pain, usually made worse with cold environments.

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis) has been associated with the onset of erythema elevatum diutinum.  EED has also been reported in patients with Celiac disease and resolved with a gluten-free diet.

Other reported associations include rheumatoid arthritis, granulomatosis with polyangiitis, relapsing polychondritis, pyoderma gangrenosum, Sweet syndrome, cutaneous lupus erythematosus, nodular scleritis and panuveitis, Hashimoto thyroiditis, juvenile idiopathic arthritis, Sjögren syndrome, dermatomyositis.  EED can be associated with systemic infections, including streptococcal infections, HIV, hepatitis B, tuberculosis, and syphilis

ANCAs (60% IgA and 33% IgG) are found in EED, however, other ANCA-positive vasculitides such as granulomatosis with polyangiitis and microscopic polyangiitis, do not present with these lesions.

Differential diagnosis includes granuloma faciale which also involves the dermis. Granuloma faciale, however, shows mostly eosinophils whereas EED shoes more neutrophils. Sweet Syndrome is another form of neutrophilic disease with rapid onset of tender and erythematous plaques and nodules, but it is differentiated by the lack of leukocytoclastic vasculitis.

Treatment

Since EED is generally associated with an underlying systemic disease, such as hematologic conditions, autoimmune disease, chronic infections, HIV- it is imperative to control the underlying cause as well as directly targeting the lesions.

In this particular case, the patient’s EED is likely associated to Crohn’s Disease. Treatment for Crohn’s Disease include anti-inflammatory drugs such as aminosalicyclates, corticosteroids, sulfasalazine and azathioprine. Aminosalicyclates are generally first-line treatment, and suppress inflammation to the intestine. Antibiotics such as tetracyclines and sulfa drugs can also be given adjunctively to kill bacteria in certain areas of the bowel, and also decrease inflammation.

Focusing on the nodules themselves, oral Dapsone is the most common drug given, with a response rate of up to 80%. Dapsone works by inhibiting neutrophil chemotaxis. Second-line drug treatments include corticosteroids, colchicine, and methotrexate.

Surgical excision of the nodules in a progressed disease state has also been found to provide symptomatic relief, however since EED nodules are quite recurrent, multiple surgeries are needed to keep the patient nodule-free.

References:

Rinard, J., R. Mahabir, J. Greene, and P. Grothaus. Successful surgical treatment of advanced erythema elevatum diutinum. Can J Plast Surg 18(1): 28-30 (2010).

Wollina, U., C. Kronert, A. Koch, J. Schonlebe, A. Vojvodic, T. Lotti. Erythema elevatum diutinum – two case reports, two different clinical presentations, and a short literature review. Global dermatology. 18(7):3039-3042 (2019).

Crohn’s Disease. Harvard Health Publishing : Harvard Medical School. https://www.health.harvard.edu/a_to_z/crohns-disease-a-to-z. November 2018.

Calonje E, McKee PH, undefined undefined undefined. Vascular Diseases. In: McKees Pathology of the Skin: with Clinical Correlations; 5th ed. Philadelphia, PA: Elsevier, Saunders; 2020:714-770

James WD, Elston DM, Treat JR, Andrews GC, undefined undefined undefined. In: Andrews Diseases of the Skin: Clinical Dermatology. 13th ed. Elsevier; 2020:813-861

Sandhu JK, Albrecht J, Agnihotri G, Tsoukas MM. Erythema elevatum et diutinum as a systemic disease. Clinics in Dermatology. 2019; 37(6): 679-683.




Blastomycosis

By Morgan Baxter, DPM, Aron Block, DPM, Lillian Youhkana, DPM

Blastomycosis is a type of fungal infection that can be acquired from inhaling fungal spores

History

A 53 year old healthy male presents to clinic with concerns of a rash involving raised bumps for about a month. He thought it was a cluster of warts, but has not had any relief with over the counter topical medications. He does mention that about a month ago, he was raking leaves barefoot. The bumps are not painful but have started to leak and have not gone away. He resides in Ohio near Lake Erie.

A punch biopsy of a representative lesion was submitted.

Histologic findings:

Verrucous lesion with pseudoepitheliomatous hyperplasia and a polymorphous dermal inflammatory cell infiltrate with scattered giant cells and neutrophils with occasional microabcesses.  PAS and GMS stains are positive for thick walled yeasts with broad based budding.  Yeasts, which measure 7-15 micrometers are found in the center of the abscess and sometimes in the giant cells.

Diagnosis

Blastomycosis

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Differential Diagnosis

Other cutaneous infections can mimic cutaneous blastomycosis including other endemic mycosis such as histoplasmosis and coccidioidomycosis. It has been found that cutaneous blastomycosis may very closely resemble pyoderma gangrenosum or keratoacantoma or malignancies such as basal cell carcinoma or squamous cell carcinoma. For proper diagnosis a skin biopsy is vital in differentiating blastomycosis infection from these other diseases.

Discussion

Blastomycosis is a type of fungal infection that can be acquired from inhaling fungal spores from the air.   It is found in the United States and Canada and is concentrated in the Ohio and Mississippi river valleys and the Great Lakes region.  Blastomycosis is typically found in soil and decaying organic matter. It manifests as a primary lung infection in the majority of cases.  In individuals with weakened immune systems, the infection can spread to other areas of the body such as the skin. Following pneumonia, cutaneous lesions are the next most common manifestation of blastomycosis. The skin lesions are either verrucous or ulcerative. Bone, prostatic and CNS blastomycosis are also fairly common presentations of this infection. The disease is often misdiagnosed, particularly as malignancy. Search for the organism by microscopy and culture should be considered, even in those with a classic presentation of other illnesses. Most people with blastomycosis will need treatment with prescription antifungal medications. Depending on the severity of the infection, the course of treatment can range from six months to a year. Mild and moderate fungal infections involving the skin and lungs are best treated with Itraconazole. Amphotericin B should be used in severe infections involving the lungs. In conclusion, a thorough history including a geographical location is imperative to help make the accurate diagnosis of a blastomycosis infection.

References:

Chapman SW, Dismukes WE, Proia LA, Bradsher RW, Pappas PG, et al. (2008) Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America. Clinical Infectious Diseases 46: 1801–1812

Larson DM, Eckman MR, Alber RL, Goldschmidt VG. Primary cutaneous (inoculation) blastomycosis: an occupational hazard to pathologist. Am J Clinc Pathol. 1983;79(2):253–255.

McBride, J. A., Gauthier, G. M., & Klein, B. S. (2017). Clinical Manifestations and Treatment of Blastomycosis. Clinics in chest medicine, 38(3), 435–449. doi:10.1016/j.ccm.2017.04.006

Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010

Smith JA, Riddell J, IV, Kauffman CA. Cutaneous manifestations of endemic mycoses. Curr Infect Dis Rep. 2013;15(5):440–449