Clinical Reference / Therapeutic Strategies / Deep Fungal Infections (Sporotrichosis, Coccidioidomycosis, Chromomycosis, Mycetoma, Blastomycosis, Histoplasmosis)

Deep Fungal Infections (Sporotrichosis, Coccidioidomycosis, Chromomycosis, Mycetoma, Blastomycosis, Histoplasmosis)


Initial Evaluation

The possibility of a deep fungal infection should be considered in a patient presenting with new papulonodular, sporotrichoid, or ulcerative skin lesions, with or without respiratory or systemic symptoms. Of note, erythema nodosum may also be seen in some deep fungal infections, but is considered a reactive phenomenon and therefore of low yield for locating the fungal pathogen. Patients should be referred to dermatology for biopsy of a lesion, which should be sent for both formalin fixation (with both H&E and fungal stains such as PAS or GMS) and tissue culture. Patients with respiratory symptoms should have a chest x-ray performed and be referred to infectious disease and/or pulmonology for further evaluation. Treatment with systemic antifungals is usually warranted and should be prescribed by either an infectious diseases specialist, or, if appropriate, a dermatologist (if skin-only disease is being treated with only oral antifungals).

Differential Diagnosis

Molluscum contagiosum

Atypical mycobacterial infections

Cutaneous tuberculosis

Leishmaniasis

Sarcoidosis

Syphilis

Squamous cell carcinoma

Also:

Actinomycosis
Botryomycosis
Halogenodermas (bromoderma, iododerma)
Nocardiosis
Staphylococcal lymphangitis (esp. for sporotrichosis)
Ulceroglandular tularemia (esp. for sporotrichosis)

Sporotrichosis | Initial Evaluation & Treatment

Sporotrichosis is acquired from decaying vegetation or sphagnum moss or from infected felines and other animals. The causative organisms are dimorphic saprophytic fungi of the Sporothrix schenckii complex. Disease follows accidental inoculation of the organism by thorns or splinters or scratches.

After an approximately three-week incubation period, a papule or nodule develops at the inoculation site (most commonly on a limb, though facial involvement has been reported more frequently in pediatric cases). The condition may progress in one of three primary ways: lymphocutaneous disease (most common form, in which additional nodulo-ulcerative lesions appear proximally in a lymphangitic distribution), fixed cutaneous (seen in patients with preexisting immunity), and disseminated cutaneous disease. Systemic visceral and/or joint involvement may eventuate from either primary pulmonary disease or hematogenous dissemination from cutaneous or lymphatic disease. The diagnosis may be made by histopathology with fungal staining of skin biopsy tissue, though the organism may be difficult to visualize, and tissue culture may be more successful.

The recommendations provided are for the treatment of the chronic lymphocutaneous form of the disease. Systemic/pulmonary involvement requires treatments of longer duration and higher dosage, in collaboration with an infectious diseases specialist.

Treatment

First steps

First line treatment is oral itraconazole 200 mg daily (though 100 mg daily may be often, but not always, sufficient) until all lesions have resolved, then an additional four weeks of treatment. Total duration of treatment is usually three to six months. Pediatric dosing for itraconazole is 6-10 mg/kg daily (not to exceed maximum of 400 mg per day, elevated dose reserved for refractory cases).

Alternative steps

  1. Local hyperthermia (direct application of hot compresses or pocket warmers at 42-43° C for 15-to 60-minute periods two to three times per day) may be helpful as an adjunctive treatment especially in localized cutaneous disease, due to direct injury, growth inhibition, and possible augmentation of neutrophil intracellular destruction.
  2. In refractory cases, the dose of itraconazole may be increased to 200 mg twice daily. The duration of therapy may be quite prolonged in refractory cases.
  3. Alternatives include terbinafine 250 mg daily until complete clinical resolution, then four more weeks or fluconazole 200-400 mg daily may be used for the same timeframe.
  4. Saturated solution of potassium iodide (SSKI). Begin with five drops three times daily and increase over several weeks to maximum dose of 30-40 drops three times daily until the disease is cleared and then four more weeks. Pediatric dosing is started at half of the adult dosing regimen and similarly titrated, up to a maximum dose of 15 drops three times daily.

Pitfalls

  1. Iodism is a dose-related adverse effect of SSKI therapy. Symptoms include rhinorrhea, nausea, salivary gland swelling, metallic taste, and a toxic iododerma. Therapy should be adjusted according to drug tolerance.
  2. Amphotericin B may be needed in cases refractory to the above treatments, in conjunction with an infectious disease specialist.
  3. For AIDS patients with sporotrichosis, lifelong prophylaxis with itraconazole 200 mg once daily is recommended.

Coccidioidomycosis | Initial Evaluation & Treatment

The dimorphic fungus Coccidioides immitis (endemic to the Southwestern US) and C. posadasii (endemic to northern Mexico and South America), are the etiologic agents of coccidioidomycosis. Most cases of the disease begin with inhalation of spores (arthroconidia) from disrupted soil, causing primary pulmonary infection. The majority of cases are asymptomatic, but after a ten-day to several-week incubation period, some go on to develop a flu-like syndrome known as “Valley Fever.” A small number (overall approximately 1%) of these cases will go on to develop disseminated disease, which may affect bones, viscera (with predilection for the meninges), and frequently the skin. Skin disease may also rarely manifest from primary inoculation. Immunosuppressed, pregnant, Black (14-fold increase) and Filipino (175-fold increase) patients have increased rates of dissemination.

Skin involvement of coccidioidomycosis can be quite polymorphic and range from papules / nodules / plaques with or without sinus tracts and abscesses, commonly involving the face, to ulcerations, to diffuse morbilliform eruptions, to reactive processes such as erythema multiforme and erythema nodosum. Extrapulmonary disease is serious and should be treated aggressively. Cutaneous lesions containing the spherules on biopsy may be the presenting sign of dissemination. The therapeutic strategy is to eliminate the causative organism.

In addition to skin biopsy, there are several other available methods for diagnosing coccidioidomycosis. The organisms can be cultured from tissue samples or blood; however, it is important to inform the laboratory of the suspected organism so that appropriate precautions may be taken to avoid the potential risk of accidental infection of laboratory personnel by this highly infectious and virulent organism.

Additionally, serologic testing is often utilized in making this diagnosis. Tube precipitin and immunodiffusion tube precipitin testing can detect IgM antibodies which become positive in weeks 1-3 after symptom onset and stay positive for up to four months. A positive result is suggestive of either primary infection or a reactivation. IgG antibodies may be detected via complement fixation and immunodiffusion complement fixation tests, which turn positive at weeks 8-10 after symptom onset and stay positive for up to eight months. These titers may be followed to monitor the course of disease.

First steps

Itraconazole or fluconazole at a dose of at least 400 mg daily (with itraconazole being divided into two daily doses of 200 mg) for at least three to six months are used for cutaneous dissemination or primary cutaneous disease. Fluconazole is preferred if there is concurrent evidence of coccidioidal meningitis. Azole therapy may not be effective in eradicating CNS involvement, and treatment in such cases should be undertaken in collaboration with an infectious diseases specialist. Pediatric dosing for itraconazole is 6-10 mg/kg daily (not to exceed maximum of 400 mg per day, elevated dose reserved for refractory cases).

Subsequent steps

Intravenous liposomal amphotericin B (in conjunction with an infectious disease specialist) is used in cases failing azole therapy and in pregnant patients. Note: For patients with meningeal involvement, amphotericin must be given intrathecally as well.

Ancillary steps

Surgical drainage and/or debridement may be required for localized chronic lesions in the skin such as encapsulated abscesses or avascular necrotic lesions.

Pitfalls

  1. Coccidioidomycosis may become a chronic disease, and patients may require lifelong maintenance therapy.
  2. Relapses may occur after cessation of azole or amphotericin B therapy.
  3. Amphotericin B can produce toxicity especially if infused too rapidly. Reactions, including chills, fever, nausea, malaise, and anorexia, although reversible, can be severe. These symptoms can be aborted by premedication regimens. Kidney function must be monitored closely. Other side effects include hypokalemia, hypomagnesemia, and anemia. While many of these adverse effects are decreased with the liposomal formulation compared to the older deoxycholate form, these side effects may still occur and close monitoring is warranted.

Chromoblastomycosis | Initial Evaluation & Treatment

Chromoblastomycosis (AKA chromomycosis) is a chronic infection of the dermis and epidermis caused by dematiaceous (melanized) fungi from the soil and decaying plant matter. The most common causative organisms including Fonsecaea pedrosoi, Fonsecaea compacta, Phialophora verrucosa, Cladosporium carrionii, Rhinocladiella aquaspersa. Lesions present as vegetative, verrucous plaques. Unlike in mycetoma, granules are not extruded from the wounds. The treatment strategy is to eradicate the infectious agent via either physical modalities, medical therapy, or a combination of both. The diagnosis is confirmed via either direct visualization of the organisms on microscopy from scrapings or tissue biopsy demonstrating clusters of thick-walled melanized organisms (sclerotic bodies or medlar bodies). The organisms can be cultured from tissue as well.

First steps

  1. Itraconazole 200 mg twice daily until the lesion is resolved (often up to six months), then for an additional month. Pediatric dosing for itraconazole is 6-10 mg/kg/day (not to exceed maximum of 400 mg per day, elevated dose reserved for refractory cases).
  2. Voriconazole 200 mg twice daily as above.

Ancillary steps

Limited lesions may be approached surgically, if antibiotic therapy is given appropriately before, during, and after the surgery. Several case series have described success with the use of repeated cryotherapy treatments.

Subsequent steps

In refractory cases, terbinafine 500 mg twice daily may be considered.

Mycetoma (Actinomycetoma & Eumycetoma) | Initial Evaluation & Treatment

Mycetoma (AKA maduromycosis), a disease primarily of tropical climatic zones, is a chronic, slowly progressive infection of the subcutaneous tissue and deeper structures that may invade bone. It is characterized by scarring, tumefaction, and sinus tracts exuding variously colored “grains” which are aggregates of organisms. The therapeutic strategy is to identify the infectious agent and attempt to eradicate it. Mycetoma is divided into two groups for therapeutic purposes: Actinomycetoma, caused by filamentous aerobic bacteria; and eumycetoma, caused by true fungi. Diagnosis is usually made by biopsy (H&E and bacterial/fungal and AFB stains), though the grains may be directly examined on KOH preparation. While the color of the grains may be somewhat helpful in identifying the organism, definitive speciation is by tissue culture.

Actinomycetoma

The most common causative organisms include species of Nocardia, Actinomadura and Streptomyces, among others. Feet, legs and back are the most common body sites affected. Most cases respond to medical therapies, though prolonged treatment courses are generally required.

First steps

Medical treatment is ideally directed at the identified infectious agent, and its documented susceptibilities, however, several empiric regimens have been published demonstrating strong efficacy against a range of causative organisms.

  1. One such commonly employed regimen is the modified Welsh regimen, consisting of acute phase of treatment cycles of IV amikacin 15 mg/kg/day divided twice daily plus oral sulfamethoxazole-trimethoprim 35 mg/kg/day +7 mg/kg/day plus oral rifampin 10 mg/kg/day for 21 days, with overall number of cycles determined by response to treatment.
  2. An alternative to this is the modified Ramam regimen, consisting of an acute phase of gentamicin 80 mg IV every 12 hours and two tabs sulfamethoxazole-trimethoprim double-strength (400 mg / 80 mg) twice daily for four weeks. This regimen offers a shorter IV treatment duration and more convenient dosing however may be less efficacious in more advanced cases with bony involvement.

Subsequent steps

  1. The modified Welsh regimen is followed by a maintenance phase consisting of oral sulfamethoxazole-trimethoprim 35 mg/kg/day +7 mg/kg/day plus oral rifampin 10 mg/kg/day for three months.
  2. The second/maintenance phase of the modified Ramam regimen consists of oral doxycycline 100 mg twice daily and two tabs sulfamethoxazole-trimethoprim double strength (400 mg / 80 mg) twice daily for five to six months after complete healing of all sinus tracts.
  3. Surgery is of limited benefit in most cases, but may help manage some small refractory areas once antibiotics have been used for six to nine months.
  4. In unresponsive cases, streptomycin up to 2 g daily intramuscular plus dapsone 100–200 mg daily has been employed.

Pitfalls

Various toxicities associated with the above regimens may complicate therapy, particularly the risks of ototoxicity and nephrotoxicity associated with aminoglycoside antibiotics, as well as severe hypersensitivity reactions to sulfamethoxazole.

Eumycetoma

Causative organisms include Pseudallescheria boydii, Madurella spp (especially mycetomatis and grisea), and Leptosphaeria senegalensis (these agents account for over 90% of cases), as well as Acremonium spp, Exophiala jeanselmei, among others. Response rates to medical treatment alone are often poor, and surgical treatment is generally needed in conjunction with prolonged medical therapy. In very advanced cases with bony involvement, amputation may be required.

First steps

  • Itraconazole 200 mg daily or terbinafine up to 500 mg twice daily for 9-12 months may be attempted. Pediatric dosing for itraconazole is 6-10 mg/kg/day (not to exceed maximum of 400 mg per day, elevated dose reserved for refractory cases).
  • Excision of localized lesions may be useful. There is a lack of consensus on whether surgery should take place before or after medical treatment.

Subsequent steps

  1. Itraconazole 200 mg twice daily or terbinafine up to 500 mg twice daily for 9–12 months.
  2. Amphotericin may be attempted as rescue therapy, but many of the fungi causing eumycetoma are amphotericin resistant.
  3. Voriconazole or posaconazole have been used in a few cases of invasive infection by these organisms in immunocompromised patients.

Pitfalls

Fluconazole is not effective against eumycetoma.

Blastomycosis | Initial Evaluation & Treatment

Blastomycosis (AKA North American blastomycosis) presents most commonly with lung infection (either acute or chronic) acquired via inhalation but may disseminate to the skin, bones, and central nervous system, or any other organ system. Primary cutaneous disease secondary to inoculation is also possible but rare. The causative organism is the dimorphic fungus Blastomyces dermatitidis, endemic to North America. All patients with cutaneous lesions of blastomycosis are considered to have disseminated infection and require treatment. Clinical lesions may include verrucous nodules or plaques, and classically an expending ulcerative plaque with a raised peripheral border. The diagnosis may be made by visualization of broad-based budding yeast on KOH preparation or histopathology with fungal staining from skin biopsy, and confirmed via tissue culture.

First steps

  1. Itraconazole 200-400 mg daily for at least six months. Pediatric dosing for itraconazole is 6-10 mg/kg/day (not to exceed maximum of 400 mg per day, elevated dose reserved for refractory cases).
  2. Fluconazole up to 200-400 mg twice daily is an alternative.

Subsequent steps

Amphotericin B may be employed in severe and refractory cases, in conjunction with an infectious diseases specialist. After clinical improvement, the patient may be switched back to itraconazole oral therapy.

Histoplasmosis | Evaluation & Treatment

Histoplasmosis is caused by the dimorphic fungus Histoplasma capsulatum, endemic to the river valleys of the United States (primarily Ohio and Mississippi River valleys) as well as those of Central America, and some areas of southern and eastern Europe, Asia, Australia and Africa. Soil with high levels of bat or bird droppings may present especially elevated risk of infection. Most patients develop asymptomatic pulmonary infection via inhalation, with a subset developing disseminated disease that affect the skin, central nervous system, gastrointestinal or cardiac organs. Risk factors for disseminated infection include HIV/AIDS, solid organ transplant, and hematologic malignancy, among others. Additionally, the variant Histoplasma capsulatum var. duboisii, endemic to parts of Africa and Madagascar, has been implicated in a similar disease with a greater predilection for the skin and soft tissues. Cutaneous lesions of histoplasmosis often indicate immune compromise, and appropriate evaluation of the immune system for underlying defects is indicated. The diagnosis may be made by visualization of the organism in tissue histopathology or by tissue culture. Serum and urine antigen testing are also available. All patients with symptomatic disseminated infection or skin lesions should receive systemic antifungal treatment.

First steps

  1. In most cases of disseminated histoplasmosis with skin involvement, itraconazole 200 mg twice daily is given for 6-12 months. Pediatric dosing for itraconazole is 6-10 mg/kg/day (not to exceed maximum of 400 mg per day, elevated dose reserved for refractory cases).
  2. Severe cases may require a few weeks of amphotericin B treatment (in collaboration with an infectious disease specialist) followed by a switch to prolonged azole treatment.

Subsequent steps

  1. Alternatives to itraconazole include fluconazole (less effective), voriconazole and posaconazole, though data is more limited for the latter two.
  2. Continue treatment until all signs and symptoms have resolved, which may be longer than 12 months.
  3. Chronic, lifelong suppressive therapy of itraconazole 200 mg once daily is required for immunosuppressed patients and may be started after the patient has received three months of twice daily itraconazole therapy.

Clinical Cases

Case 1

  • 50-year-old healthy male
  • Presents for evaluation and management of one-month history of spreading tender nodules on arm
  • Has been doing heavy yard work
  • Denies fevers, chills, weight loss, shortness of breath

Initial evaluation

  • Exam reveals ulcerative nodule on dorsal hand with proximal lymphangitic extension of nodules
  • Biopsy shows granulomatous inflammation, culture is positive for S. schenckii
  • Diagnosis: sporotrichosis (lymphocutaneous)
  • Recommendation: oral itraconazole 200 mg daily until all lesions have resolved, then an additional four weeks of treatment. (Total duration of treatment is usually three to six months)

Follow-up evaluation

  • Gradual resolution is expected. Patient should be followed regularly throughout his treatment course.

Case 2

  • 45-year-old healthy African-American man
  • Presents for evaluation and management of several-weeks’ history of bumps/crusting on nose, also notes recent cough/shortness of breath
  • Recent road trip to Grand Canyon
  • Denies fevers, chills, weight loss, headaches, joint or bone pain

Initial evaluation

  • Healthy-appearing middle aged African-American man
  • On the L nasal sill and floor is an eroded and crusted plaque extending into the mucosa
  • Chest X-ray reveals subtle pulmonary infiltrates bilaterally
  • Precipitin test is positive for Coccidioides immitis IgM and skin biopsy shows fungal spherules in tissue with granulomatous and suppurative inflammation
  • Diagnosis: Coccidioidomycosis (disseminated with secondary cutaneous involvement)
  • Recommendation:
    • Start itraconazole 200 mg two times daily
    • Refer to the infectious disease department for co-management and further evaluation to rule out other systemic involvement

Follow-up evaluation

  • Regular follow-up is needed to monitor treatment response
  • Itraconazole is continued for at least three to six months depending on treatment response and other systemic involvement (should be managed in collaboration with an infectious disease specialist)

References

Agarwal US, Besarwal RK, Gupta R, Agarwal P. (2013). Treatment of actinomycetoma foot—our experience with ten patients. J Eur Acad Dermatol Venereol, 27(12):1505-1513.

Castro LG, Pimentel ER, Lacaz CS. (2003). Treatment of chromomycosis by cryosurgery with liquid nitrogen: 15 years’ experience. Int J Dermatol, 42(5):408-412.

Galgiani JN, Ampel NM, Blair JE, Catanzaro A, Geertsma F, Hoover SE, Johnson RH, Kusne S, Lisse J, MacDonald JD, Meyerson SL, Raksin PB, Siever J, Stevens DA, Sunenshine R, Theodore N. (2016). 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clin Infect Dis, 15;63(6):e112-146.

Garcia Garcia SC, Salas Alanis JC, Flores MG, Gonzalez Gonzalez SE, Vera Cabrera L, Ocampo Candiani J. (2015). Coccidioidomycosis and the skin: a comprehensive review. , 90(5):610-619.

Kauffman CA, Bustamante B, Chapman SW, Pappas PG. (2007). Infectious Diseases Society of America. Clinical practice guidelines for the management of sporotrichosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis, 15;45(10):1255-1265.

Kauffman CA. (2007). Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev, 20(1):115-132.

Mahajan VK. (2014). Sporotrichosis: an overview and therapeutic options. Dermatol Res Pract, 2014:272376.

Motswaledi HM, Monyemangene FM, Maloba BR, Nemutavhanani DL. (2012). Blastomycosis: a case report and review of the literature. Int J Dermatol, 51(9):1090-3109.

Welsh O, Al-Abdely HM, Salinas-Carmona MC, Fahal AH. (2014). Mycetoma medical therapy. PLoS Negl Trop Dis, 16;8(10):e3218.