Dermatologic Manifestations of Aspergillosis

Cutaneous aspergillosis is usually a cutaneous manifestation of disseminated infection with the fungus Aspergillus. Primary cutaneous disease is rare and is most commonly caused by Aspergillus fumigatus and Aspergillus flavus. Rare cutaneous infections have been reported with Aspergillus terreus and Aspergillus ustus.

Colonization of burn eschars by Aspergillus is common, and reports have described primary cutaneous infection in immunocompetent patients in association with agricultural trauma.[1] Usually, however, aspergillosis begins as a pulmonary infection subsequent to inhalation of fungal spores. In the immunocompromised host, hematogenous dissemination and invasion of other organ systems, including the skin, often follows the initial pulmonary infection.

Dermatologic manifestations of disseminated aspergillosis include single or multiple erythematous-to-violaceous plaques or papules, often characterized by a central necrotic ulcer or eschar. Skin lesions occur in 5-10% of patients with disseminated aspergillosis. In primary cutaneous aspergillosis, the most typical presentation is implantation of the fungus following trauma, including infections at the site of intravenous cannulas, or venipuncture wounds, especially those that have been covered with occlusive dressings. Note the image below. Aspergillus is a frequent contaminant found in cultures of dystrophic nails, but it can occasionally cause a true onychomycosis.

Cutaneous aspergillosis is caused by infection with ubiquitous soil- and water-dwelling saprophytes of the Aspergillus genus. Infection from Aspergillus could happen through a wound in the skin (eg, surgery or scratch), where it enters the immunocompromised body (eg, from organ transplantation). Cutaneous aspergillosis could also develop from invasive aspergillosis spreading to different parts of the body. Typically, infection of the pulmonary system occurs via inhalation of fungal spores, which then leads to disseminated hematogenous infection with the organism. A fumigatus is the most common pathogen associated with disseminated disease with cutaneous involvement, whereas A flavus[2] or A terreus most often causes the less frequent primary infections of the skin. Aspergillus niger and A ustus have also been cultured from cutaneous lesions.[3] Infections of the sinuses, lungs, or skin can lead to disseminated disease, especially in patients who are immunocompromised, are on the rise. Initial cutaneous lesions may appear in the form of either macules, papules, nodules, or plaques.[4] Although rare, cases of primary cutaneous infection with Aspergillus have been described in immunocompetent patients.[5, 6]

Aspergillosis is an uncommon disease in patients who are not immunocompromised because normal neutrophilic and macrophagic functions prevent infection; however, any deficiency in these immunologic parameters increases the risk of aspergillosis. For example, systemic corticosteroid therapy is a known risk factor for cutaneous aspergillosis. Secondary cutaneous aspergillosis has been reported in an asthma patient on 1 month of steroid treatment.[7]

Some environmental risk factors have also been implicated in cutaneous aspergillosis; these factors include construction sites and contaminated ventilation systems, presumably caused by effects on spore distribution.

Frequency

Aspergillosis is the second most common opportunistic fungal infection in patients who are immunocompromised, accounting for as many as 20% of fungal infections in patients who have received bone marrow or solid organ transplants. Key risk factors for cutaneous aspergillosis include neutropenia from hematologic malignancy or chemotherapy, immunosuppressive therapy, AIDS, diabetes, tissue damage, allogenic hematopoietic stem cell transplant, and cytomegalovirus infection.

Sex

No clear sexual predilection is reported for cutaneous aspergillosis.

Age

Neonates occasionally develop disseminated aspergillosis, presumably because of their immature immune mechanisms.

When cutaneous aspergillosis occurs in the setting of systemic aspergillosis, the prognosis is poor. Disseminated aspergillosis is associated with a mortality rate of greater than 90%. In contrast, multiple case reports have documented resolution of primary cutaneous aspergillosis after surgical excision followed by, in some cases, systemic antifungal therapy.

Patients with disseminated aspergillosis often present with febrile illness, pneumonia, or sinusitis unresponsive to antibiotics. Other possible presentations include the following:

• Gradual onset of central nervous system symptoms

• Endocarditis

• Myocarditis

• Esophageal and intestinal ulcers

The pertinent physical findings of cutaneous aspergillosis as described below are limited to the skin examination.

Cutaneous presentations of systemic aspergillosis most frequently begin as solitary or multiple erythematous or violaceous indurated papules or plaques. The lesions are often tender, but they can be asymptomatic. These manifestations evolve rapidly into centrally placed pustules, hemorrhagic vesicles, and, ultimately, black eschars. Involved areas can be large or small, can be localized or diffuse, and most often arise on the limbs and head. Truncal lesions are much less common.

Primary cutaneous infections usually develop at the sites of an intravenous catheter or a venipuncture. Reports have also associated the use of occlusive dressings, armboards, nonsterile gauze, plaster casts, and adhesive tape with primary cutaneous aspergillosis.[8]

Infection with A niger in a nonhealing surgical wound in an elderly immunocompetent patient has been reported.[9]

Skin lesions often initially appear as a localized cellulitis that develops into the typical necrotic ulcer or a black eschar. Aspergillus chevalieri has been reported to cause a distinct skin lesion that is more hyperkeratotic and vesiculopapular in nature.[10]

Findings from skin biopsy with special staining for fungus, such as with periodic acid-Schiff or methenamine silver stain, can be supportive or suggestive of Aspergillus infection, but other fungi may appear nearly identical in histopathologic sections.

Tissue, sputum, or blood culturing is usually performed, but the results may be negative or unreliable because Aspergillus is a common laboratory contaminant. If truly present in tissue, Aspergillus is a rapidly growing fungus that can be isolated in culture within 1-3 days, but longer incubation times may be required if the inoculum is very small. Molecular and genomic laboratory testing with polymerase chain reaction combined with DNA microarray could be used to detect Aspergillus species.[11] It is recommended to use molecular techniques in conjunction with culture or staining.[12] Bronchoalveolar lavage fluid could be tested using quantitative polymerase chain reaction in combination with colony-forming assays.[13] Molecular and genomic assays are increasingly important in the sensitivity and specificity of detecting aspergillosis.

In disseminated disease, the serum galactomannan assay can be used in conjunction with cultures and/or histologic examination. Galactomannan, an Aspergillus cell wall constituent, can be detected by enzyme-linked immunosorbent assay with an approximate sensitivity of 81% and specificity of 89%.[14]

 

Chest radiography can help in diagnosing a primary pulmonary infection, or it can confirm the presence of a fungal ball. CT scanning or MRI may help reveal fungal abscesses in the brain.

In tissue sections, narrow septate hyphae with delicate chitinous walls, bubbly blue cytoplasm, and acute-angle branching can be demonstrated, especially with special staining. Keep in mind that on sectioning, other fungi may appear to have acute-angle branching and Aspergillus species may appear to have more of a right-angle branching. Primary cutaneous infection often involves a granulomatous reaction in the dermis and the formation of multinucleated giant cells. Hematogenous disease is usually characterized by numerous branching hyphae surrounding and, occasionally, eroding into blood vessel lumens.

In both disseminated and limited cutaneous aspergillosis, high-dose intravenous amphotericin B, in traditional or liposomal form has been the traditional antifungal used to eradicate the underlying organism. However, voriconazole is also approved as a first-line agent for aspergillosis and is being used with increased frequency. Other treatment options for aspergillosis include itraconazole, caspofungin, or voriconazole in combination with terbinafine.[15, 16, 17] Topical voriconazole solution combined with a systemic antifungal has also been reported as effective for secondary cutaneous aspergillosis.[18] Voriconazole should be the main agent used to treat invasive aspergillus.[12] For Aspergillus-induced onychomycosis, treatment is with oral itraconazole because topical medications have very limited efficacy eradicating fungus from the nails. However, topical efinaconazole treatment, a strong antifungal, has been shown to successfully eradicate ungual Aspergillus infection.[19]

From a more homeopathic standpoint, a recent study showed in vitro antifungal activity of essential oil of Juniperus communis against A flavus, A fumigatus, and A niger.[20]

In the case of secondary wound infection of the scalp with A niger, treatment with ketoconazole 2% gel and retapamulin ointment resulted in resolution of the nonhealing wound.[9]

Several case reports have documented the effectiveness of surgical excision or debridement in the treatment of primary cutaneous aspergillosis. Some of the patients also received concurrent or subsequent systemic antifungal therapy.

Consult a dermatologist for diagnosis, excision, and wound care.

Consult an infectious diseases specialist for treatment recommendations in the setting of systemic disease.

Laminar airflow protection and high-efficiency particulate air filters have been reported as effective ways to prevent nosocomial pulmonary aspergillosis in patients who are immunocompromised. To prevent primary cutaneous aspergillosis, use sterile dressings at catheter sites or other susceptible areas. It is recommended that patients at high risk for invasive aspergillosis avoid gardening and construction sites. Allogenic hematopoietic stem cell transplant recipients should have a sterile environment to reduce the risk of infections. In addition, leukemia and transplantation patients should have regular checkups for invasive mold infections.[12]

Guidelines on the management of aspergillosis by the Infectious Diseases Society of America are as follows[12, 21] :

• Submit tissue and fluid specimens for histopathologic, cytologic, and culture examination to diagnose invasive aspergillosis. However, molecular techniques, such as DNA sequencing, should be used to identify Aspergillus species in cases that involve either isolates with atypical growth or concern for resistance.

• If invasive pulmonary aspergillosis is suspected, the guidelines recommend performing CT scanning of the chest, regardless of chest radiography findings. Bronchoscopy with bronchoalveolar lavage is also recommended in such cases, unless significant comorbidities (eg, bleeding, severe hypoxemia) preclude it.

• Detection of galactomannan (a component of the Aspergillus cell wall) in serum or bronchoalveolar lavage fluid is recommended as an accurate marker for the diagnosis of invasive aspergillosis in adults and children, when used in certain patient subpopulations, such as hematopoietic stem cell transplant recipients or patients with hematologic malignancies.

• Serum assays for (1 → 3)-β-D-glucan and serum galactomannan are recommended for diagnosing invasive aspergillosis in high-risk patients and their response to treatment (hematologic malignancy, allogeneic hematopoietic stem cell transplant), but are not specific for Aspergillus.

• If invasive pulmonary aspergillosis is suspected, antifungal therapy should be initiated while diagnostic evaluation is ongoing. Voriconazole is recommended for primary treatment of invasive pulmonary aspergillosis, although combination therapy with voriconazole and echinocandin may be warranted for some high-risk patients.

• Antifungal therapy for invasive pulmonary aspergillosis should continue for at least 6-12 weeks. Antifungal prophylaxis should also be instituted for patients with prolonged neutropenia who are at high risk for invasive aspergillosis. Prophylactic regimens with posaconazole, voriconazole, and/or micafungin are considered to be most effective.

• Amphotericin B deoxycholate and its lipid derivatives are appropriate options for initial and salvage therapy of Aspergillus infections when voriconazole cannot be administered. However, amphotericin B deoxycholate should be reserved for use in resource-limited settings in which no alternative agents are available. Lipid formulations of amphotericin B should be considered in settings in which azoles are contraindicated or not tolerated.

• Aerosolized formulations of amphotericin B may be considered as prophylaxis in patients with prolonged neutropenia (patients receiving induction/reinduction therapy for acute leukemia and allogeneic hematopoietic stem cell transplant recipients following conditioning or during treatment of graft versus host disease) and in lung transplant recipients.

• Echinocandins are effective in salvage therapy (either alone or in combination) against invasive aspergillosis, but they are not recommended for routine use as monotherapy for the primary treatment of invasive aspergillosis.

• Triazoles and voriconazole are preferred agents for the treatment and prevention of invasive aspergillosis in most patients.

• Surgery for aspergillosis should be considered for localized disease that is easily accessible to debridement (eg, invasive fungal sinusitis, localized cutaneous disease).

• The guidelines recommend that both surgery and either systemic voriconazole or a lipid formulation of amphotericin B be used in invasive Aspergillus fungal sinusitis, but surgical removal alone can be used to treat an Aspergillus fungal ball of the paranasal sinus. Enlargement of the sinus ostomy may be needed to improve drainage and prevent recurrence.

• Recommend prophylaxis with posaconazole, voriconazole, and/or micafungin during prolonged neutropenia for those who are at high risk for invasive aspergillosis.

• The guidelines do not recommend routine antifungal susceptibility testing. Instead, it should be reserved for cases in which infection with an azole-resistant isolate is suspected, or in which a patient is unresponsive to antifungal agents.

• The guideline recommends using the same antifungal agents for the treatment of aspergillosis in children as are used in adults. However, dosing of many of these agents may be different for children. The authors also note that although voriconazole is only approved by the US Food and Drug Administration for children aged 12 years and older, it is the cornerstone of aspergillosis treatment in children of all ages.

• Suggest a follow-up chest CT scan to assess the response of invasive pulmonary aspergillosis to treatment after a minimum of 2 weeks of treatment; earlier assessment is indicated if the patient clinically deteriorates. When a nodule is close to a large vessel, more frequent monitoring may be required.

The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology, and the European Respiratory Society Joint Clinical Guidelines are summarized below.[22]

Strongly recommended diagnostic methods are as follows:

• Chest CT and bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis

• Direct microscopy, preferably using optical brighteners, histopathology, and culture

• Pathogen identification to species complex level for all clinically relevant Aspergillus isolates; antifungal susceptibility testing in patients with invasive disease in regions with resistance found in contemporary surveillance programs

Recommended and other diagnostic methods are as follows:

• Serum and BAL galactomannan measures as markers for the diagnosis of invasive aspergillosis

• Polymerase chain reaction should be considered in conjunction with other diagnostic tests

Treatment guidance is as follows:

• Preferred agents for first-line treatment of pulmonary invasive aspergillosis: Isavuconazole and voriconazole

• Moderately support agent: Liposomal amphotericin B

• Not recommended: Combinations of antifungal agents as primary treatment option

• Strongly recommended practice: Therapeutic drug monitoring for patients receiving posaconazole suspension or any form of voriconazole for invasive aspergillosis treatment

• Strongly recommended practice: In refractory disease, where a personalized approach may consider reversal of predisposing factors, switch drug classes and implement surgical intervention

Prophylaxis recommendations are as follows:

• Primary prophylaxis with posaconazole strongly recommended in patients with acute myelogenous leukemia or myelodysplastic syndrome receiving induction chemotherapy

• Secondary prophylaxis strongly recommended in high-risk patients

In aspergillosis, high-dose intravenous amphotericin B has traditionally been used to eradicate the underlying organism. Voriconazole has been approved as a first-line agent in the treatment of invasive aspergillosis and is available in both parenteral and oral formulations. Typically, voriconazole is used with caspofungin. A multicenter, randomized, open-label trial comparing the efficacy of voriconazole to amphotericin B demonstrated better response rates, improved survival, and fewer severe adverse effects in those receiving voriconazole therapy.[23] Ungual aspergillosis patients have been successfully administered topical efinaconazole.[19]

Itraconazole, corticosteroids, posaconazole, caspofungin, terbinafine, and micafungin have also been reportedly effective in some cases of aspergillosis. Itraconazole and corticosteroids are mainly used for allergic bronchopulmonary aspergillosis (ABPA) or allergic Aspergillus sinusitis. The length of treatment varies in the literature, but treatment is likely to be most effective if prolonged. Studies show posaconazole as an alternative treatment for invasive aspergillosis in patients previously resistant to or intolerant of other antifungal therapies.[24] Combination antifungal therapies have also been used in patients with aspergillosis that is associated with a greater degree of treatment resistance.

Class Summary

The mechanism of action may involve an alteration of RNA and DNA metabolism or an intracellular accumulation of peroxide that is toxic to the fungal cell.

Amphotericin B (Amphocin, Fungizone)

Amphotericin B is a polyene antibiotic produced by a strain of Streptomyces nodosus; it can be fungistatic or fungicidal. Amphotericin B binds to sterols (eg, ergosterol) in the fungal cell membrane, causing intracellular components to leak with subsequent fungal cell death.

Itraconazole (Sporanox)

Itraconazole has fungistatic activity. It is a synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP-450–dependent synthesis of ergosterol, a vital component of fungal cell membranes.

Voriconazole (VFEND)

Voriconazole is used for primary treatment of invasive aspergillosis and salvage treatment for infection with Fusarium species or Scedosporium apiospermum. It is a triazole antifungal that inhibits fungal CYP450–mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Caspofungin (Cancidas)

Caspofungin is used to treat refractory invasive aspergillosis. It is the first of a new class of antifungal drugs (glucan synthesis inhibitors). It inhibits synthesis of beta-(1,3)-D-glucan, an essential component of the fungal cell wall.

Micafungin (Mycamine)

Micafungin is a member of new class of antifungal agents, echinocandins, that inhibit cell wall synthesis. It inhibits the synthesis of 1,3-beta-D-glucan, an essential fungal cell wall component not present in mammalian cells. It is used to treat invasive aspergillosis.

Posaconazole (Noxafil)

Posaconazole is a triazole antifungal agent. It blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. It is indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk because of severe immunosuppression.

It is available as an oral suspension (200 mg/5 mL), 100-mg delayed-release tablet, and injection. Posaconazole injection is administered as a loading dose of 300 mg twice on the first day of treatment, followed by 300 mg once daily thereafter. The tablets are administered as a loading dose of 300 mg twice daily on day 1, followed by a once-daily maintenance dose of 300 mg.