Dermatology

Aspergillosis

Are You Confident of the Diagnosis?

Infection of the skin with Aspergillus species can occur through primary inoculation of fungal spores directly into the skin from the environment; through spread from infected contiguous organs, particularly the nasal sinuses; and from hematogenous spread from a distant infected organ, often the lungs.

Rarely, Aspergillus species may be responsible for causing white superficial or other types of onychomycosis, and may cause an associated fungal paronychia in immunosuppressed patients. Indeed, all types of aspergillosis infection are more likely to occur in immunosuppressed patients.

  • What to be alert for in the history

Patients with primary cutaneous aspergillosis often give a history of injured skin exposure to a possibly contaminated object. An outpatient may give a history of penetrating trauma involving soil or vegetation. A hospitalized patient may report the presence of an arm board, adhesive tape or occlusive dressings over an intravenous catheter site, wound, or macerated skin.

Other risk factors commonly obtained in the patient's history include immunosuppression, particularly neutropenic hospitalized patients receiving chemotherapy for acute leukemia or corticosteroids for graft versus host disease during the course of an allogeneic stem cell transplant. Primary cutaneous aspergillosis can occasionally be seen in healthy patients, or can rarely be the presenting sign of an underlying immunosuppression, and in the right clinical circumstances this diagnosis should be suspected even if there is no apparent immune defect.

  • Characteristic findings on physical examination

Primary cutaneous aspergillosis can have various clinical manifestations, but the most characteristic lesion is a black eschar overlying a red or purple patch, plaque, or nodule at the location of skin injury (Figure 1). Red to purple macules, papules, or nodules with or without overlying erosions or eschars and abscesses may also be found adjacent to the site of injury. There are no pathognomonic lesions, and hemorrhagic bullae and lesions in a sporotrichoid pattern have also been described.

Figure 1.

Primary cutaneous aspergillosis in a pediatric patient. This patient had an arm board secured over an IV site and developed this lesion at the IV site. (Courtesy of James Treat, MD)

  • Expected results of diagnostic studies

Diagnosis of all types of cutaneous aspergillosis depends on seeing the hyphal forms in the tissue. Prompt biopsies for touch prep; frozen section examination; permanent fixation with routine hematoxylin and eosin (H&E) staining as well as special stains for fungus such as Periodic acid-Schiff (PAS) and Gomori methenamine-silver (GMS) stains; and for tissue staining and culture are required. Although the fungal elements can be seen on H&E staining, the special stains will help to highlight the hyphae.

A touch prep can provide immediate information, and is accomplished by collecting a punch biopsy and smearing the deep tissue edge on a slide, staining the slide with chlorazole black or 10% potassium hydroxide solution, and evaluating for the presence of hyphae. The tissue used for the touch prep can then be used for histology, providing that it was not crushed.

Tissue for these tests should ideally be taken prior to the start of antifungal therapy, but the presence of antifungal therapy should not deter a biopsy, and if a biopsy is unable to be immediately obtained, antifungal therapy should not be deferred. The area under and including a necrotic black eschar is most likely to demonstrate hyphae and is ideal for biopsy. If a black eschar is not present, biopsies should be taken from the largest and most pronounced lesions.

On touch prep and frozen and permanent sections, Aspergillus species appear as septate hyphae 3um in diameter that branch at 45 degrees, and can have dermal and epidermal necrosis. Immunocompetent patients may demonstrate a significant granulomatous reaction and few hyphae. Mucor and Rhizopus species have non-septate hyphae that branch at 90 degrees. Candidal species have pseudohyphae with characteristic thick walls and may have round spores also visible in tissue. Aspergillus hyphae are microscopically identical to Fusarium hyphae, but tissue culture can help to distinguish these entities (Figure 2).

Figure 2.

Aspergillosis. H&E, X10)

Aspergillus species can be cultured on Sabouraud dextrose agar; however, they are a common saprophyte and may grow in culture as a contaminant. If a tissue culture of aspergillosis is obtained in an unexpected setting, confirmation through observing the hyphae in a biopsy or through repeated culture is advised. Nonetheless, in an immunosuppressed patient, appropriate caution with antifungals and careful observation should be taken even if the culture may be a false positive.

  • Diagnosis confirmation

The differential diagnosis of primary cutaneous aspergillosis includes primary skin infections with other opportunistic fungal organisms such as Candida, Fusarium, and Rhizopus species; Majocchi's granuloma; bacterial infections including staphylococcal or streptococcal abscesses or ecthyma gangrenosum; and typical or atypical mycobacteria. Non-infectious entities which may present like primary cutaneous aspergillosis and are often seen in similar settings include early or localized Sweet's syndrome and leukemia or lymphoma cutis.

In the case of fungal paronychia extending from aspergillosis of the nail plate, the presentation may be similar to that of a bacterial paronychia with acute edema, tenderness, and erythema of the periungual skin. The presence of a black eschar overlying the red periungual plaque or patch as well as the failure of the lesion to respond to antibacterial therapy will help to suggest Aspergillus or Fusarium species as the cause of the infection.

Lesions resulting from opportunistic fungal infections and ecthyma gangrenosum tend to develop rapidly over a matter of hours, helping to distinguish them from other conditions. The presence of an enlarging black eschar or purple macule, papule or nodule with an associated intravenous catheter site, arm board, occlusive dressing, or adhesive tape should alert physicians to the possibility of primary cutaneous aspergillosis or other opportunistic fungal infection, and should be considered an emergency, particularly in an immunosuppressed patient.

Extension of an infection from a contiguous source occurs most often in patients with aspergillosis infection of the sinuses. The classic fungal infection of the sinuses is a Mucor infection in poorly-controlled diabetics, but Aspergillus can cause an identical picture in the severely immunosuppressed.

Symptoms of fungal sinusitis include fever, nasal congestion or discharge, and facial pain. Extension to the overlying skin is an emergency, and should be suspected if there is edema, or if red to purple patches or plaques or black eschars appear on the nasal sidewall, nasal philtrum, the hard or soft palate or the eyelids. If appropriate medical and surgical management is not instituted, progression can involve the brain and lead to seizures, loss of consciousness, and death.

Secondary cutaneous involvement from hematogenous spread of the fungal hyphae occurs almost exclusively in profoundly neutropenic hematologic oncology patients. Fever, hypotension, tachycardia and tachypnea can be seen, and the patient often has pulmonary symptoms from underlying Aspergillus pneumonia. Skin findings are tender red to purple macules, papules or nodules that can develop central eschars. Lesions are classically 2-3 cm, and are few in number.

Skin involvement from other disseminated opportunistic fungal infections including Fusarium, Candida, Mucor and Rhizopus species are the most likely mimics of secondary cutaneous aspergillosis, and can present an identical clinical picture. Up to 75% of patients who are fungemic with Fusarium species have skin findings. Candidemia and disseminated aspergillosis are more common than disseminated fusariosis in neutropenic patients, but less commonly involve the skin.

The typical findings of skin involvement in disseminated candidal infection are 5-10 mm pink to red papules that may become purpuric in thrombocytopenic patients. These lesions do not classically develop central eschars, and there are usually many lesions over the trunk and extremities. Fusariosis lesions may be identical to those of secondary cutaneous aspergillosis, but are generally smaller and more numerous. Patients with disseminated Mucor or Rhizopus species may also have tender red plaques with central eschars the same size and in the same number as patients with disseminated aspergillosis. These may be distinguished by biopsy and culture.

Finally, it is important to remember that patients with aspergillosis may be co-infected with other organisms or have additional skin disease. Particularly in neutropenic patients or in patients who have had penetrating trauma, multiple organisms may be present and causing infection simultaneously. Aspergillosis may also occur at the same time as graft versus host disease, drug eruptions, or other inflammatory dermatoses.

In addition to culture and histology, serum biomarkers can sometimes be used to support or confirm diagnosis of invasive aspergillosis. Serum galactomannan and beta-D-glucan assays have recently become available, although their sensitivity and specificity are varied depending on the clinical context.

Who is at Risk for Developing this Disease?

Primary cutaneous aspergillosis is more likely to occur and to become disseminated in immunosuppressed patients and low-birth weight premature neonates, but has been reported to occur in healthy hosts as well. Risk factors include degree of immunosuppression and local skin barrier dysfunction from injury, surgery, burns, and maceration, as well as skin exposure to fomites contaminated with Aspergillus spores.

Immunosuppression from many causes, including a variety of inherited immune defects; advanced HIV infection; cytotoxic and corticosteroid therapy for inflammatory and autoimmune diseases, solid organ malignancies, and following solid organ transplantation is a risk factor for all types of aspergillosis. However, the more profound and lengthy the immunosuppression, and specifically the neutropenia, the more likely disseminated disease will occur. Prolonged neutropenia in the course of an allogeneic stem cell transplant or resulting from treatment for acute leukemia or graft versus host disease is the most common setting in which to see disseminated aspergillosis.

Patients with chronic granulomatous disease, a type of inherited immune defect, are at particular risk for all types of aspergillosis, and disseminated aspergillosis is a significant cause of mortality in this population. These patients have defective NADPH oxidase, which is an essential part of humans' defenses against Aspergillus and other fungal species.

Patients have also been reported with aspergillosis osteomyelitis and keratitis following penetrating trauma, and endovascular infection following vascular grafting of material contaminated with Aspergillus spores.

What is the Cause of the Disease?

Over 900 species of Aspergillus have been described, but the majority of human disease is caused by A flavus, A fumigatus, A niger, A terreus and A ustus. A flavus is the most common cause of primary cutaneous aspergillosis. These filamentous dichotomous fungi are ubiquitous in soil, water, air and vegetation, and cause a spectrum of human disease ranging from acute, life-threatening disseminated infections in the immunosuppressed to chronic allergic sinusitis and bronchopulmonary disease due to inflammation and inappropriate immune stimulation in colonized patients.

There are three ways in which Aspergillus species cause skin disease; primary cutaneous aspergillosis, secondary cutaneous aspergillosis, and direct extension of infection to the skin from an underlying fungal sinusitis. All three types can rarely be seen in immunocompetent patients, but they are significantly more common, and in the case of disseminated disease occur almost exclusively, in immunocompromised hosts. All types are associated with a high mortality if not treated and therefore require immediate diagnosis and therapy.

Primary cutaneous aspergillosis occurs when conidia (spores) in the air, soil, or on fomites are exposed to injured skin. Infection is then more likely to occur if the host is immunocompromised, if there is penetrating trauma, or if the contamination source is allowed prolonged contact with the skin. In hospitalized patients, arm boards, adhesive tape, and occlusive dressings over macerated skin or intravenous catheter sites are settings in which primary cutaneous aspergillosis has been described.

Epidermal injuries of many types have been associated with primary cutaneous aspergillosis, including burns, surgical wounds, chronic foot and leg ulcers, pressure ulcers, intertrigo, and atrophic skin resulting from systemic steroids. In these settings aspergillosis occurs when the injured skin comes into contact with a contaminated fomite.

Skin barrier dysfunction occurs frequently in immunosuppressed patients, and these combined factors put patients at most risk for developing primary cutaneous aspergillosis. Low-birth weight premature neonates are also at risk for primary cutaneous aspergillosis due to their immature immune status and dysfunctional skin barrier.

Once the conidia gain access to injured skin, they germinate into the hyphal forms seen in tissue specimens and can invade all layers of the skin. Aspergillus species have a predilection for invading blood vessels, and tissue destruction resulting from vascular injury contributes to the black eschars and purple color often seen clinically. Angioinvasion also rapidly allows the infection to travel to deeper tissues and to disseminate hematogenously in an immunosuppressed host, making primary cutaneous aspergillosis an emergency.

Secondary cutaneous aspergillosis results from disseminated disease. Following exposure of injured tissue to the conidia, most often through the sinopulmonary tract, the hyphae travel from the original site of infection primarily in the blood to distant sites, and about 5-10% of patients with disseminated aspergillosis develop skin findings. The clinical findings of tender red to purple macules, papules or nodules that can develop central eschars reflect the vascular invasion.

Pulmonary infection is most often the primary source preceding disseminated aspergillosis, reflecting the frequency with which fungal spores are inhaled. A fumigatus is the most common cause pulmonary and thus of disseminated disease, with the exception of a few extremely dry, hot climates in which A flavus is the most common. Construction in or around hospitals has been associated with nosocomial outbreaks of aspergillosis. The increased turnover of the soil results in more spores in the air coming into contact with the immunosuppressed.

Analogous to epidermal injury and immunosuppression being risk factors for the fungus to cause primary cutaneous aspergillosis, underlying structural lung disease and immunosuppression increases the likelihood of invasive disease resulting from inhalation. In some patients, particularly those with asthma, colonization of the sinopulmonary tract occurs and can lead to allergic disease which does not have associated skin findings. Secondary cutaneous disease may also result from primary disease due to sinusitis, osteomyelitis, contaminated vascular grafts, endocarditis, keratitis, and skin sources.

Aspergillosis infection of the skin can also result from direct extension from a fungal sinusitis. Inhaled spores can transiently inhabit the upper aerodigestive tract or can colonize the sinuses, and in immunosuppressed patients, including patients with poorly-controlled diabetes, acute fungal sinusitis may occur.

If it is not promptly treated, destruction of the soft and bony tissues of the nose, orbits, or palate may occur, resulting in eye, facial and mouth pain; red, tender plaques or nodules anywhere on the central face and eyelids; proptosis, or nasal discharge and congestion. Extension can also progress to the cavernous sinus and brain, causing seizures, focal neurologic signs and death.

Systemic Implications and Complications

The diagnosis of primary cutaneous aspergillosis or skin extension from underlying infection in a patient who does not have a known underlying immune defect should prompt an investigation for immunosuppression, specifically in pediatric patients in whom the diagnosis of chronic granulomatous disease may not have been discovered yet. The patient or family should also be questioned about previous bacterial and fungal infections.

Testing for HIV may be performed because this is a diagnosis not to be missed, although primary cutaneous aspergillosis is not typically a presenting sign of HIV. Generally the type of immunosuppression associated with aspergillosis is iatrogenic for treatment of cancers, and the history is easily obtained.

In any patient with primary cutaneous aspergillosis, or skin extension from underlying infection, rapid antifungal and possibly surgical treatment is necessary to prevent systemic progression. Disseminated disease carries an extremely high mortality even when treatment is instituted, up to 75% in some series.

Fungal blood cultures are often negative in disseminated aspergillosis, making the dermatologist's role a particularly important one in diagnosis of these patients. If a primary source has not already been identified, chest radiographs or high-resolution computed tomographic (CT) scans, consideration of bronchoscopy, magnetic resonance imaging (MRI) of the sinuses, possible otorhinolaryngeal evaluation for nasal endoscopy, and careful examination of the entire cutaneous surface and mucous membranes should be undertaken. If a primary source is found, surgical therapy may be directed at that site.

Disseminated aspergillosis has been associated with an elevated serum galactomannan level, and a test for this fungal cell wall component is available in many centers. However, falsely elevated serum galactomannan levels have been reported in patients on certain batches of piperacillin-tazobactam and amoxicillin-clavulanate, in neonates colonized with Bifidobacterium, and in other invasive mycotic infections.

Other systemic tests available measure the serum beta-D-glucan level, which is not specific for aspergillosis but can elevated in any invasive fungal infection. These tests must be interpreted in the context of all the other clinical information available.

Treatment Options

Treatment of all types of aspergillosis has been addressed by guidelines created by the European Convention on Infections in Leukemia (ECIL) and the Infectious Disease Society of America (IDSA) that are regularly updated and available online. It is best to consult these resources as well as consultation with infectious disease specialists when treating patients with disseminated disease.

Treatment of primary cutaneous aspergillosis is aimed at curing the infection and preventing hematogenous dissemination. Antifungal medication, consideration of surgical debridement of infected tissue, and decreasing immunosuppression are the three elements of therapy for this and all types of aspergillosis.

Due to the rarity of the condition, there have not been controlled trials comparing antifungal medications specifically for primary cutaneous aspergillosis. Information based on trials performed in patients with disseminated or pulmonary disease is often used to drive decision-making in primary cutaneous aspergillosis and aspergillosis of other sites.

The triazole antifungal voriconazole has been considered first-line treatment for all types of aspergillosis. One notable exception to this guideline is in the case of fungal sinusitis when aspergillosis has not yet been proven. In this situation, there is a likelihood of the infection being due to Mucor species, and requires some form of amphotericin B or other antifungal with activity against Mucor species as first-line therapy.

In 2016, a novel triazole antifungal, isavuconazole, was granted approval by the Federal Drug Administration for the treatment of both invasive aspergillosis and invasive mucormycosis in adults and might be better tolerated compared to voriconazole. As further clinical data becomes available, isavuconazole might replace voriconazole as first-line treatment in some clinical scenarios. Isavuconazole is available in both an oral and intravenous form, and it is not yet approved for pediatric use.

Although amphotericin B has long been the medical treatment of all types of aspergillosis, in a recent clinical trial voriconazole was demonstrated to be more effective and to have fewer adverse effects than amphotericin B. Recommended adult dosing for voriconazole is 6mg/kg IV every 12 hours for one day followed by 4mg/kg IV every 12 hours is recommended. Pediatric dosing of intravenous voriconazole for aspergillosis is 5-7mg/kg every 12 hours.

Because the trial was done with intravenous therapy, initial intravenous treatment in disseminated disease or any hospitalized patient is recommended. Immunocompetent, healthy patients with primary cutaneous aspergillosis who can tolerate oral therapy can be given voriconazole 200mg orally every 12 hours.

If patients are not able to tolerate voriconazole or if their disease progressed, a switch to liposomal formulations of amphotericin B is recommended. At this time, there is not enough evidence to support adding another agent to the first line treatment, and a switch to a different class of medication, either to amphotericin B or its liposomal forms or to one of the echinocandins. Recent clinical trials have compared various doses of liposomal amphotericin B, and currently doses of 3-5mg/kg/day of recommended.

A notable exception to the use of amphotericin B for aspergillosis is if A terreus is the species identified. High rates of resistance to amphotericin have been seen with A terreus. Amphotericin B, even in liposomal formulations, has significant side effects, requires close monitoring during treatment, is only available as an intravenous formulation, and is often not able to be tolerated long term.

The echinocandin caspofungin is approved in the United States for salvage therapy for aspergillosis patients who are not able to tolerate or progress despite voriconazole and or amphotericin B. Adult dosing of 70mg IV on day one followed by 50mg IV daily, and pediatric dosing of 50mg/m2/day is recommended. Other echinocandins, micafungin and anidulafungin, have not been shown to be effective monotherapy for invasive or primary cutaneous aspergillosis, but could be considered as part of combination regimens in some scenarios.

The other triazole antifungals, itraconazole and posaconazole, have also demonstrated some success in treatment of aspergillosis. Posaconazole is currently used for primary prophylaxis against aspergillosis in certain neutropenic leukemia and graft versus host disease patients. Itraconazole is currently approved for second-line treatment, but may be considered in healthy outpatients with primary cutaneous aspergillosis who cannot tolerate voriconazole or if voriconazole is not available. Generally, if a patient has progressed despite voriconazole, a switch to a different class, or a switch to a combination of an echinocandin, an alternative triazole and/or liposomal amphotericin, is suggested because the organism may then demonstrate resistance to other triazoles.

Fluconazole has been demonstrated to be ineffective against aspergillosis.

The ideal duration of medical therapy for aspergillosis has not been defined. For disseminated disease and advanced infections, therapy for 6-12 weeks, until all clinical and radiographic evidence of disease is resolved, or for the duration of the immunosuppression has been recommended.

Individual cases of primary cutaneous aspergillosis in immunocompetent patients have described shorter periods of treatment, from 2-6 weeks. If a patient is undergoing a repeat period of immunosuppression following an episode of secondary cutaneous aspergillosis, re-instituting antifungal therapy is suggested because small foci may remain in the skin.

Immunocompetent patients with primary cutaneous aspergillosis have been reported who respond to oral therapy with voriconazole alone, but when possible surgical debridement should be considered. Particularly in immunosuppressed patients, surgical debridement of infected tissue along with frozen sections to evaluate margins for the presence of hyphae may be necessary for controlling spread of disease. In all cases of aspergillosis in which a primary focus can be found, surgical removal of foci of infected tissue should be considered.

The mortality rate of disseminated aspergillosis can be as high as 75%, and patients rarely survive long term without the recovery of some level of immune function. Patients with HIV should have antiretroviral medication optimized. Often patients with aspergillosis are iatrogenically immunosuppressed, and the condition can be reversed.

For neutropenic patients, therapies such as granulocyte colony stimulating factor, granulocyte-macrophage colony stimulating factor, and infusion of granulocytes should be considered. Withdrawal of, or decrease in, corticosteroids and cytotoxic or chemotherapy agents should be strongly considered, even if it risks a patient developing organ rejection.

Optimal Therapeutic Approach for this Disease

Primary cutaneous aspergillosis treatment in an otherwise healthy patient should begin with voriconazole at the dosing listed above. If voriconazole is not available or the patient does not tolerate it, itraconazole can be used. Surgical debridement should be considered. If the patient progresses, a switch to a different class of medications, either to amphotericin B and its formulations or to the echinocandins, and a reconsideration of surgical therapy is warranted.

In an immunosuppressed patient, surgical debridement, decreasing immunosuppression, and intravenous therapy with voriconazole should all be considered. If the patient is not able to tolerate voriconazole or if the disease progresses, liposomal formulations of amphotericin B should be used. If amphotericin B fails or is not tolerated, a class switch to the echinocandins, specifically caspofungin, is recommended. The diagnosis should be revisited if the patient continues to progress. Combination therapy may be cautiously used if single-agent therapies have failed.

Patient Management

If any type of aspergillosis is suspected, confirmatory testing and antifungal therapy must be instituted immediately. Surgical consultation for possible debridement should be considered in order to prevent progression of disease. If the patient is being seen in the outpatient setting, admission to the hospital directly or transfer to an emergency setting where these therapies can begin is required.

Limited primary cutaneous aspergillosis in immunocompetent patients can initially be treated with outpatient oral voriconazole therapy if the patient is well, will be able to be closely monitored, and if surgery is not a reasonable option. Immunosuppressed patients with any type of aspergillosis require a multidisciplinary approach including dermatology, infectious disease, oncology or transplant medicine depending on the cause of the underlying immunosuppression, and surgical subspecialties.

Unusual Clinical Scenarios to Consider in Patient Management

Patients with secondary cutaneous aspergillosis or any type of immunosuppressed patients usually have comorbidities. Ventricular, renal and hepatic function must be closely monitored and abnormalities adjusted for in all types of antifungal medical therapy. Antifungal plasma drug level monitoring in consultation with a pharmacokinetics expert may be necessary in patients on combination therapy and in patients with organ dysfunction.

Patients who have secondary cutaneous aspergillosis may have a partial response to therapy with some cutaneous lesions remaining. These lesions may harbor organisms that can cause a relapse of disease when antifungal treatment is suspended or if immunosuppression is reinstituted. Antifungal therapy at treatment doses, not prophylactic doses, should be reinstituted.

What is the Evidence?

Morrissey, CO, Chen, SC, Sorrell, TC. "Galactomannan and PCR versus culture and histology for directing use of antifungal treatment for invasive aspergillosis in high-risk haematology patients: a randomised controlled trial". Lancet Infect Dis. vol. 13. 2013. pp. 519-28.

(Two hundred forty patients undergoing hematopoetic stem cell transplantation were randomized to starting treatment for invasive aspergillosis based on either traditional histology and culture versus serum galactomannan and PCR tests. Significantly fewer patients who were treated on the basis of the biomarkers received empiric antibiotics [15%] compared to the group who had traditional diagnostics applied [32%].)

Maertens, JA, Raad, II, Maar, KA. "Isavuconazole versus voriconazole as primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase-3, randomised-controlled, noninferiority trial". Lancet. vol. 387. 2016. pp. 760-769.

(Phase-3 international multicenter trial of 527 adult patients with hematologic malignancies and/or alloegenetic stem cell transplants and suspected or proven invasive mold disease who were randomized on a 1:1 basis to isavuconazole or voriconazole treatment. Isavuconazole was demonstrated to be noninferior and better tolerated than voriconazole. All cause mortality after 42 days of the study drug was 18% in the isavuconazole-treated arm and 20% in the voriconazole-treated arm. Drug-related adverse events were statistically significantly fewer in the isavuconazole-treated group [42%] compared to the voriconazole-treated group [60%].)

Herbrecht, R, Denning, DW, Patterson, TF. "Voriconazole versus amphotericin B for primary treatment of invasive aspergillosis". N Engl J Med. vol. 347. 2002. pp. 408-15.

(Two hundred seventy-seven immunosuppressed patients with definite or probably invasive aspergillosis were randomized to initial treatment with either voriconazole or amphotericin B, and complete or partial responses at week 12 were seen in 55% of the voriconazole-treated group and in 32% of the amphotericin B-treated group. The voriconazole group also had a higher survival rate and fewer serious adverse reactions at 12 weeks. Other antifungals after the initial dose of treatment and withdraw of immunosuppressive therapy or immune system support was allowed.)

Cornely, OA, Maertens, J, Bresnik, M. "Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial)". Clin Infect Dis. vol. 44. 2007. pp. 1289-97.

(Prospective randomized trial of 201 patients comparing liposomal amphotericin B at 3mg/kg/day versus 10mg/kg/day for primary treatment of invasive mold infection (including aspergillosis as well as other molds) in immunosuppressed patients. Survival and response rates were similar in both groups, and greater toxicity was seen in the higher-dose group.)

Walsh, TJ, Hiemenz, JW, Seibel, NL. "Amphotericin B lipid complex for invasive fungal infections: analysis of safety and efficacy in 556 cases". Clin Infect Dis. vol. 26. 1998. pp. 1383-96.

(In the 130 mycologically confirmed cases of invasive aspergillosis in patients who were not tolerant of or progressed despite other mycologic therapy, there was a response rate of 42%.)

Maertens, J, Raad, I, Petrikkos, G. "Efficacy and safety of caspofungin for treatment of invasive aspergillosis in patients refractory to or intolerant of conventional antifungal therapy". Clin Infect Dis. vol. 39. 2004. pp. 1563-71.

Ninety patients with aspergillosis who had progressed despite or were not able to tolerate liposomal amphotericin B or triazoles were treated with caspofungin. An overall response rate of 45% was seen, although only 23% of patients with disseminated disease responded.)

Denning, DW, Lee, JY, Hostetler, JS. "NIAID Mycoses Study Group multicenter trial of oral itraconazole therapy for invasive aspergillosis". Am J Med. vol. 97. 1994. pp. 497.

(In 76 patients with various forms of aspergillosis and most with underlying immunosuppression on itraconazole therapy, 39% overall had a complete or partial response at the end of the treatment period [the duration of which was up to the treating physicians].)

Walsh, TJ, Raad, I, Patterson, TF. "Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial". Clin Infect Dis. vol. 44. 2007. pp. 2-12.

(This study matched 107 posaconazole-treated patients to a retrospective group of 86 control patients to demonstrate a 42% response rate in patients with invasive aspergillosis and various underlying diseases.)

Singh, N, Limaye, AP, Forrest, G. "Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study". Transplantation. vol. 81. 2006. pp. 320-6.

(Transplant recipients who developed invasive aspergillosis and received primary therapy with either liposomal amphotericin B or a combination of voriconazole and caspofungin were compared. Survival rates in the combination arm and the amphotericin B treated arm were 68% and 51% respectively at 90 days.)

Nakashima, K, Yamada, N, Yoshida, Y, Yamamoto, O.. "Primary cutaneous aspergillosis". Acta dermato-venereologica. vol. 90. 2010. pp. 519-20.

(Single case report of an immunocompetent patient with primary cutaneous aspergillosis who had no response to topical ketoconazole or to itraconazole at a dose of 100mg daily, but did respond completely to itraconazole 200mg daily after 13 weeks of treatment.)

Craiglow, B, Hinds, G, Antaya, R, Giardi, M.. "Primary cutaneous aspergillosis in an immunocompetent patient: successful treatment with oral voriconazole". Pediatr Dermatol. vol. 26. 2009. pp. 493-5.

(A single case report of an immunocompetent pediatric patient with nosocomial primary cutaneous aspergillosis who responded completely to oral voriconazole in 2 weeks.)
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