Current Diagnosis & Treatment in Infectious Diseases

Section VI - Histoplasma Capsulatum

75. Aspergillus, Pseudallescheria, & Agents of Mucormycosis

Michael R. Keating MD


Essentials of Diagnosis

  • Filamentous fungus with septate hyphae 3–6 µm in diameter.
  • Branching of hyphal elements typically at 45° angle.
  • Specific IgG antibodies generally of no use diagnostically since most patients are immunosuppressed and will not generate antibody response.
  • Pulmonary lesions, localized or cavitary in susceptible host.

General Considerations

  1. Epidemiology.Aspergillusspp. are found worldwide and grow in a variety of conditions. They commonly grow in soil and moist locations and are among the most common molds encountered on spoiled food and decaying vegetation, in compost piles, and in stored hay and grain. Aspergillus spp. often grow in houseplant soil, and such soil may be a source of Aspergillus conidia or spores in the home, office, or hospital setting. The airborne conidia are extremely heat resistant and can withstand extreme environmental conditions.

Most human disease with Aspergillus spp. is acquired via inhalation of conidia. Conidia are 2.5–3 µm in size and can easily reach the alveoli with inhalation. Other routes of transmission are by direct inoculation of skin, inhalation into the nose and sinuses, or injection into the bloodstream among drug abusers. Person-to-person transmission does not occur.

Nosocomial acquisition is an important problem among severely immunosuppressed, hospitalized patients. Hospital air and air ducts are known sources of A conidia. Unfiltered air is more likely to contain spores. Construction, building remodeling, and other forms of environmental disruption have been associated with nosocomial outbreaks of aspergillosis. Potted plants are frequently excluded from patient care areas where high-risk patients may be present.

The most critical determinant for inhalation of A conidia progressing to invasive disease is the status of the host defenses. The pulmonary macrophage is the first line of defense against inhaled conidia. Macrophage function may be rendered ineffective by high-dose corticosteroid therapy or other immunomodulating chemotherapy. The tissue neutrophil is also pivotal. Altered phagocytosis or cellular killing by the neutrophil may lead to invasive disease. Neutropenia caused by leukemia, chemotherapy, bone marrow transplantation, or aplastic anemia is a well-known risk factor for invasive aspergillosis. Patients with late stages of HIV infection also are prone to invasive disease. Increased risk is also associated in children with chronic granulomatous disease and in patients with poorly controlled diabetes mellitus.

  1. Microbiology.Aspergillusspp. are rapidly growing filamentous fungi or molds that are ubiquitous in the environment and found worldwide. The septate hyphae are characteristically 3–6 µm in diameter and usually branch at 45° angles. Growth usually occurs in the laboratory within 2–3 days. Of the > 500 species of Aspergillus, only a few cause human infection. A fumigatus is the most common human pathogen. Others, such as A niger, A flavus, and A terreus, can also cause human infection but are encountered less frequently. Isolated cases have been caused by a number of other Aspergillus spp. The species of Aspergillus are differentiated by the structure of the asexual conidiaphore or spore-forming structure on growth in the laboratory.
  2. Pathogenesis.Aspergillusspp. may invade tissue in patients with altered host defenses or may colonize ectatic segments or cavities in the lung. Following inhalation of conidia, in the absence of appropriate host response, hyphal elements invade bronchial tissue with a particular propensity for angioinvasion. Angioinvasion may lead to disseminated invasive aspergillosis involving multiple organs in profoundly immunosuppressed patients. Furthermore, angioinvasion causes hemorrhagic infarction and necrosis of involved tissue. This may result in hemoptysis when there is pulmonary involvement or stroke when the brain is infected. The enlarging site of Aspergillus infection with central necrosis has a tendency to cavitate, yielding characteristic findings on imaging studies.

Colonization of preexisting cavitary lesions may lead to the formation of a fungus ball or aspergilloma composed of exuberant filamentous growth of Aspergillus spp. The cavity of an aspergilloma is lined by vascular granulation tissue, while the cavity itself contains hyphal elements, inflammatory cells, amorphous debris, and mucus. Superficial invasion of the cavity wall may occur, but dissemination is rare unless the patient also has other risk factors for invasive disease. Erosion into adjacent pulmonary vessels may occur and result in hemoptysis, which on occasion may be massive and result in death.


Most individuals who are exposed to Aspergillus spores are asymptomatic. In fact, inhalation of spores is probably a common event; however, in an at-risk patient, the spectrum of disease caused by Aspergillus spp. can range from hypersensitivity phenomenon to colonization to overwhelming and rapidly progressing disseminated life-threatening disease (see Box 75-1).


Invasive pulmonary aspergillosis in the immunocompromised host is among the most serious manifestations of disease caused by Aspergillus spp. Key risk factors for invasive aspergillosis include neutropenia, especially profound neutropenia (< 100 neutrophils/mL) and prolonged neutropenia (> 12 days); prolonged high-dose corticosteroid therapy, graft-versus-host disease after bone marrow transplantation, acute rejection after solid-organ transplantation, cytomegalovirus disease after transplantation, advanced AIDS, and poorly controlled diabetes mellitus. On very rare occasions, invasive pulmonary aspergillosis may occur in previously healthy adults or in patients with alcoholic liver disease. Chronic necrotizing aspergillosis is an indolent form of invasive pulmonary aspergillosis that occurs in patients who are less profoundly immunosuppressed than those with the risk factors cited above.

Clinical Findings

  1. Signs and Symptoms.Severely immunosuppressed patients with invasive aspergillosis may be completely asymptomatic when the disease is first suspected. The initial clue may only be a positive sputum culture or an abnormal chest x-ray. Nonproductive cough, dyspnea, and chest pain are common among patients with symptoms. Pleuritic chest pain is occasionally seen. Fever is usually present but may be suppressed by corticosteroid therapy. Hemoptysis may develop as a consequence of angioinvasion and, in the appropriate host, should raise the suspicion of invasive pulmonary aspergillosis.
  2. Laboratory Findings.Hypoxemia is often present in patients with extensive pulmonary involvement. Other laboratory abnormalities are nonspecific. Because of the immunodeficient state, serum antibodies to Aspergillusspp. are usually negative. The detection of circulating Aspergillus antigen is a promising investigational test but is not yet available commercially. Cultures of the sputum or respiratory secretions are often positive. Unfortunately, recovery of Aspergillus isolates from the sputum of otherwise healthy people is occasionally seen so it may be difficult and a challenge to distinguish airway colonization from positive cultures caused by invasive disease. Furthermore, 20–30%of patients with invasive pulmonary aspergillosis will have negative sputum cultures unless serial sampling is done. Positive blood cultures for Aspergillus spp. are exceedingly rare.
  1. Imaging.The chest x-ray findings in patients with invasive pulmonary aspergillosis vary considerably. Focal pneumonitis, diffuse patchy disease, mononodular and multinodular densities, and pleural-based infiltrates may be seen. Rounded nodular infiltrates are the most common finding. Serial chest x-rays may show rapid progression of pulmonary involvement, and cavitation in this setting is common. Computed-tomography (CT) imaging of the chest may show a characteristic halo sign around nodular infiltrates that are highly suggestive of angioinvasive Aspergillusinfection.
  2. Differential Diagnosis.The differential diagnosis of a new infiltrative lung process in an immunosuppressed patient is very broad. Other fungi including Pseudallescheria boydiiand the order Mucorales can cause an identical syndrome. Nocardia lung infection can be similar in presentation. Mycobacterial infection is less likely but must be considered. Bacterial infection including that caused by Staphylococcus aureus and Pseudomonas aeruginosa is possible. Rhodococcus equi is a rare but emerging pathogen that presents this way, especially if cavitation is present.
  3. Complications.The propensity for angioinvasion leads to hematogenous dissemination in undiagnosed or untreated cases. Virtually any organ may be involved (see disseminated aspergillosis).

BOX 75-1 Aspergillus Infection




More Common

· Allergic bronchopulmonary aspergillosis

· Aspergilloma

· Invasive pulmonary aspergillosis

· Disseminated aspergillosis

· Farmer's lung

· Allergic bronchopulmonary aspergillosis

· Aspergilloma

· Invasive pulmonary aspergillosis

· Disseminated aspergillosis

· Aspergillus sinusitis

Less Common

· Osteomyelitis

· Endocarditis

· Endophthalmitis

· Endophthalmitis

· Osteomyelitis

· Disk space infection

· Endocarditis

· Otomycosis

· Aspergillus tracheobronchitis


The diagnosis of invasive pulmonary aspergillosis in the immunosuppressed patient is a significant challenge. A definitive diagnosis is established when tissue specimens demonstrate invasive fungal elements (see Figure 75-1); however, a positive sputum specimen in a high-risk patient and imaging evidence consistent with Aspergillus infection should be regarded as presumptive invasive pulmonary aspergillosis and justification for empiric antifungal therapy. In patients with negative cultures or in whom sputum cultures cannot be obtained, bronchoscopy and bronchoalveolar lavage may help establish a microbiologic diagnosis. Bronchoscopic transbronchial biopsy may yield a false negative result due to the patchy nature of pulmonary aspergillosis and to a sampling error of the biopsy. In patients with pleural-based nodular disease, percutaneous lung biopsy may be considered. Pneumothorax and bleeding are potential complications of this approach. Thorascopic or open lung biopsy is the most effective method to establish the diagnosis.


Invasive pulmonary aspergillosis may be a rapidly progressive infection and prompt institution of antifungal therapy is critical once the diagnosis is suspected or confirmed (see Box 75-2). Amphotericin B remains the drug of choice. Treatment failures are common. Alternatives to amphotericin B include lipid amphotericin B preparations. These preparations are considerably less nephrotoxic than standard amphotericin B and appear to be equally efficacious. Unfortunately, these new lipid preparations are currently exceedingly expensive. Itraconazole is an oral azole with activity against Aspergillus spp. Its use should be reserved for patients who are not severely immunosuppressed, who have an indolent or chronic infection, or who are intolerant of amphotericin B therapy. The optimal duration of antifungal therapy is not known, but the cumulative total dose is ≤2 g of amphotericin B. In patients with a single focus of pulmonary infection, resection should be considered.


Figure 75-1. Invasive fungal elements of Aspergillus fumigatus in a lung biopsy specimen from a patient with invasive pulmonary aspergillosis. Note the septate hyphae and branching (×200, methenamine silver stain).


The prognosis for invasive pulmonary aspergillosis is generally poor. Cure or improvement on therapy is seen in ~50% of cases. Response is more likely if neutropenia recovers and immunosuppression is reduced or reversed.

Prevention & Control

Because invasive aspergillosis in the immunosuppressed or neutropenic patient is difficult to diagnosis and treat, much attention has been focused on prevention as a way of reducing the frequency of infection (Box 75-3). Two general approaches have been used: reduction of environmental exposure and prophylactic antifungal therapy. Aspergillus spp. are an ubiquitous component of dust, building material, and organic debris.

BOX 75-2 Treatment of Aspergillus Infection in Children and Adults

Treatment Option

Farmer's Lung

Allergic Bronchopulmonary Aspergillosis


Invasive Pulmonary Aspergillosis and Disseminated Asperillosis

Aspergillus Sinusitis


Prolonged subacute or chronic symptoms may require prednisone therapy at 1 mg/kg for 1–2 wks followed by a tapering regimen

Prednisone, 0.5 mg/ kg/d prolonged with slow taper


Stop or reduce if possible


Amphotericin B




1.0–1.5 mg/kg/d IV (2–3 g total target dose) in adults; 30–35 mg/kg total dose in children

1–1.5 mg/kg, if needed (2–3 g total target dose) in adults; 30–35 mg/kg total dose in children





400 mg PO once daily as secondline option for indolent case or after IV amphotericin B induction therapy; itraconazole dose for children, 5–6 mg/kg/d





In selected cases

An option for localized disease

Surgical débridement; surgical excision and drainage may be adequate


Reducing exposure to at-risk hospitalized patients can be achieved in several ways. Potted plants should be removed from the environment adjacent to at-risk patients. Certain foods, such as cereal and spices, have been found to be contaminated with Aspergillus spores and should not be offered to hospitalized patients that are at risk for aspergillosis. Construction in and adjacent to hospitals has been associated with outbreaks of nosocomial aspergillosis. Patients should not be treated in areas of the hospital where construction or remodeling is occurring. If a patient must be transported through areas of construction within the hospital, an efficient mask should be worn by the patient. Efforts should be made to seal areas undergoing construction or remodeling to prevent contamination of the air in patient areas.

HEPA filtration of air has been shown to significantly reduce or eliminate Aspergillus spores. Patient rooms with laminar airflow and HEPA filtration appear to be effective in reducing the risk of exposure in the hospital. Unfortunately, the construction and maintenance of HEPA-filtered facilities are very expensive and not available to all patients. Other strategies that have been used include high air exchange rates, surveillance air sampling, positive pressure in the patient's room and immediate environment, and regular filter changing of point-of-use air filtration systems.

BOX 75-3 Control and Prevention of Nosocomial Invasive Aspergillus spp. in Immunosuppressed Patients



Goal or Limitations

Reduction of environmental exposure

· Remove potted plants from patient care areas

· Avoid dried spices (eg, pepper) and cereals

· Seal off hospital remodeling projects

· HEPA filtration and laminar air flow patient room and care areas

· Wear high filtration masks during transportation in hospital

· Eliminate source of spores

· Reduce air contamination

· Remove spores from air in key domiciliary areas; reduce exposure risk in non-domiciliary areas

Prophylactic antifungal therapy

· Amphotericin B, 1 mg/kg/d IV

· Amphotericin B, 0.1–0.15 mg/kg/d

· Lipid preparations of amphotericin B

· Oral itraconazole, 200–400 mg/d; for children 3–6 mg/kg/d

· Intranasal or aerosolized amphotericin B

· Too toxic to be used prophylactically

· Usually can be tolerated but dose may be too low to be effective

· No clinical data; prohibitive cost

· Limited clinical data; unpredictable absorption

· Promising approach; more data needed


The use of intravenous amphotericin B for prophylaxis against Aspergillus spp. has been investigated. When given prophylactically at a dose of 1 mg/kg/d, the toxicity is prohibitively high. When used prophylactically at lower doses of 0.1–0.25 mg/kg/d, the toxicity is less, but in most studies, this dosage was insufficient to prevent aspergillosis. The lipid formulations of amphotericin B are attractive for prophylaxis alternatives; however, the high cost of these preparations limit their widespread use.

Among the oral azoles, only itraconazole has sufficient activity against Aspergillus to be considered as a viable prophylactic agent. There are limited data confirming its efficacy in preventing aspergillosis in high-risk patients. Moreover, the absorption of itraconazole from the gastrointestinal tract may be inadequate in these patients.

Use of intranasal installation of amphotericin B or aerosolization of amphotericin B was an effective prophylaxis in several small pilot studies. More data are necessary regarding optimal dose, frequency, and duration before this approach can be widely recommended for prophylaxis.


An aspergilloma of the lung may develop in individuals who have preexisting cavitary lung disease caused by conditions such as tuberculosis, sarcoidosis, silicosis, or bronchiectasis. Also known as a fungus ball or mycetoma, aspergillomas can be regarded as heavy Aspergillus colonization of the preexisting cavity.

Clinical Findings

  1. Signs and Symptoms.The most common symptom is hemoptysis, and, on rare occasions, severe or fatal hemoptysis can develop. Other symptoms are usually related to the underlying lung disease.
  2. Laboratory Findings.Patients with an aspergilloma of the lung typically have elevated IgG levels specific for Aspergillusspp. Sputum smear may show the presence of filamentous fungi, and culture is intermittently positive for Aspergillus spp.
  3. Imaging.The chest x-ray will show typical findings of a fungus ball with an air crescent sign. Both CT and magnetic resonance imaging (MRI) of the chest reveal the fungus ball (see Figure 75-2).
  4. Differential Diagnosis.In a patient with a history of prior lung disease, hemoptysis should lead to the suspicion of a fungus ball. Other fungi including Pseudallescheria boydiican cause a similar syndrome. Other causes of hemoptysis including tuberculosis, pulmonary embolism, lung cancer, and bronchiectasis need to be considered.
  5. Complications.Death due to overwhelming hemoptysis is a rare complication of aspergilloma.


The diagnosis is established by demonstrating the typical findings on imaging studies and the presence of Aspergillus organisms from sputum culture. The other common causes of hemoptysis need to be excluded with the appropriate investigations.


Treatment for aspergilloma must be individualized (see Box 75-2). For patients with mild hemoptysis, observation alone is warranted. Patients with more significant hemoptysis may benefit from lobectomy, but preexisting lung disease may place the patient at increased risk for surgical complications. There is no role for systemic antifungal therapy. No consistent benefit has been derived from intracavitary installation of amphotericin B.


Figure 75-2. Nonenhanced high-resolution chest CT showing a large aspergilloma in a patient with bronchiectasis of the right lung.


Most patients with mild stable hemoptysis do very well. In some patients, the fungus ball may gradually enlarge, and close observation of these patients is warranted.


Disseminated aspergillosis is a life-threatening, usually fatal form of aspergillosis that occurs in immunosuppressed patients. By definition, two or more noncontiguous sites are involved. Most patients with disseminated disease have invasive pulmonary aspergillosis as the primary site of infection. Common sites of dissemination include central nervous system, skin, liver, kidney, skin, and gastrointestinal tract.

Clinical Findings

  1. Signs and Symptoms.Patients with disseminated aspergillosis are usually critically ill. There are no typical signs or symptoms of disseminated disease, and findings will depend on the sites of dissemination. Pulmonary symptoms may predominate if invasive pulmonary aspergillosis is present. Altered mental status, particularly when associated with focal neurological findings, is suggestive of central nervous system involvement. Renal and hepatic involvement may be completely asymptomatic. Invasion of the renal artery or vein may cause thrombosis or infarction. Cutaneous involvement may appear as small erythematous papules and microabscesses or as large black necrotic lesions.
  2. Laboratory Findings.Despite hematogenous route of dissemination, blood cultures are rarely positive. Urine cultures may be positive for Aspergilluscells when the kidney is involved. Elevated hepatic enzymes or serum creatinine may reflect involvement of the liver or kidney.
  3. Imaging.CT imaging or MRI of the brain may show a single lesion or multiple mass lesions. CT imaging of the abdomen may reveal nodules in affected organs. Cavitation is common.
  4. Complications.The complications of disseminated disease are related to the sites of specific organ involvement. For example, brain abscesses may be associated with mental status changes or seizure, splenic abscesses may be suspected if there is left upper quadrant pain, or complete heart block may be present if there is cardiac involvement. Multiorgan dysfunction often develops.


The diagnosis can be suspected in severely immunosuppressed hosts with multiorgan dysfunction. Often the diagnosis is presumptive, but the diagnosis may be confirmed by biopsy of suspected sites of dissemination. Unfortunately, in ≤30% of cases of disseminated aspergillosis, the diagnosis is established at autopsy.

Treatment, Prevention, & Control

The treatment, prevention, and control of disseminated aspergillosis are identical to that of invasive pulmonary aspergillosis.


Allergic bronchopulmonary aspergillosis is an eosinophilic pneumonia or hypersensitivity reaction, which generally occurs in adults with a prior history of allergic asthma. It is also seen in patients with cystic fibrosis.

Clinical Findings

  1. Signs and Symptoms.The presenting symptoms are usually worsening asthma that is difficult to control and cough productive of thick brownish plugs of sputum. Low-grade fever may be present, and some patients may exhibit nonspecific constitutional symptoms such as malaise and fatigue.
  2. Laboratory Findings.Peripheral eosinophilia is a hallmark of allergic bronchopulmonary aspergillosis and is usually > 1000 cells/mL. Other findings include elevated serum IgE levels, serum precipitans to Aspergillus fumigatus, and immediate wheal and flare response to Aspergillusskin testing.

Culture of the sputum reveals large numbers of A fumigatus colonies. Antibodies in both the IgG and the IgE class that are specific for A fumigatus are elevated.

  1. Imaging.Pulmonary infiltrates are commonly seen on chest x-ray and usually involve the upper lobes. Transient recurrent infiltrates may also be seen. CT imaging of the chest is helpful in identifying the presence of central bronchiectasis that may develop in untreated patients.
  2. Differential Diagnosis.Other common causes of eosinophilic pneumonia include parasitic infestation and drug-induced lung disease. Allergic bronchopulmonary aspergillosis must also be distinguished from a number of idiopathic eosinophilic pneumonias including Löffler's syndrome, chronic eosinophilic pneumonia, Churg-Strauss syndrome, and hypereosinophilic syndrome.
  3. Complications.Undiagnosed disease may develop into a chronic state typically with involvement in the upper lobes of the lungs. Bronchiectasis, usually involving the central airways, and fibrosis may develop. Hemoptysis with chronic disease is common.


The main criteria for establishing the diagnosis of allergic bronchopulmonary aspergillosis are a history of bronchial asthma, presence of peripheral eosinophilia, immediate reaction to Aspergillus fumigatus antigen, pulmonary infiltrates on chest x-ray, serum precipitants to A fumigatus, elevated serum IgE level, and central bronchiectasis on CT imaging of the chest (see Table 75-1). Supportive diagnostic criteria include a history of brownish sputum production, sputum culture positive for A fumigatus, and elevated antibodies specific for A fumigatus of the IgG and IgE class. Microscopic examination of sputum may reveal brown, lancet-shaped crystals originating from the Charcot-Leyden crystal proteins found in the cytoplasm of eosinophils.


Treatment of allergic bronchopulmonary aspergillosis requires corticosteroids therapy (Box 75-2). After initial control of symptoms, the corticosteroid therapy should be slowly tapered. Itraconazole has been used in some patients who have difficulty controlling allergic bronchopulmonary aspergillosis, but its role is still under investigation. Inhaled corticosteroid therapy does not appear to be effective.

Table 75-1. Diagnostic criteria for allergic bronchopulmonary aspergillosis.

Key diagnostic criteria

1. Bronchial asthma

2. Peripheral eosinophilia

3. Immediate wheal and flare response to Aspergillus fumigatus antigen

4. Pulmonary infiltrates on chest x-ray

5. Serum precipitans to A fumigatus

6. Elevated serum IgE level

7. Central bronchiectasis

Specific supportive criteria

1. Brownish sputum production

2. Sputum cultures positive for A fumigatus

3. Elevated specific IgG and IgE


Recurrent disease is common, and prolonged maintenance of low-dose corticosteroid therapy is required in many patients.


Farmer's lung, also known as extrinsic allergic alveolitis or hypersensitivity pneumonitis, is an allergic inflammatory reaction induced by inhalation of Aspergillus spores, often in exposure to mold and hay. It usually occurs after inhalation during an overwhelming exposure to spores. A multitude of other antigenic stimuli can induce a similar syndrome. Other examples of hypersensitivity pneumonitis induced by Aspergillus include compost lung, tobacco worker's disease (from mold on tobacco leaves), and malt worker's lung (from moldy barley).

Clinical Findings

  1. Signs and Symptoms.Symptoms include cough and shortness of breath, which generally develop 6–8 h after exposure. On occasion, fever and chills may be present. The presentation tends to be acute, but subacute and chronic forms of the disease may be present when there is chronic low-level exposure.
  2. Laboratory Findings.Neutrophilia may be seen, but eosinophilia is typically not present. Aspergillusserum precipitans will be elevated in most cases, but their presence is not diagnostic. Skin testing with Aspergillus antigen may be positive but is not diagnostic and is most helpful for epidemiological purposes.
  3. Imaging.Chest x-ray findings may be normal even in patients with significant symptoms. Conversely, the chest x-ray may show diffuse bilateral pulmonary infiltrates or discrete nodular infiltrates. With more chronic symptoms, pulmonary function testing may show a restrictive pattern.
  4. Differential Diagnosis.Acute and subacute Farmer's lung will occasionally resemble an infectious pneumonitis. Farmer's lung must be distinguished from other conditions that cause respiratory symptoms and pulmonary infiltrates, including collagen vascular diseases, eosinophilic pneumonitis, and drug-induced lung disease. In its more chronic form, it may resemble idiopathic pulmonary fibrosis and other interstitial lung disorders.
  5. Complications.Recovery from acute Farmer's lung is the most common outcome. Individuals with chronic exposure and ongoing allergic reaction may develop pulmonary fibrosis with a restrictive pattern seen on pulmonary function testing.


The diagnosis should be suspected from the history of exposure and the symptom complex. Laboratory testing can help distinguish Aspergillus-induced Farmer's lung from other causes of Farmer's lung.


The optimal treatment for Farmer's lung is removal or avoidance of exposure. In most individuals, the syndrome is self-limited; however, patients with prolonged subacute or chronic symptoms may require prednisone therapy (see Box 75-2).


In most individuals, symptoms are self-limited, especially when the source of exposure can be avoided or removed. In patients with more chronic symptoms, with exposure avoidance and short-course prednisone therapy, the prognosis is excellent.

Prevention & Control

The cornerstone of prevention of Farmer's lung involves identification and avoidance of exposure to Aspergillus spores. Since the majority of individuals will not develop a hypersensitivity reaction after exposure, prevention and control measures only need to be instituted after the initial diagnosis.


Aspergillus spp. are capable of causing a variety of infections involving the paranasal sinuses (Table 75-2). Although uncommon, Aspergillus sinusitis is related to the immune status and immunologic response of the host.

  1. Signs and Symptoms.In the severely immunosuppressed or neutropenic patient, Aspergillussinusitis or rhinosinusitis may occur. Symptoms include headache, toothache, nasal congestion, purulent nasal discharge, and sinus or eye pain. Fever is commonly encountered. The nasal mucosa may exhibit hyperemia or necrosis that may extend into the mouth. Ptosis and loss of extraocular eye movement are prominent signs, indicating extensive invasion into the orbit. Sudden onset of blindness may occur.

In patients with normal immune status and a history of chronic sinusitis, a fungus ball or aspergilloma can form in the sinus. Persistent pain and discharge are common symptoms. An allergic fungal sinusitis may develop in patients with a history of allergic rhinitis and recurrent sinusitis. Facial pain and nasal discharge are predominant symptoms of this syndrome.

  1. Laboratory Findings.Cultures of nasal secretions are usually positive for Aspergillusspp. in patients with invasive and noninvasive forms of sinus infection.
  2. Imaging.High-resolution CT imaging of the sinuses is essential for assessing the extent of invasive disease. Destruction of bone is common in advanced cases with erosions into the orbit, the brain, or the roof of the mouth. No bony destruction occurs in noninvasive disease.
  3. Differential Diagnosis.The differential diagnosis of fungal sinusitis varies according to the extent of invasion. Noninvasive sinusitis must be distinguished from neoplasia, inflammatory conditions, and bacterial causes. Other noninvasive fungal pathogens include Fusariumspp., Curvularia spp., Bipolaris spp., and Pseudallescheria boydii. Other fungal pathogens capable of causing invasive disease include the order Mucorales, Fusarium spp., and P boydii.
  4. Complications.Untreated invasive fungal sinusitis can rapidly develop into the rhinocerebral form with direct invasion into the central nervous system. Angioinvasion may lead to widespread dissemination and death.


Aspiration of sinus contents should be cultured and stained for fungal elements. Endoscopic examination of the nose should be considered. High-resolution CT imaging can detect invasion and extent of involvement.


Treatment of invasive sinusitis in the immunosuppressed patient requires a combination of surgical débridement and antifungal therapy. Proper presurgical assessment of the extent of disease is vital to ensure that operative débridement and drainage are adequate.

Antifungal therapy with amphotericin B is illustrated in Box 75-2. For noninvasive disease, including chronic sinusitis and sinus aspergilloma, surgical excision and drainage alone are adequate, and systemic antifungal therapy is usually not needed.

Table 75-2. Clinical aspects of Aspergillus sinusitis.






Immunosuppressed and usually profoundly

Tempo of Infection

Chronic and indolent

Acute and progressive

Pathologic features

Fungus ball and chronic local infeciton

Bony destruction with invasion of adjacent structures

Clinical features

Pain, congestion, and discharge

Pain, congestion, and discharge



Usually present


Excision and drainage

Wide surgical débridement and amphotericin B, 1.0 mg/kg/d


The prognosis of noninvasive fungal sinusitis is excellent after adequate débridement and drainage. For locally invasive disease, the prognosis is fair with débridement and antifungal therapy. The prognosis with extensive invasive disease is poor.

Prevention & Control

Prevention and control of invasive sinusitis is identical to that for invasive pulmonary aspergillosis.


A variety of less commonly encountered infections may occur in both immunocompetent and immunosuppressed patients. Endophthalmitis may occur following surgery or trauma to the globe or as a rare manifestation of invasive disseminated aspergillosis. Osteomyelitis may occur in children with chronic granulomatous disease and in adults who are immunosuppressed. Disk space infection with adjacent vertebral osteomyelitis has been described in both normal hosts and in injection drug abusers. Endocarditis may occur in patients with a prosthetic valve or native valve endocarditis may occur in injection drug abusers. Otomycosis can occur in the setting of chronic external otitis.

In immunosuppressed patients, an invasive form of the disease with extensive bony destruction can occur. Aspergillus tracheobronchitis is seen most commonly in lung transplant recipients but can also occur in other immunosuppressed patients (Figure 75-3). Invasive aspergillosis may begin in the skin and disseminate to other sites. For example, focal infection may develop at intravenous catheter sites in neutropenic patients and cause progressive local infection before there is evidence of systemic dissemination.


Essentials of Diagnosis

  • Filamentous fungus that is morphologically similar to Aspergillusspp.
  • Most serious infections occur in immunosuppressed patients.
  • Recovery from culture must be distinguished from colonization or contamination.

General Considerations

P boydii is a mold that is capable of causing infection in immunosuppressed patients and less frequently in immunocompetent patients. Overall, infection with P boydii is rare.


Figure 75-3. Direct stain of a tracheal aspiration specimen in a patient with Aspergillus tracheobronchitis. Note the fruiting body of Aspergillus fumigatus. It is unusual to see this in direct patient specimens (× 800, KDH stain).

  1. Epidemiology.Although a relatively common environmental mold, P boydiiis a rare cause of human disease. It can be easily recovered from soil, water, and manure. Both community and nosocomial acquisition have been documented. In most instances, its recovery from culture specimens will reflect colonization or contamination; however, it is capable of causing serious infection in selected patients. When recovered from clinical specimens, it cannot be dismissed as a nonpathogen without careful consideration of its pathogenic potential in the clinical setting from which it was recovered.
  2. Microbiology.P boydiiis a common environmental mold sometimes referred to as Petrolidium boydii. It is the sexual spore-producing form of Scedosporium apiospermum. In tissue, P boydii produces thin septate hyphae that are similar in appearance to Aspergillus hyphae. Hence it is not possible to distinguish P boydii infection from Aspergillus infection based on histopathology, and culture confirmation is necessary to establish the diagnoses and guide therapy.
  3. Pathogenesis.The portal of entry of P boydiiis inhalation for lung and sinus infection or by direct inoculation of the skin at the site of trauma. Little is known about specific host defense mechanisms that permit opportunistic infection. Abscess formation and tissue necrosis are the typical findings of infection.

Clinical Findings

Infection caused by P boydii is similar to that caused by Aspergillus spp. but considerably rarer. Among normal hosts, P boydii may cause fungus balls in the sinuses or in the lungs in patients with preexisting cavitary lung disease or chronic sinusitis. Penetrating trauma may result in soft tissue infection. It is the most common cause of maduromycosis in the United States. Infection involving the globe after penetrating trauma has been reported relatively frequently. A unique syndrome of P boydii in normal hosts is an overwhelming pneumonia after near drowning and aspiration of fresh or brackish water. Dissemination to the brain and other tissues has been reported in this setting.

Among immunosuppressed patients, infection occurs in those with prolonged and profound immunodeficiency. Susceptible hosts include those with severe neutropenia, those with prolonged high-dose corticosteroid therapy, children with chronic granulomatous disease, and patients with HIV infection. Clinically and histologically, P boydii opportunistic infection in the immunosuppressed patient resembles invasive aspergillosis. This includes the propensity for hematogenous dissemination. Pulmonary infection is the most commonly encountered site of infection, but soft tissue infection, central nervous system infection, and other sites may be seen.


Diagnosis of infection with P boydii is based on the recovery from biopsy specimens taken from the site of infection. Its recovery from sputum in a susceptible host with an appropriate syndrome is presumptive evidence of infection. Blood cultures are rarely positive.


The microbiologic differentiation of P boydii infection from that of aspergillosis is important because P boydii is resistant to amphotericin B. The preferred therapy in adults is intravenous miconazole (see Box 75-4). Miconazole is rarely used to treat other fungal infections because of its substantial toxicity, which includes nausea, vomiting, anemia, and a variety of central nervous system effects. Cardiac arrest while receiving miconazole therapy has been reported. Nevertheless, for life-threatening infections, miconazole remains the drug of choice. Preliminary data suggest that other azoles, such as itraconazole and ketoconazole, are effective. Their use should be reserved for indolent cases or in patients who are intolerant of miconazole. The duration of therapy is not well established and should be based on response to treatment and improvement of underlying predisposing factors.

BOX 75-4 Treatment of Pseudallescheriosis

First Choice

Miconazole, 800 g IV every 8° for children: 20–40 mg/k in 3 divided doses

Second Choice

Itraconazole, 400 mg PO once daily; for children; 5–6 mg/kg/d

Role of Surgery

In selected cases


Amphotericin B resistant


Essentials of Diagnosis

  • Filamentous fungus with hyphae of uneven, often very large diameter (5–50 µm).
  • No or rare septation of the hyphal elements, which branch at irregular angles.
  • No availability of antibody or antigen testing to assist diagnosis.
  • Often abundant in biopsy or clinical specimens on fungal stain but no growth from fungal cultures.

General Considerations

Mucormycosis refers to a spectrum of infections caused by fungi of the phylogenetic order Mucorales. These infections are generally quite rare and usually occur in patients with either severe immunodeficiency, uncontrolled diabetes, or trauma.

  1. Epidemiology.The agents of mucormycosis are ubiquitous in nature and commonly recovered from decaying organic manner. Rhizopusspp. are especially common on moldy bread. Nevertheless, in contrast to Aspergillus species, the agents of mucormycosis are rarely recovered in the hospital setting.
  2. Microbiology.Although there are numerous fungi capable of causing mucormycosis, the four most common genera in order of frequency are Rhizopus, Rhizomucor, Absidia, and Cunninghamella.These fungi are relatively rapid growing and will grow on most media in the mycology laboratory in 2–5 days. They grow only as mold, and the hyphae tend to be uneven in diameter and often quite large, ranging in size from 5 to 50 µm (Figure 75-4). Branching occurs at irregular angles, in contrast to the 45° angles of branching by Aspergillus spp. Septation of the hyphae is usually absent. Environmental specimens often grow rapidly and abundantly, but it is common for no growth to occur from specimens obtained from infected tissue in patients with mucormycosis. The reason for this is unknown.
  3. Pathogenesis.Although inhalation of spores produced by these fungi is probably a daily occurrence, infection rarely occurs, even among susceptible hosts. Therefore the presumed portal of entry is respiratory with deposition of spores on the nasal mucosa for rhinocerebral mucormycosis and in the alveoli for pulmonary mucormycosis. Gastrointestinal mucormycosis is thought to occur following ingestion of spores, and cutaneous mucormycosis is a consequence of direct inoculation of traumatized skin. Alteration of macrophage and neutrophil function secondary to diabetic ketoacidosis and corticosteroids allows the initial sporulation and filamentous growth. Once tissue invasion is achieved in a susceptible host, the disease can progress at an alarming rate or be quite indolent. Angioinvasion by hyphal elements is common and results in ischemic and hemorrhagic necrosis.

Figure 75-4. Culture specimen of Mucor sp., showing irregular hyphae without septation. The fruiting body of Mucor sp. is also present (× 800, lactophenol cotton blue mount).



Rhinocerebral mucormycosis occurs most commonly in patients with uncontrolled diabetes, especially after an episode of diabetic ketoacidosis. It may also occur in leukemic patients who have had prolonged neutropenia and therapy with broad-spectrum antibiotics and occasionally in organ transplant recipients.

Clinical Findings

  1. Signs and Symptoms.The earliest symptoms in rhinocerebral mucormycosis are facial pain, headache, and nasal stuffiness. As the disease progresses, orbital pain and facial anesthesia may be noted. Double vision or loss of vision may develop after invasion of the orbit by the rapidly spreading infection. Mental status changes herald the penetration into the brain with ensuing cavernous sinus thrombosis, carotid artery thrombosis, and cerebral abscess formation. Serial cranial nerve abnormalities, especially of nerves 5 and 7, can occur.

Physical findings include proptosis of the globe and loss of extraocular movement as orbital involvement progresses. Inspection of the nares may reveal black necrotic tissue indicative of angioinvasion and necrosis. A black eschar on the hard palate is a hallmark of mucormycosis.

  1. Laboratory Findings.There are no typical laboratory abnormalities associated with the condition except as noted above. The onset of symptoms may occur during the recovery phase of diabetic ketoacidosis. Most leukemic patients that develop this syndrome do so while still profoundly neutropenic. Cultures of nasal secretions or biopsy specimens are commonly negative even when hyphal elements are present.
  2. Imaging.X-rays of the sinuses are generally insensitive but will demonstrate opacification of one or more sinuses. CT imaging or MRI is an essential part of the evaluation. Bony destruction can be found where disease has extended into the orbit, the mouth, or the central nervous system.
  3. Differential Diagnosis.Few other conditions are able to produce the syndrome of rhinocerebral mucormycosis in the appropriate patient population. Invasive Aspergillusor Fusarium sinusitis may cause a similar syndrome, particularly in the neutropenic leukemic patient.

Pulmonary mucormycosis occurs most commonly in patients with prolonged neutropenia due to chemotherapy for the treatment of leukemia or malignancy. Most of the patients have had antecedent prolonged courses of broad-spectrum antibiotics. It occurs less commonly in diabetic patients and tends to be less fulminant in this setting.

  1. Signs and Symptoms.The onset of symptoms may be subacute to acute to fulminant. Most patients are critically ill and toxic appearing. Respiratory localization is evident based on the common occurrence of cough and shortness of breath. Pleuritic pain and hemoptysis are common. Fever is usually present and may have an abrupt spiking onset. Physical findings may be absent or reflect focal pulmonary infection.
  2. Laboratory Findings.Hypoxemia may be present depending on the extent of pulmonary involvement. Sputum cultures may grow an agent of mucormycosis or may be negative.
  3. Imaging.Chest x-ray may reveal unifocal or multifocal infiltrates or nodules. As the disease progresses, cavitation is very common.
  4. Differential Diagnosis.Mucormycosis may simulate other opportunistic fungal infections involving the lung such as invasive pulmonary aspergillosis. At the onset of symptoms, pulmonary mucormycosis can resemble pulmonary embolization caused by the presence of dyspnea, hemoptysis, and pleuritic chest pain.
  5. Complications.Hematogenous dissemination of infection, particularly in the fulminant form of disease is common. Frequent sites of dissemination include the central nervous system, gastrointestinal tract, spleen, kidneys, heart, and liver. Fulminant disease is almost uniformly fatal, and patients rarely survive > 2 weeks.


Mucormycosis endocarditis is a rare infection that occurs in patients with prosthetic valves. Most of the symptoms are caused by embolization from the large valvular vegetations that form. Valve replacement surgery can be curative. Gastrointestinal mucormycosis develops in patients with profound malnutrition. Involvement of multiple sites in the gastrointestinal tract is seen. Abdominal pain and fever are the usual symptoms. Cutaneous mucormycosis can occur by direct inoculation of the skin in patients with burns, diabetes mellitus, or trauma (Figure 75-5). The skin may also be a sight of hematogenous dissemination. Hemodialysis patients receiving desferoxamine therapy for aluminum overload are at increased risk for any form of mucormycosis caused by Rhizopus spp.


The diagnosis of mucormycosis usually requires demonstration of the organism in biopsy specimens (Figure 75-6). In the rhinocerebral form of mucormycosis, nasal specimens are usually satisfactory for establishing the diagnosis. The tendency to angioinvasion and tissue necrosis often produces a black eschar that should suggest a diagnosis from physical findings. Open lung biopsy may be necessary to establish the premortem diagnosis of pulmonary mucormycosis in the absence of sites of hematogenous dissemination that may be sampled. In general, the full-blown clinical syndrome in the appropriate host should suggest the diagnosis. It requires a high index of suspicion in the early stages of infection. Culture of infected material may be negative, but staining of biopsy specimens can show abundant angioinvasive hyphal elements, suggesting the diagnosis.


Figure 75-5. Large black necrotic ulceration on the thigh of a patient with poorly controlled diabetes mellitus. This fatal infection began as a papule and enlarged over 4 weeks.


Figure 75-6. Sinus biopsy specimen in a patient with rhinocerebral mucormycosis. Note the large, aseptate hyphae with irregular branching (× 400, methenamine silver stain).


Once the diagnosis of mucormycosis has been established, the initial approach to therapy should be to correct aggressively any predisposing factors (see Box 75-5). In patients with diabetic ketoacidosis or hyperglycemia, metabolic abnormalities need to be corrected and controlled. Patients receiving immunosuppressive therapy, especially corticosteroids, should have this reduced as much as possible. Antifungal therapy should be instituted with amphotericin B. The duration of therapy should be based on clinical response. The available azoles do not appear to be effective against the agents of mucormycosis. The newer liposomal preparations of amphotericin B are attractive alternatives to standard amphotericin B because of their reduced nephrotoxicity, although they are no more effective than the standard preparation. Amphotericin B toxicity is high in patients with mucormycosis because of the high dose required and underlying patient conditions.

BOX 75-5 Treatment of Mucormycosis in Children and Adults

First Choice

Amphotericin B, 1–1.5 mg/kg/d IV

Second Choice

Lipid formulation ofamphotericin B

Role of Surgery

Débridement required for rhinocerebral form


Azoles appear to be ineffective

In the rhinocerebral form of mucormycosis, aggressive débridement of the involved sinuses, enucleation, and extensive orbital débridement may be necessary. Some patients will require serial débridements that can be quite disfiguring but may improve their chances for survival. Cutaneous mucormycosis should also be aggressively débrided.


Patients with pulmonary mucormycosis, gastrointestinal mucormycosis, or disseminated disease rarely survive. Rhinocerebral infection also has a poor prognosis but with early diagnosis and aggressive surgical and antifungal therapy, survivors have been reported.

Prevention & Control

Fortunately, mucormycosis is rare. There are no proven preventative or prophylactic strategies. Because it is a relatively ubiquitous spore-transmitted fungal infection, many of the strategies used to prevent transmission of Aspergillus spp. may be effective in reducing the transmission of the agents of mucormycosis. It is unknown whether antifungal prophylaxis has any impact on the incidence of mucormycosis.


Andriole V: Infections with Aspergillus species. Clin Infect Dis 1993;17(Suppl 2):S481. (Authoritative overview of the diagnosis and management of aspergillosis.).

Bohme A, et al: Itraconazole for prophylaxis of systemic mycoses in neutropenic patients with haematological malignancies. J Antimicrob Chemother 1996;38(6):953. (Nonrandomized trial of itraconazole prophylaxis, showing no definite benefit in the reduction of Aspergillus infection.)

Denning D: Therapeutic outcome in invasive aspergillosis. Clin Infect Dis 1996;23(3):608. (Comprehensive literature review of the therapeutic response and mortality of invasive aspergillosis.)

Denning D: Treatment of invasive aspergillosis. J Infect 1994;28(Suppl 1):25. (Review of the therapeutic options available for the treatment of aspergillosis.)

DeShazo RD, Chapin K, Swain RE: Fungal sinusitis. N Engl J Med 1997;337(4):254. (State-of-the-art discussion of the spectrum of infection associated with fungal sinusitis.)

Walsh T, et al: Recent progress and current problems in management of invasive fungal infections in patients with neoplastic diseases. Curr Opin Oncol 1992; 4(4):647. (Summary of the progress and challenges in the management of invasive fungal infection in cancer patients.)

Walsh T, et al: Recent advances in the epidemiology, prevention and treatment of invasive fungal infections in neutropenic patients. J Med Vet Mycol 1994;32(Suppl 1):33. (Summary of recent advances in the understanding of the epidemiology of invasive fungal infections in neutropenic patients.)

Warnock D: Fungal complications of transplantation: diagnosis, treatment, and prevention. J Antimicrob Chemother 1995;36(Suppl B):73.