Michael R. Keating MD
ASPERGILLUS INFECTION
Essentials of Diagnosis
General Considerations
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.
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.
CLINICAL SYNDROMES
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
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BOX 75-1 Aspergillus Infection |
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Diagnosis
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.
Treatment
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.
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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). |
Prognosis
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.
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BOX 75-2 Treatment of Aspergillus Infection in Children and Adults |
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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.
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BOX 75-3 Control and Prevention of Nosocomial Invasive Aspergillus spp. in Immunosuppressed Patients |
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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
Diagnosis
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
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.
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Figure 75-2. Nonenhanced high-resolution chest CT showing a large aspergilloma in a patient with bronchiectasis of the right lung. |
Prognosis
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
Diagnosis
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
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.
Diagnosis
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
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.
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Table 75-1. Diagnostic criteria for allergic bronchopulmonary aspergillosis. |
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Prognosis
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
Diagnosis
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.
Treatment
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).
Prognosis
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.
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.
Diagnosis
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
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.
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Table 75-2. Clinical aspects of Aspergillus sinusitis. |
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Prognosis
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.
PSEUDALLESCHERIA BOYDII INFECTION
Essentials of Diagnosis
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.
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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). |
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
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.
Treatment
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.
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BOX 75-4 Treatment of Pseudallescheriosis |
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MUCORMYCOSIS
Essentials of Diagnosis
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.
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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). |
CLINICAL SYNDROMES
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
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.
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.
4. OTHER FORMS OF MUCORMYCOSIS
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.
Diagnosis
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.
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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. |
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Figure 75-6. Sinus biopsy specimen in a patient with rhinocerebral mucormycosis. Note the large, aseptate hyphae with irregular branching (× 400, methenamine silver stain). |
Treatment
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.
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BOX 75-5 Treatment of Mucormycosis in Children and Adults |
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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.
Prognosis
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.
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