Pediatric Aspergillosis

Ubiquitous saprophytic molds, Aspergillus species are common on decaying material throughout the world. More than 900 species are included in the genus Aspergillus. The agent responsible for more than 90% of human infections is Aspergillus fumigatus. Aspergillus flavus accounts for about 10% of invasive disease; Aspergillus niger and Aspergillus terreus each are responsible for approximately 2% of all invasive diseases. Other pathogens of interest include Aspergillus amstelodami, Aspergillus avenaceus, Aspergillus caesiellus, Aspergillus carneus, Aspergillus clavatus, Aspergillus oryzae, Aspergillus versicolor, and Aspergillus wentii. The most common cause of sinusitis is A flavus; the predominant cause of otomycosis is A niger.

Aspergillus species are characterized by dichotomously branching septate hyphae. Conidiophores are tubular structures arising from the hyphae, and the terminal ends of these widen to form vesicles. Spores or conidia are formed from long chains of sterigmata, which cover these vesicles. Abundant sporulation is demonstrated by every conidial head producing numerous conidia. These conidia are easily airborne, and their small size (ie, 2-3 µm) aids access to the lower respiratory tract. Characteristically, A fumigatus organisms are identified by the morphology of the conidia and conidiophores. A fumigatus organisms have green echinulate conidia produced basipetally from greenish phialides.

In most patients, the respiratory tract is the usual portal of entry and site of infection. Disease is classified by the site involved within the respiratory tract and by the extent of mycelial colonization or invasion of tissue, both of which are influenced by the host's immune status. Allergic disease (eg, allergic sinusitis, asthma, alveolitis) occurs following repeated exposure to Aspergillus conidia or antigens in patients without mycelial colonization or invasion. In contrast, allergic bronchopulmonary aspergillosis (ABPA), aspergilloma, and invasive aspergillosis syndrome involve mycelial growth in the body of the host.

Noninvasive aspergillosis is usually seen in immunocompetent individuals, whereas invasive aspergillosis is seen in immunocompromised patients.[1] Noninvasive disease usually manifests as allergic bronchopulmonary aspergillosis, aspergilloma, and allergic sinusitis, whereas invasive disease can lead to widespread organ involvement, including pulmonary, cerebral, ocular, and cutaneous disease.

The histopathologic/cytopathologic view of invasive aspergillosis from a needle aspiration or biopsy demonstrates septate acutely branching hyphae or spherule formation (filamentous fungi without yeast forms), with evidence of associated tissue damage (either microscopically or unequivocally by imaging). Probable cases of invasive aspergillosis have been defined to include those with a clinically documented site of infection, and a culture from this site positive for Aspergillus species. Clinically documented infection is defined when fever is accompanied by cellulitis, sinusitis, pneumonia, or esophagitis. Possible invasive aspergillosis is defined as a clinically documented infection with undetermined microbiological etiology that did not respond to antibacterial therapy during persistent neutropenia.

Allergic bronchopulmonary aspergillosis

The pathogenesis of ABPA involves allergic reactions to Aspergillus species. Patients with chronic respiratory disease (eg, asthma, cystic fibrosis [CF]) may trap A fumigatus in their tenacious secretions, leading to an immune response that exacerbates their respiratory symptoms. Chronic mucosal colonization with A fumigatus causes elevated immunoglobulin G (IgG) and immunoglobulin E (IgE) levels, which lead to recurrent bronchospasm. ABPA occurs in 1-2% of patients with asthma and in 11% of patients with CF.

Aspergilloma

Aspergilloma is a nonallergic colonization by Aspergillus species in patients who are immunocompetent. Preexisting pulmonary cavities form a nidus for aspergilloma. These include cavities caused by tuberculosis, sarcoidosis, and chronically obstructed paranasal sinuses.

Invasive aspergillosis

Aspergillus disseminates by means of conidia, which disperse readily throughout the environment because of their lightweight. Airborne conidia enter the human host via inhalation or inoculation. An increase in the environmental load of conidia leads to increased risk of disease. Construction or renovation of hospital buildings or demolition of air-handling ducts near hospitals may lead to outbreaks of aspergillosis, especially in patients who are immunocompromised because these actions release concentrated bursts of conidia, which contaminate the surroundings.

Phagocytic cells, including pulmonary macrophages and neutrophils, are the first lines of defense against the conidia that are inhaled into the respiratory tract. Hyphae are destroyed by neutrophils, and macrophages ingest the conidia. This is why patients with immunocompromising conditions (eg, patients preparing for bone marrow transplantation, patients with graft versus host disease or graft rejection) have the highest risk of developing invasive aspergillosis.

Aspergillus species are second only to candida organisms as the cause of opportunistic infections in patients who are immunocompromised. Profound neutropenia (ie, polymorphonuclear leucocytes < 100/μL) and prolonged neutropenia (>12-15 d) create significant risks of patients developing invasive aspergillosis. Patients on corticosteroid therapy, cytotoxic chemotherapy, intravenous drug use, and broad-spectrum antimicrobial therapy also have increased susceptibility to invasive aspergillosis. Allogenic hematopoietic stem cell transplantation (HSCT) recipients are at much higher risk of invasive aspergillosis compared with autologous HSCT recipients, especially in the first month of conditioning regimens, which usually lead to profound neutropenia.

Functional neutrophil defects, including defective oxidative killing, are responsible for invasive aspergillosis that occurs in chronic granulomatous disease. Defects in cell-mediated immunity alone rarely predispose patients to invasive aspergillosis. For example, invasive aspergillosis occurs only in patients with advanced acquired immunodeficiency syndrome (AIDS) when significant neutrophil dysfunction occurs.

In patients who are immunosuppressed, widespread dissemination of Aspergillus is secondary to vascular invasion. This angiotropism is associated with infarction and tissue necrosis. In addition to pulmonary involvement, other sites of infection include the brain, skin, GI tract, kidneys, and peritoneum.

Frequency

United States

Frequency in the United States is similar to international frequency.

International

The incidence of invasive aspergillosis varies according to the underlying condition. The incidence is 19-26% in patients who have undergone heart and lung transplantation, 25-40% in patients with chronic granulomatous disease, 5-24% in patients with acute leukemia, and 3-7% in patients undergoing bone marrow transplantation. ABPA incidence rates are unavailable; however, the frequency of ABPA is increasing because of the increasing incidence of asthma. The incidence of aspergillomas is declining.

Mortality/Morbidity

The mortality rate of invasive aspergillosis ranges from 45-94%. CNS involvement is invariably fatal.

Race

Aspergillosis equally affects all races.

Sex

Aspergillosis equally affects both sexes.

Age

Aspergillosis may affect individuals at any age.

Patient history depends on whether the Aspergillus infection is invasive or noninvasive. Invasive aspergillosis (IA) includes acute and chronic pulmonary aspergillosis, tracheobronchitis, sinusitis, and disseminated disease, such as CNS involvement. Disseminated disease is the more severe manifestation and is defined as involvement of 2 or more contiguous organs.

• Invasive aspergillosis

  • Acute invasive pulmonary aspergillosis: Pulmonary disease occurs in 80-90% of patients with invasive aspergillosis. Fever, dyspnea, nonproductive cough, mild hemoptysis, and pleuritic chest pain are the cardinal clinical manifestations of invasive pulmonary aspergillosis. Severely immunocompromised patients may have no initial symptoms but diagnosis warrants a high index of suspicion.

  • Chronic invasive pulmonary aspergillosis usually occurs in patients with underlying diseases (eg, advanced AIDS, chronic granulomatous disease, sarcoidosis, diabetes mellitus). Patients usually complain of chronic nonproductive cough, often with hemoptysis. Low-grade fever, weight loss, and malaise are also common.

  • Tracheobronchitis caused by Aspergillus species usually occurs in lung transplant recipients and patients with advanced AIDS. Most of these patients experience symptoms including fever, cough, hemoptysis, dyspnea, and chest pain. Occlusion of the airways may result in death if the condition remains undiagnosed and untreated.

  • Patients with sinusitis caused by Aspergillus species usually complain of headache. Other symptoms include fever, cough, epistaxis, nasal discharge, sinus pain, and sore throat.

  • Primary involvement of the skin rarely occurs; the skin is more commonly a secondary site of hematogenous spread from a pulmonary infection. Surgical wounds, burn wounds, vascular catheters, and adhesive dressing applied to the skin may predispose to the development of cutaneous aspergillosis, especially in immunocompromised patients. The usual presentation of skin involvement is the appearance of raised red lesions, which may progress to ulceration and eschar formation.

  • Cerebral involvement almost always occurs in patients who are neutropenic and in those undergoing bone marrow or solid organ transplantation. Patients that are severely immunocompromised usually present with altered mentation and seizures; prognosis is dismal. Fever is uncommon.

  • Patients with Aspergillus endophthalmitis may complain of pain, photophobia, and diminished visual acuity. Most of these patients have no other systemic symptoms. Orbital cellulitis may complicate invasive sinusitis. The patient may present with pain on lateral gaze and diplopia.

• Noninvasive aspergillosis

  • Patients with allergic bronchopulmonary aspergillosis (ABPA) often have histories of worsening respiratory symptoms in association with asthma or cystic fibrosis (CF). ABPA occurs in approximately 11% of patients with CF. The main complaints of these patients are wheezing and cough. As the disease progresses, patients may expectorate mucous plugs containing eosinophils, and they may develop bronchiectasis.

  • Exacerbation and remission characterize the natural history of disease. Progression to respiratory failure may occur occasionally because of irreversible airway obstruction and pulmonary fibrosis. It may mimic pneumonia with mucopurulent bloody sputum, fever, and respiratory distress. Predominant wheezing may be the only manifestation suggesting an exacerbation of bronchial asthma.

  • The staging system developed by Greenberger and Patterson (1986) classifies ABPA into 5 stages, as follows:[2]

    • Stage I (acute): The patient exhibits moderate or severe asthma, a productive cough, and infiltrates on chest radiograph.

    • Stage II (remission): The patient has mild or no asthma following steroid treatment. Serum immunoglobulin E (IgE) levels decline. The patient may remain in Stage II permanently or may progress to further disease.

    • Stage III (recurrent exacerbation): Exacerbation with the appearance of new infiltrates, elevated IgE, and eosinophilia.

    • Stage IV (corticosteroid dependent asthma): Tapering doses of steroids leads to acute exacerbation or recurrence of disease.

    • Stage V (fibrotic lung disease): The diagnosis is based on pulmonary fibrosis on radiograph. Irreversible deterioration in pulmonary function occurs, which cannot improve, even with steroid therapy.

  • Patients with allergic fungal rhinosinusitis usually have symptoms of long-standing sinusitis. The patient may have a history of nasal polyposis, prior nasal surgery, or atopic disease. Rubbery particles composed of tenacious allergic mucin may be expectorated.

  • Aspergillomas may remain asymptomatic until hemoptysis occurs.

Physical signs of aspergillosis include the following:

• Pulmonary

  • Initially, 25-33% of patients with acute invasive pulmonary aspergillosis may have no obvious clinical signs. In some cases, physical findings may reveal a pleural rub.

  • Patients with extensive involvement may be hypoxemic.

  • Pneumothorax is occasionally a presenting feature, and breathing sounds on auscultation may decrease and exhibit hyperresonance on percussion.

  • Patients with chronic granulomatous disease may have local extension into the chest wall, brachial plexus, or vertebral column.

• Cutaneous: Cutaneous lesions present as erythematous papules or nodules, which progressively enlarge, ulcerate, and are covered by a black necrotic crust. Patients with central venous catheter associated aspergillosis may develop hemorrhagic bullous skin lesions. Disseminated disease may lead to multiple papulopustular or macular lesions in the extremities. These lesions may ulcerate with eschar formation.

• Cerebral

  • Severely immunocompromised patients who have cerebral aspergillosis may present with nonspecific findings (eg, altered mental status, seizures).

  • Patients with less immunocompromising conditions are more likely to present with focal features, such as hemiparesis, cranial nerve palsies, or focal seizures.

  • Papilledema and meningeal signs are uncommon.

• Sinusitis

  • Patients with sinusitis usually have dark nasal lesions, with or without nasal discharge.

  • Sinus tenderness, nasal or oral ulceration, and duskiness or necrosis of the nasal septum and inferior turbinates may occur.

  • Facial swelling is unusual, and extension into the brain or orbit may cause proptosis or focal neurological signs (eg, hemiparesis, cranial nerve palsies, focal seizures).

• Eye

  • Retinal examination of patients with fungal endophthalmitis may reveal focal retinitis, vitreitis, and retinal hemorrhage.

  • Periorbital edema and proptosis may occur with orbital cellulitis.

See the list below:

• Patients with granulocytopenia or defects in neutrophil function secondary to underlying illness have increased risk of developing invasive aspergillosis. Other predisposing factors for acquiring invasive aspergillosis include the following:

  • Corticosteroid and cytotoxic chemotherapy

  • Quantitative immunodeficiencies (eg, chronic granulomatous disease)

  • Advanced AIDS

  • Bone marrow transplant

  • Solid organ transplant

  • Graft versus host disease

  • Graft rejection

• ABPA usually occurs in patients with CF or underlying bronchial asthma.

• Aspergilloma usually occurs in preexisting pulmonary cavities such as in cysts caused by tuberculosis or sarcoidosis.

Laboratory studies in patients with aspergillosis include the following:

• Microscopic examination and culture

  • The most common and definitive methods for the diagnosis of aspergillosis are direct microscopic examination and isolation of organism by culture; whenever possible, use both approaches because combining these techniques increases the yield by 15-20% over culture alone.

  • Microscopic examination of potassium hydroxide wet preparations or Gomori methenamine silver histopathological stains provide presumptive evidence of aspergillosis if they reveal dichotomously branched and septate hyphae. Stains such as calcofluor white may increase the sensitivity for microscopy.

  • Other fungi, such as Pseudallescheria boydii and Scopulariopsis species may appear similar to Aspergillus species under microscopy and may be mistaken for aspergillosis. Hence, definitive diagnosis relies on isolating the organism from culture media. Aspergillus can be isolated from culture of specimens (eg, blood, spinal fluid, bronchoalveolar fluid, bronchial lavage fluid, endotracheal aspirates), other fluids (eg, synovial, pleural, peritoneal), bone marrow, and from biopsies of internal organs and nonsterile specimens (eg, skin scrapings, nail, hair, urine, mucosal surfaces).

  • Aspergillus is a thermophilic species that grows easily on most mycologic media. The use of fungal media, such as Sabouraud agar, increases the likelihood of isolation. Fluffy white colonies appear after 36-90 hours on the agar surface.

  • Specialized media, such as Czapek-Dox and malt extract, may be required to confirm the species' identity. Agar dilution and microtiter methods have been used for susceptibility testing against azoles.

  • Definitive diagnosis sometimes is difficult, especially in patients whose invasive aspergillosis (IA) involves nonsterile sites, such as sinuses and the respiratory tract. The reason for this difficulty is that the culture sensitivity of sputum and respiratory tract secretions obtained by bronchoalveolar lavage (BAL) and bronchial washings may vary 50-60%. A positive culture result may also represent simple colonization. Nevertheless, in the appropriate clinical setting, repeated positive BAL culture findings have proven reliable evidence for diagnosis.

  • The isolation of Aspergillus from BAL fluid in patients with immunosuppression is highly indicative of invasive aspergillosis and has a specificity of 97%. For these patients, histological analysis must be combined with culture to confirm a definite diagnosis. For example, BAL culture findings may be combined with positive transbronchial biopsy specimen findings obtained at bronchoscopy.

  • Recovery of Aspergillus species from a sterile site, such as the brain (eg, brain abscess), or from the eye provides a valuable tool for definitively diagnosing invasive aspergillosis. Blood culture results are seldom positive.

• Serology/antigen and polymerase chain reaction (PCR)

  • Although serological tests are not widely advocated to help diagnose invasive aspergillosis, these tests have a role in diagnosing aspergillosis in immunocompetent patients[3] , including those with allergic bronchopulmonary aspergillosis (ABPA) or aspergilloma. In this group of patients, the most commonly used techniques to detect anti-Aspergillus antibodies are double immunodiffusion and counter immunoelectrophoresis. In contrast, results from these tests are unlikely to be positive in an immunocompromised host because neither can elicit a sufficient antibody response.

  • Circulating antigens in the biological fluids, such as galactomannan (GM) and 1-3-beta-glucan, have been used to help diagnose invasive aspergillosis.[4, 5, 6] The US Food and Drug Administration has approved a commercial assay for the diagnosis of invasive fungal infections called the Fungitell assay. The limitations of this assay are that it can be positive in several other invasive fungal infections, including candidiasis and Pneumocystis jiroveci infection.[7, 8]

  • The sandwich enzyme-linked immunosorbent assay (ELISA) test detects as much as 0.5 ng of GM per mL of serum and is currently the most sensitive method.[9] This test has been recently approved by the US Food and Drug Administration (FDA) and is available for use in the United States. A meta-analysis has shown moderate accuracy in immunocompromised patients, especially for those patients with hematological malignancies or hematological transplant recipients.[10]

  • GM is a heat-stable heteropolysaccharide released from aspergillus hyphae during periods of active growth. The negative predictive value of the ELISA test is very good and allows the diagnosis to be made prior to clinical manifestations

  • Aquino et al have described the reasons for false-positive and false-negative results, which are the primary limitation for this test.[9] False-positive results could be attributed to use of antibiotics in the pediatric population, infections caused by penicillin species, autoantibodies, contaminated swabs, bacteremia, and airway colonization by Aspergillus. The quantity of GM released can vary according to the species involved and several non-Aspergillus species can give rise to false-positive GM ELISA reactions. False-negative results could be ascribed to prior exposure to antifungal drugs or a cut-off that is too high.

  • EB-A2 rat monoclonal antibody is used in the presently available commercial ELISA testing for serum; this has detection limit of 0.5-1 ng/mL (10-15 times lower than the previously used tests).

  • GM can also be recovered from urine, cerebrospinal fluid, BAL samples but further testing is warranted to compare sensitivity and specificity prior to widespread use.

  • Animal studies performed by Francesconi et al have shown that combining GM and quantitative PCR (qPCR) may lead to a better diagnostic outcome than either alone.[11] Further studies are warranted in humans though to reach similar conclusions. It could be used as a prognostic indicator; titers of GM have been shown to fall with clinical response to therapy. However, in patients receiving caspofungin, the titers may not be in concordance with response and may be paradoxically high.

  • A probable diagnosis of invasive aspergillosis can be made in a patient with profound neutropenia, radiological evidence, and 2 consecutive positive serum GM test results. Further studies are needed prior to the use of GM assay as a surveillance tool in diagnosing invasive aspergillosis.[12] Use of PCR to detect these antigens in specimens of blood or BAL is also under investigation. One study showed high sensitivity and specificity and good agreement of PCR with the GM assay.

• Other laboratory tests

  • A diagnosis of ABPA often requires fulfillment of the following criteria:

    • Asthma

    • Elevated total serum immunoglobulin E (IgE) level

    • Peripheral blood eosinophilia

    • Precipitating serum antibodies against A fumigatus

    • Proximal bronchiectasis

    • Immediate cutaneous reactivity to A fumigatus antigens or specific serum IgE to A fumigatus, based on radioallergosorbent test (RAST) results

  • ABPA is suggested by an unexplained exacerbation of bronchial asthma. In patients with cystic fibrosis, wheezing, failure of antibiotherapy, and changes in the radiographic findings may suggest ABPA. A possible diagnosis of ABPA may be made with the presence of asthma or eosinophilia. Fleeting pulmonary infiltrates make the diagnosis of probable ABPA, whereas central bronchiectasis makes the diagnosis almost certain. Serologic assessment consistent with ABPA includes precipitins against A fumigatus, positive IgE antibody more than 2 times asthma control, immunoglobulin G (IgG) antibody more than 2 times asthma control, and total serum IgE more than 1000 ng/mL. Diagnosis is established if all 4 serology test results are positive; 3 positive serology test results make the diagnosis very likely. A decline in the serum IgE levels by 50-75% after treatment with prednisone is consistent with the diagnosis of ABPA.

  • Allergic fungal rhinosinusitis is diagnosed by the demonstration of type 1 hypersensitivity, presence of nasal polyps, characteristic CT scan findings (central areas of hyperattenuation within the sinus cavity), positive fungal stain or culture, and allergic mucin with fungal elements and no tissue invasion.

See the list below:

• Pulmonary

  • For patients with immunocompromise, perform a detailed radiographic evaluation, consisting of chest radiography and CT scans, within 24 hours after suspecting an invasive aspergillosis diagnosis.

  • Plain film chest radiography may reveal pleural-based wedge-shaped lesions and cavitations, which are characteristic of invasive pulmonary aspergillosis.

  • CT scanning is a valuable adjunct for early diagnosis of invasive aspergillosis. A characteristic early finding on CT scan is the halo sign, which consists of ground glass attenuation surrounding a soft tissue nodule. The halo sign is caused by hemorrhage around the central necrotic nodule. With cavitation of this nodule, an air crescent sign may subsequently develop. A halo sign on CT scan, combined with positive Aspergillus antigen test results, supports a diagnosis of invasive pulmonary aspergillosis.

• Sinuses

  • Characteristic CT scan findings include unilateral involvement of several sinuses, absence of air fluid levels, and smooth thickened sinus linings.

  • MRIs of the sinuses are a useful adjunct tool for early invasive aspergillosis diagnosis. Fluid opacification of the sinuses is characteristic.

• Cerebral: CT scans may reveal brain abscess with ring enhancement or infarction with contrast enhancement.

See the list below:

• If invasive pulmonary aspergillosis is strongly suspected in patients with diffuse disease and bilateral consolidation, bronchoscopy and bronchial biopsy can be used to help establish the diagnosis.

• In patients with peripheral pulmonary lesions, consider a needle biopsy or surgical resection because of difficult access through bronchoscopy.

• Perform invasive procedures with care in patients who are debilitated and neutropenic.

See the list below:

• Histological section of tissues obtained by biopsy reveals a characteristic pattern that may help diagnose aspergillosis. Fungal mycelia usually have a radiating pattern with invasion of the surrounding blood vessels. Features suggestive of Aspergillus species in biopsy specimens include dichotomously branching hyphae at 45° angles, uniform mycelial width, and septate hyphae.

• Extensive tissue necrosis with hemorrhagic infarction may be apparent at the infection site.

A study by Koo et al reported that an Aspergillus secondary metabolite signature in the patients’ breath can identify individuals with invasive aspergillosis in patients suspected of fungal pneumonia.[13, 14]

Aspergillosis treatment is based on the disease manifestation, which includes invasive disease in an immunocompromised host or allergic disease that includes allergic bronchopulmonary aspergillosis (ABPA) and colonizing syndromes (eg, aspergilloma, otomycosis) in an immunocompetent host.

• When invasive aspergillosis (IA) is strongly suspected in an immunocompromised patient, empiric treatment with antifungal medications is the consensus therapy. Suspicion may be based on the clinical course of the illness, isolation of the fungus from the pulmonary and/or nasopharyngeal secretions, and failure to respond to initial antibacterial treatment. If a patient with profound neutropenia does not respond to broad spectrum antibiotics within 5-7 days, empiric treatment for invasive aspergillosis with antifungals is indicated.

• Voriconazole has now become the drug of choice for invasive aspergillosis. This is due to the increased efficacy and significantly less toxicity compared to amphotericin B.

• Caspofungin is a newer antifungal agent that is effective against invasive aspergillosis but more pediatric studies are needed prior to its widespread use. Currently caspofungin has been approved for use as salvage therapy for invasive aspergillosis that does not respond to existing antifungals.

  • Treatment duration has not been well defined and is based on the clinical response and the tolerance to the drug. Continue therapy 4-12 weeks or longer.

  • Itraconazole is used as prophylaxis in some cancer centers for immunocompromised patients.

• ABPA exacerbations are treated with corticosteroids.[15]

  • The desired goal is to reduce serum immunoglobulin E (IgE) levels to a range consistent with levels obtained from patients with asthma (without ABPA) living in the same geographic area. Reinstitution of corticosteroid therapy may be required if the serum IgE levels rise to twice this level or higher.[16]

  • Immediately obtain IgE levels after corticosteroid therapy.

• For asthma exacerbation, as indicated, administer other agents, such as beta-adrenergic agonists, high-dosage inhaled corticosteroids, and, possibly, nedocromil or theophylline.

• Administer prednisone as a single morning dose for 2 weeks and then convert to an alternate-day dosage for 3 months.

• Systemic antifungal therapy is not indicated for ABPA.

See the list below:

• Invasive aspergillosis requires surgical care in the following situations:

  • In invasive pulmonary aspergillosis, resection of the fungal lesion is indicated when the lesion in localized, and or if disease is likely to cause perforation of the pulmonary artery with consequent hemoptysis.

  • In immunocompromised patients, resection and surgical reduction of the Aspergillus mass is indicated before myeloablative procedures.

  • In patients with osteomyelitis, surgical intervention, including thorough debridement, may help chronic invasive sinusitis and cutaneous lesions.

• Surgical care is recommended in patients with aspergilloma only when severe hemoptysis occurs.

  • Resection is the mainstay therapy for patients with adequately functioning lungs, although bronchial artery embolization may be considered for patients who are not candidates for resectional surgery.

  • Systemic antifungal therapy is not indicated in patients with nonallergic colonization.

The Infectious Diseases Society of America (IDSA) published practice guidelines on the management of aspergillosis and recommended using the same antifungal agents for treatment of aspergillosis in children as are used in adults. However, the guidelines added that dosing of many of these agents may be different for children. The authors also note that although voriconazole is only approved by the US Food and Drug Administration for children aged 12 yr and older, it is the cornerstone of aspergillosis treatment in children of all ages.[17, 18]

The guidelines also include the following recommendations[17, 18] :

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

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

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

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

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

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

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

• Aerosolized formulations of AmB may be considered as prophylaxis in patients with prolonged neutropenia (patients receiving induction/reinduction therapy for acute leukemia and allogeneic HSCT recipients following conditioning or during treatment of graft-vs-host disease [GVHD]) and in lung transplant recipients.

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

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

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

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

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

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

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

Voriconazole is now the drug of choice for the treatment of invasive aspergillosis (IA). Although disease outcomes substantially improve with antifungal treatment, patient survival and infection resolution depend on improved immunosuppression. Response rates are low if the patient remains neutropenic. Voriconazole has shown a good outcome in 34% of patients with cerebral aspergillosis, which was previously associated with a high mortality. Caspofungin is an echinocandin that is primarily used as a salvage drug either alone or in combination with amphotericin B lipid preparations.

Amphotericin B has a broad antifungal spectrum but has limited use in view of significant nephrotoxicity and dose-limiting side effects. Various amphotericin B lipid preparations are available to help reduce nephrotoxicity. Lipid preparations of amphotericin B (ABLC, Abelcet) are approved by the FDA to treat invasive fungal infections in patients who are intolerant or refractory to conventional amphotericin (ie, deoxycholate). Amphotericin B cholesteryl sulfate complex (Amphotec) and the liposomal formulation of amphotericin B (AmBisome) have received FDA approval for the treatment of invasive aspergillosis in patients who cannot tolerate or who fail to respond to conventional amphotericin B deoxycholate. These lipid formulations are picked up preferentially by the reticuloendothelial system and are broken down by lipases locally at the site of infection.[19]

Caspofungin and voriconazole combinations have also shown to be successful as salvage drug therapy for invasive aspergillosis. Posaconazole is a new triazole that was recently approved by the FDA. Itraconazole has a status of a prophylaxis drug and is used in neutropenic patients in several centers. Steroid administration is the mainstay treatment for allergic bronchopulmonary aspergillosis (ABPA).

Class Summary

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

The azole group of drugs, including voriconazole, inhibit the cytochrome P450 (CYP)-dependent enzyme, 14-a-demethylase, which leads to the accumulation of toxic sterol precursors. Echinocandins (eg, caspofungin) inhibit synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.

Voriconazole (VFEND)

Used for primary treatment of invasive aspergillosis and salvage treatment of Fusarium species or Scedosporium apiospermum infections. A triazole antifungal agent that inhibits fungal CYP450-mediated 14 alpha-lanosterol demethylation, which is essential in fungal ergosterol biosynthesis.

Amphotericin B (Amphocin, Fungizone)

Polyene antibiotic produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal. Binds to sterols in the fungal cell membrane, such as ergosterol, causing intracellular components to leak and the subsequent death of fungal cell.

Amphotericin B lipid complex (Abelcet) - - Amphotericin B liposome (AmBisome)

FDA approved to treat invasive fungal infections in patients who are intolerant to or refractory to conventional amphotericin therapy.

Itraconazole (Sporanox)

Fungistatic activity. Synthetic triazole antifungal agent that slows fungal cell growth by inhibiting CYP450–dependent synthesis of ergosterol. Used alone as an alternative treatment for nonmeningeal cases and for patients who are intolerant of or whose infections are refractory to amphotericin B therapy.

Caspofungin (Cancidas)

Used to treat refractory invasive aspergillosis. First of a new class of antifungal drugs (glucan synthesis inhibitors). Inhibits synthesis of beta-(1,3)-D-glucan, an essential component of fungal cell wall.

Posaconazole (Noxafil)

Triazole antifungal agent. Blocks ergosterol synthesis by inhibiting the enzyme lanosterol 14-alpha-demethylase and sterol precursor accumulation. This action results in cell membrane disruption. Available as PO susp (200 mg/5 mL). Indicated for prophylaxis of invasive Aspergillus and Candida infections in patients at high risk due to severe immunosuppression.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. These agents also modify the body's immune response to diverse stimuli.

Prednisone (Deltasone, Orasone, Meticorten, Sterapred)

Immunosuppressant for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity.

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• Patients who continue to undergo treatment with oral or intravenous antifungal medications require periodic follow-up care as outpatients.

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• Patients with aspergillosis who have concomitant underlying illness may need additional medical care.

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• Transfer to an ICU for close monitoring for patients with acute invasive pulmonary aspergillosis who develop complications such as hemoptysis.

• Patients with cerebral aspergillosis and patients with invasive aspergillosis (IA) who are severely immunocompromised require frequent monitoring and assessment.

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• Because Aspergillus conidia are usually acquired from the environment, measures to reduce exposure to conidia are essential to prevent disease transmission. An effective method of protecting immunocompromised patients is to confine them to a room with sterile laminar airflow.

• Episodic outbreaks of invasive aspergillosis have been documented in hospitalized immunosuppressed patients during construction in hospitals. To prevent this, installation of barriers between patient care areas and construction sites, cleaning of airflow systems, repairing faulty airflow meters help reduce the spread of aspergillosis.

• Reducing exposure of immunosuppressed patients is one of the most important preventive strategies. High-risk patients should be isolated in rooms equipped with high-efficiency particulate air filters. An antifungal powder, aerosolized copper-8-quinolinolate, has been used to control spread.

• Prophylactic antifungal therapy, such as amphotericin B nasal spray, may be effective in controlling respiratory and sinus colonization. The use of itraconazole and voriconazole as prophylactic agents have shown to be beneficial in some studies to protect granulocytopenic patients from invasive aspergillosis. Trials regarding the use of intravenous itraconazole and cyclodextrin oral solution for the prophylaxis of aspergillosis are in progress. No regimen has been reported to be clearly effective in the prophylaxis of aspergillosis, and further studies are required before recommendations can be made.

• Recommendations for effective patient isolation by the Centers for Disease Control and Prevention include the following:

  • Provide a minimum of 15 air changes per hour in sealed rooms.

  • Filter air with high-efficiency particulate air (HEPA) filters, which remove more than 95% of particles 0.3 µm and larger.

  • Maintain higher (ie, positive) air pressure inside the room than pressures outside.

  • Provide directed airflow within the patient's room.

• HEPA filter masks can be fitted to patients as young as 5 years and can be used during patient transport.

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• Erosion of a major pulmonary artery caused by angiotropism of the Aspergillus species may lead to severe hemorrhage.

• Fungal and necrotic debris obstructing the airway may cause fatality in patients with pseudomembranous tracheobronchitis.

• Disseminated intravascular coagulation and jaundice may be complications of disseminated aspergillosis.

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• Of all forms of invasive aspergillosis, the worst prognosis is for patients with cerebral involvement; most die despite appropriate systemic antifungal therapy.

• Bilateral diffuse disease usually occurs in patients with an allogenic bone marrow transplant, and patients with this condition have a worse prognosis than patients with focal nodular disease.

• Patients with AIDS usually have a poor prognosis if invasive aspergillosis develops.

• Poor prognoses are also associated with evidence of angioinvasion, continued immunosuppression, persistent neutropenia, leukemia relapse, and delayed or suboptimal therapy.

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• Patients at risk should be counseled to avoid exposure to Aspergillus organisms.

  • Educate patients, especially those with granulocytopenic conditions, about measures to reduce exposure to conidia, including instructions to avoid areas under construction.

  • Emphasize to patients who have immunosuppression the importance of wearing a fitted HEPA mask while in nonprotected areas to avoid contact with airborne conidia.

• For excellent patient education resources, see eMedicineHealth's patient education article Bronchoscopy.