Aspergillosis

• Sajeev Handa, M.D.

 Basic Information

Definition

Aspergillosis refers to several forms of a broad range of illnesses caused by infection with Aspergillus species. Fig. 1 illustrates the spectrum of Aspergillus infection.

ICD-10CM CODES
B44.0	Invasive pulmonary aspergillosis
B44.1	Other pulmonary aspergillosis
B44.2	Tonsillar aspergillosis
B44.7	Disseminated aspergillosis
B44.81	Allergic bronchopulmonary aspergillosis
B44.89	Other forms of aspergillosis
B44.9	Aspergillosis, unspecified

Epidemiology & Demographics

Incidence & Prevalence

1. •

   Aspergillus species are ubiquitous in the environment internationally and occur as a mold found in soil.

2. •

   Cause a variety of illness from hypersensitivity pneumonitis to disseminated overwhelming infection in immunosuppressed patients.

3. •

   Frequently cultured from hospital wards from unfiltered outside air circulating through open windows as well as water sources.

4. •

   Reach the patient by airborne conidia (spores) that are small enough (2.5 to 3 μm) to reach the alveoli on inhalation.

5. •

   Can invade the nose, paranasal sinuses, external ear, or traumatized skin.

Risk Factors

1. •

   The clinical syndrome depends on the underlying lung architecture, the host’s immune response, and the degree of inoculum.

2. •

   Incidence of invasive aspergillosis is increasing with advances in the treatment of life-threatening diseases, such as aggressive chemotherapy or bone marrow and organ transplantation. It also can rarely occur in normal hosts, especially associated with influenza A. Liver and lung transplant recipients are at highest risk for pulmonary disease. Genetic deficiency of the soluble-pattern-recognition receptor known as long pentraxin 3 (PTX3) affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with hematopoietic stem-cell transplantation (HSCT).

3. •

   Patients with AIDS and a CD4 count <50/mm³ have an increased susceptibility to invasive aspergillosis, but it is otherwise uncommon in patients with HIV.

4. •

   Pandemic influenza A (H1N1) infection may predispose immunocompromised patients to invasive aspergillosis.

5. •

   Patients with chronic granulomatous disease are at higher risk for infections with Aspergillus species.

Etiology

1. •

   A. fumigatus is the usual cause.

2. •

   A. flavus is the second most important species, particularly in invasive disease of immunosuppressed patients and in lesions beginning in the nose and paranasal sinuses. A. niger can also cause invasive human infection.

Allergic Aspergillosis

1. •

   Is a hypersensitivity pneumonitis.

2. •

   Presents as cough, dyspnea, fever, chills, and malaise typically 4 to 8 hr after exposure.

3. •

   Repeated attacks can lead to granulomatous disease and pulmonary fibrosis.

Allergic Bronchopulmonary Aspergillosis (ABPA)

1. •

   Symptoms occur most commonly in atopic individuals during the third and fourth decades of life.

2. •

   Hypersensitivity reaction to Aspergillus fungal antigens present in the bronchial tree.

3. •

   Results from an initial type I (immediate hypersensitivity) and type III reactions (immune complexes).

4. •

   Underdiagnosed pulmonary disorder in patients with asthma and cystic fibrosis (reported prevalence in asthmatic patients varies from 6% to 28% and in cystic fibrosis 6% to 25%).

Aspergillomas (“Fungus Balls”)

1. •

   In the absence of invasion or significant immune response, Aspergillus can colonize a preexisting cavity, causing pulmonary aspergilloma.

2. •

   Forms masses of tangled hyphal elements, fibrin, and mucus.

3. •

   Patients typically have a history of chronic lung disease, tuberculosis, sarcoidosis, or emphysema.

4. •

   Manifests commonly as hemoptysis.

5. •

   Many are asymptomatic.

Invasive Aspergillosis

1. •

   Patients with prolonged and profound granulocytopenia or impaired phagocytic function are predisposed to rapidly progressive Aspergillus pneumonia.

2. •

   Typically a necrotizing bronchopneumonia, ranging from small areas of infiltrate to intensive bilateral hemorrhagic infarction.

3. •

   Most common presentation: unremitting fever and a new pulmonary infiltrate despite broad-spectrum antibiotic therapy in an immunosuppressed patient.

4. •

   Dyspnea and nonproductive cough are common; sudden pleuritic pain and tachycardia, sometimes with a pleural rub, may mimic pulmonary embolism; hemoptysis is uncommon.

5. •

   Chest radiograph (CXR) may reveal patchy bronchopneumonic, nodular densities, consolidation, or cavitation. High-resolution CT scan is more sensitive and specific than CXR in neutropenic patients.

6. •

   Immunocompromised patients: invasive pulmonary Aspergillus (IPA) generally is acute and evolves over days to weeks; less commonly, patients with normal or only mild abnormalities of the immune system may develop a more chronic, slowly progressive form of IPA.

Extrapulmonary Dissemination

1. •

   Cerebral infarction from hematogenous dissemination may occur in immunosuppressed individuals.

2. •

   Abscess formation from direct extension or invasive disease in the sinuses.

3. •

   Esophageal or gastrointestinal ulcerations may occur in the immunosuppressed host.

4. •

   Fatal perforation of the viscus or bowel infarction may occur.

5. •

   Necrotizing skin ulcers (Fig. 2).

   

6. •

   Osteomyelitis.

7. •

   Endocarditis in patients who have recently undergone open heart surgery.

8. •

   Infection of an implantable cardioverter-defibrillator has been reported.

Diagnosis

Differential Diagnosis

1. •

   Tuberculosis

2. •

   Cystic fibrosis

3. •

   Carcinoma of the lung

4. •

   Eosinophilic pneumonia

5. •

   Bronchiectasis

6. •

   Sarcoidosis

7. •

   Lung abscess

Workup

Physical examination and laboratory data

Laboratory Tests

ABPA

1. •

   Peripheral blood eosinophilia and an elevated total serum immunoglobulin E (IgE) level.

2. •

   Skin test with Aspergillus antigenic extract is usually positive but nonspecific.

3. •

   Aspergillus serum precipitating antibody is present in 70% to 100% of cases.

4. •

   Sputum cultures may be positive for Aspergillus spp. but are nonspecific.

Aspergillomas

1. •

   Sputum culture

2. •

   Serum precipitating antibody

Invasive aspergillosis: definitive diagnosis requires the demonstration of tissue invasion (i.e., septate, acute angle branching hyphae) or a positive culture from the tissue obtained by an invasive procedure such as transbronchial biopsy.

1. •

   Sputum and nasal cultures: in high-risk patients a positive culture is strongly suggestive of invasive aspergillosis.

2. •

   Serology: the Platelia Aspergillus ELISA assay detects a circulating fungal antigen, galactomannan. Galactomannan is a polysaccharide contained in the cell wall of Aspergillus. Its presence in serum or other body fluids is indicative of invasive infection, and it is recommended as an accurate marker for diagnosis in certain patient subpopulations (hematologic malignancy and hematopoietic stem cell transplantation). The β-D glucan assay can also be used to detect early infection, but is not specific for Aspergillus species.^a

3. •

   Blood cultures: usually negative.

4. •

   Lung biopsy is necessary for definitive diagnosis.

5. •

   Biopsy and culture of extrapulmonary lesions.

6. •

   Polymerase chain reaction assays may be employed, but their results should be interpreted in conjunction with other diagnostic tests and the clinical context.

Imaging Studies

ABPA

1. •

   CXRs show a variety of abnormalities, from small, patchy, fleeting infiltrates (commonly in the upper lobes) to lobar consolidation or cavitation.

2. •

   A majority of patients eventually develop central bronchiectasis.

Aspergillomas

CXR or CT scans usually show the characteristic intracavity mass (Figs. 3 and 4) partially surrounded by a crescent of air (“halo sign”).

Invasive Aspergillosis

CXR and CT scanning may also reveal cavity formation and the halo sign. Air bronchograms typically disappear as they are filled with hemorrhagic fluid.

Treatment

Acute General Rx

ABPA

1. •

   Prednisone (0.5 to 1 mg/kg PO) until the CXR has cleared, followed by alternate-day therapy at 0.5 mg/kg PO (3 to 6 mo).

2. •

   If a patient is corticosteroid dependent, prophylaxis for the prevention of Pneumocystis jiroveci infection and maintenance of bone mineralization should be considered.

3. •

   Bronchodilators and physiotherapy.

4. •

   Serial CXR and serum IgE is useful in guiding treatment.

5. •

   Itraconazole 200 mg PO bid for 4 to 6 mo, then taper over 4 to 6 mo may be considered as a steroid-sparing agent or if steroids are ineffective.

Aspergillomas

1. •

   Controversial and problematic; the optimal treatment strategy is unknown.

2. •

   Up to 10% of aspergillomas may resolve clinically without overt pharmacologic or surgical intervention.

3. •

   Observation for asymptomatic patients.

4. •

   Surgical resection/arterial embolization for those patients with severe hemoptysis or life-threatening hemorrhage.

5. •

   For those patients at risk for marked hemoptysis with inadequate pulmonary reserve, consider itraconazole 200 to 400 mg/day PO.

Invasive Aspergillosis (IA)

1. •

   Voriconazole 6 mg/kg IV/PO bid on day 1 followed by 4 mg/kg IV/PO bid. Voriconazole serum concentrations need to be monitored to achieve a target range of 1.0 to 5.5 mg/L (trough on day 4).

2. •

   Isavuconazole 200 mg (which equals 372 mg of prodrug isavuconazonium sulfate) IV/PO tid for six doses and then 200 mg PO/IV daily.

Alternative Treatment:

1. •

   Amphotericin B lipid complex (ABLC) 5 mg/kg IV daily.

2. •

   Liposomal amphotericin B (L-AMB) 3 to 5 mg/kg IV daily.

3. •

   Posaconazole 200 delayed-release tabs 300 mg PO for two doses, then 300 mg PO daily or posaconazole suspension 200 mgs qid, then 400 mg po bid after stabilization of disease or posaconazole 300 mg IV over 90 minutes bid for one day, then 300 mg IV daily.

4. •

   Because azoles and echinocandins target different cellular sites, combination therapy may have additive activity against Aspergillus species. Although still under investigation, some bone marrow transplant units use caspofungin and voriconazole as the preferred initial treatment, especially in patients receiving high-dose corticosteroids. Recent trials (Marr et al., 2015) have shown that compared with voriconazole monotherapy, combination therapy with anidulafungin, and echinocandin antifungal drug that blocks the synthesis of (13)β-D glucan led to higher survival in subgroups of patients with IA.

Referral

To an infectious diseases specialist

Pearls & Considerations

1. •

   Unlike fluconazole, the potential for drug-drug interactions with voriconazole is high. Azoles may interact with drugs used for chemotherapy by increasing toxicity and/or by reducing efficacy.

2. •

   Agitation of hospital buildings by renovations or repairs may increase the incidence of Aspergillus infections in immunosuppressed individuals.

3. •

   Echinocandins should never be used as primary treatment of aspergillosis.

4. •

   Aspergillus and Nocardia species may co-infect.

Suggested Readings

• C. Cunha, et al.: Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. N Engl J Med. 370:421–432 2014 24476432

• C. Garcia-Vidal, et al.: Invasive aspergillosis complicating pandemic Influenza A (H1N1) infection in severely immunocompromised patients. Clin Infect Dis. 53 (6):e16–e19 2011 21865184

• K.A. Marr, et al.: Combination antifungal therapy for invasive aspergillosis, a randomized trial. Ann Intern Med. 162:81–89 2015 25599346

• Miceli MH, Kauffman CA: Aspergillus galactomannan for diagnosing invasive aspergillosis, JAMA 318(12):1175

• T.F. Patterson, et al.: Practice guidelines for the diagnosis and management of aspergillosis: 2016 update by the Infectious Diseases Society of America. Clin Infec Dis. 2016:63 2016

Related Content

Aspergillosis (Patient Information)