A. Species

1. 132 distinct species; 18 variants
2. Aspergillus fumigatus is the etiologic agent >80% of human Asperillus infections
   1. Recently, a specific allergen / cytotoxin has been isolated from this species
   2. This toxin, Asp fI, is not expressed by other species of aspergillus
3. A. flavus, nidulans, niger and terreus are occasional pathogens
4. Increasing incidence and mortality due to effective treatment of other fungal infections

B. Disease Entities [8]

1. Asthma
   1. Marked wheezing
   2. Often with tracheobronchitis
   3. Hypersensitivity pneumonitis may also occur
2. Allergic bronchopulmonary aspergillosis (APBA) [1,13]
   1. Eosinophilia (peripheral blood)
   2. Hyper-IgE response
   3. Associated with mutations in cystic fibrosis chloride channel [10]
   4. Bronchial hyperreactivity often with asthma diagnosis
   5. Sinusitis and hemoptysis can occur
   6. May have flares with severe exacerbations with wheezing
   7. Infiltrates, often in upper lobes on chest radiograph (CXR)
   8. Histologically may show bronchiolitis obliterans
   9. Stages: acute, remission, exacerbation/recurrence, asthma, end-stage fibrosis
3. Aspergilloma
   1. Colonization of pre-existing bullous lesion
   2. Frequently seen in COPD (emphysemia) with bullae
   3. May also follow destructive pneumonia with cavitary lesions, including TB infection
   4. Most common cause of fungal sinusitis; usually non-invasive [2]
4. Invasive Aspergillosis [3,8,11]
   1. Immunocompromised patients are major group with invasive disease
   2. Highest risk patients - hematologic malignancies, granulocytopenia, hemapoietic stem cell transplantation, immunodeficiency diseases, chronic granulomatous disease [16]
   3. Organ transplantation, chronic glucocorticoid use, and HIV are other risk factors
   4. Invasive lung disease, sinus infection, dissemination to brain can occur [1]
   5. Chronic necrotizing pulmonary aspergillosis is more localized variant
   6. Chronic necrotizing form is likely contained by immunological response
   7. May colonize bronchocentric granulomatosis

C. Diagnosis [4]

1. Consider diagnosis in all patients with poor response to potent anti-bacterials
2. Aspergillus in sputum of immunocompromised patients predicts high risk of invasion
   1. In patients at low risk of invasive disease, positive sputum often means colonization
   2. If eosinophils are present in large numbers, ABPA may be present
3. At least 3 sputum specimens should be evaluated if fungal infection is suspected
   1. Lower respiratory tract sputum samples may be more helpful
   2. Fungal culture media is more sensitive than bacterial media for Aspergillus
4. Commercial enzyme immunoassay to detect aspergillus cell wall available
5. Polymerase chain reaction (PCR) detection methods have been used successfully
6. Radiographs are variable, but interstitial pattern is most common
7. CBC with differential should be obtained
   1. Attention to eosinophilia
   2. Acute response with marked neutrophilia may occur in invasive forms [8]
8. In patients with bronchial hyperactivity, IgE levels should be obtained
9. Sinus infections are not uncommon and may be less obvious in seriously ill patients [2]

D. Treatment [5,6,14]

1. May require surgical resection
2. Amphotericin B Formulations
   1. Dose of standard amphotericin B deoxycholate (ABD) is 1-1.5mg/kg IV qd, 4-12 weeks
   2. Liposomal, lipid complex, colloidal formulations of amphotericin better tolerated
   3. Voriconazole appears to be as effective and better tolerated than amphotercins
3. Voriconazole (Vfend®) [14,15]
   1. Broad spectrum triazole with good antifungal activity
   2. Includes activity against Aspergillus, Fusarium ssp., Scedosporium
   3. Superior response and survival in primary invasive aspirgillosis compared with ABD [15]
   4. Parenteral: 6mg/kg IV q12 hours x 2 doses, then 4mg/kg IV q12 hours
   5. Oral: 200mg (>40kg) or 100mg (<40kg) po q12 hours
   6. Maintain oral dosing as long as required
   7. Main side effects are visual symptoms (30%) and hallucinations (5%)
   8. Far better tolerated than ABD
4. Itraconazole (Sporanox®) [7]
   1. Itraconazole 200mg po bid x 6-12 weeks
   2. Much better tolerated than amphotericin but may be slightly less effective
   3. Reasonable to try this agent as a second line therapy, or following amphotericin
5. Caspofungin (Cancidas®) [12]
   1. Echinocandin class of antifungal
   2. Approved for aspirgillosis unresponsive to amphotericin or itraconazole
   3. Blocks synthesis of ß(1,3)-d-glucan found in fungal cell wall
   4. Activity against aspirgillus and candida species, as well as pneumocystis carinii
   5. Little activity against cryptococcus or mucor species
   6. Fever, rash, nausea, vomiting and phlebitis are side effects
   7. Dose is 70mg on day 1, 50mg thereafter, intravenous infusion over 1 hour
   8. Reduce dose to 35mg maintenance per day with hepatic failure
   9. No dose adjustment for renal failure
6. Treatment of ABPA
   1. Systemic glucocorticoids are mainstay of therapy
   2. Prevent exacerbations and lung inflammation
   3. ß-adrenergic agonists may be helpful
   4. Addition of itraconazole 200mg po bid for 16 weeks to standard treatment led to reduction in glucocorticoid doses by 50% in about half of the patients [9]
   5. Itraconazole also leads to reduction in IgE concentrations [9]

References

1. Thaler SJ and Bailey EM. 1996. NEJM. 334(19):1254 (Case Report)
2. DeShazo RD, Chapin K, Swain RE. 1997. NEJM. 337(4):254
3. Patterson TF. 2005. Lancet. 366(9490):10132
4. Horvath JA and Dummer S. 1996. Am J Med. 100(2):171
5. Denning DW, Lee JY, Hostetler JS, et al. 1994. Am J Med. 97(2):135
6. Itraconazole. 1994. Med Let. 36(916):18
7. Stevens DA and Lee JY. 1997. Arch Intern Med. 157(16):1857
8. Kradin RL and Mark EJ. 1998. NEJM. 339(17):1228 (Case Record)
9. Stevens DA, Schwartz HJ, Lee JY, et al. 2000. NEJM. 342(11):756
10. Super M. 2000. Lancet. 355(9218):1840
11. Rochester CL and Kradin RL. 2000. NEJM. 343(25):1876 (Case Record)
12. Caspofungin. 2001. Med Let. 43(1108):58
13. Beamis JF and Mark EJ. 2001. NEJM. 345(6):443 (Case Record)
14. Voriconazole. 2002. Med Let. 44(1135):63
15. Herbrecht R, Denning DW, Patterson TF, et al. 2002. NEJM. 347(6):408
16. Harris JB, Michelow IC, Westra SJ, Kradin RL. 2008. NEJM. 359(2):178 (Case Record)