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Aspergillosis
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Epidemiology

Invasive aspergillosis in the HIV-infected person is rare. It is most frequently caused by Aspergillus fumigatus, although certain cases are caused by A. flavus, A. niger, and A. terreus. Invasive aspergillosis occurs among patients with advanced HIV infection and was more common before the advent of ART (647Mylonakis E, Barlam TF, Flanigan T, Rich JD. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Chest 1998;114:251-62., 648Holding KJ, Dworkin MS, Wan PC, et al. Aspergillosis among people infected with human immunodeficiency virus: incidence and survival. Clin Infect Dis 2000;31:1253-7.). Specific risk factors include neutropenia, use of corticosteroids, exposure to broad-spectrum antibacterial therapy, and previous pneumonia or other underlying lung disease. Patients who have had HIV-associated aspergillosis typically have CD4+ counts <100 cells/µL, a history of other AIDS-defining OIs, and are not receiving ART (649Wallace JM, Lim R, Browdy BL, et al. Risk factors and outcomes associated with identification of Aspergillus in respiratory specimens from persons with HIV disease: Pulmonary Complications of HIV Infection Study Group. Chest 1998;114:131-7.).

Clinical Manifestations

Invasive aspergillosis in the HIV-infected patient is evidenced most commonly as a respiratory illness that can be a necrotizing pneumonia or a tracheobronchitis (650Lortholary O, Meyohas MC, Dupont B, et al. Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. Am J Med 1993;95:177-87.). Symptoms of invasive pneumonia are fever, cough, dyspnea, chest pain, hemoptysis, and hypoxemia; the chest radiograph might demonstrate a diffuse, focal, or cavitary infiltrate. A "halo" of low attentuation surrounding a pulmonary nodule or an "air-crescent" on CT scan of the lung is suggestive of disease. Tracheobronchitis is associated with fever, cough, dyspnea, stridor, and wheezing. Bronchoscopic examination demonstrates multiple ulcerative or plaque-like lesions adherent to the tracheal wall (651Kemper CA, Hostetler JS, Follansbee SE, et al. Ulcerative and plaque-like tracheobronchitis due to infection with Aspergillus in patients with AIDS. Clin Infect Dis 1993;17:344-52.). Extrapulmonary forms of invasive aspergillosis include sinusitis, cutaneous disease, osteomyelitis, and CNS infection (652Mylonakis E, Paliou M, Sax PE, et al. Central nervous system aspergillosis in patients with human immunodeficiency virus infection: report of 6 cases and review. Medicine (Baltimore) 2000;79:269-80.).

Diagnosis

The diagnosis of pulmonary aspergillosis is usually based on either 1) the repeated isolation of Aspergillus spp. from cultures or respiratory secretions or 2) the finding of dichotomously branching septate hyphae consistent with Aspergillus spp. in respiratory or other samples in association with a compatible clinical syndrome. Histological evidence of tissue invasion by hyphae with a positive culture for Aspergillus spp. represents a definite diagnosis.

Newer tests based on circulating fungal antigen have been employed to diagnose aspergillosis. These have not been formally evaluated in patients with HIV infection. A sandwich ELISA test for galactomannan, a major fungal cell wall antigen, can be used on serum and bronchoalveolar lavage fluid (653Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 20 01;97:1604-10.). Although sensitivity and specificity appear reasonable, the test has yielded both false-positive and -negative results and is currently recommended for screening for invasive aspergillosis primarily in stem-cell transplant recipients.

Preventing Exposure

Aspergillus spp. are ubiquitous in the environment, and exposure is unavoidable. Avoiding particularly dusty environments is prudent, especially in areas such as those created by construction because spore counts might be higher in such settings.

Preventing Disease

No data on the prevention of primary aspergillosis in HIV-infected patients exists, although posaconzaole has been reported to be effective among patients with hematologic malignancy and neutropenia (654Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-59.).

Treatment of Disease

Treatment of aspergillosis in the HIV-infected population has not been examined systematically. The recommended treatment for invasive aspergillosis in patients without HIV infection is voriconazole (655Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006;173:707-17.). Voriconazole is the drug of choice but should be used cautiously with HIV PIs and efavirenz (BIII). Amphotericin B deoxycholate at 1 mg/kg daily or lipid-formulation amphotericin B at 5 mg/kg daily are alternatives (AIII), as is caspofungin at 50 mg daily (BII) and posaconazole (BII). Other echinocandins, such as micafungin and anidulafungin, are reasonable alternatives. Posaconazole also has proven to be useful in patients with invasive aspergillosis without HIV infection (646) but is not approved for treatment of aspergillosis. The length of therapy is not established but should continue at least until the peripheral blood CD4+ count is >200 cells/µL and there is evidence of clinical response.

Monitoring and Adverse Events, Including Immune Reconstitution Inflammatory Syndrome (IRIS)

IRIS has rarely been reported to occur in patients with invasive aspergillosis (657Sambatakou H, Denning DW. Invasive pulmonary aspergillosis transformed into fatal mucous impaction by immune reconstitution in an AIDS patient. Eur J Clin Microbiol Infect Dis 2005;24:628-33.).

Management of Treatment Failure

The overall prognosis is poor among patients with advanced immunosuppression and in the absence of effective ART. No data are available to guide recommendations for the management of treatment failure. If voriconazole was used initially, substitution with amphotericin B, posaconazole, or echinocandins might be considered; the amphotericin B or echinocandins would be a reasonable choice for those who began therapy with voriconazole or posaconazole (BIII).

Preventing Recurrence

No data are available to base a recommendation for or against chronic maintenance or suppressive therapy among patients who have successfully completed an initial course of treatment (CIII).

Special Considerations During Pregnancy

Because of their risk for teratogenicity, azoles should not be used during the first trimester of pregnancy (EII). (See mucocutaneous candidiasis). Neonates born to women on chronic amphotericin B at delivery should be evaluated for renal dysfunction and hypokalemia.

Drug therapy for treatment and chronic maintenance therapy of AIDS-associated opportunistic infections in adults and adolescents: Aspergillosis, invasive
Preferred therapy, duration of therapy, chronic maintenanceAlternative therapyOther options/issues
Excerpted from Table 2
Definitions of abbreviations: PO = by mouth; IV = intravenous; q12h = every 12 hour
Preferred therapy
transparent gifgrey bulletVoriconazole 6 mg/kg q12h x 1 day, then 4 mg/kg q12h IV (BIII), followed by voriconazole PO 200 mg q12h after clinical improvement
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Duration of therapy: until CD4+ count >200 cells/µL and with evidence of clinical response
Alternative therapy
transparent gifgrey bulletAmphotericin B deoxycholate 1 mg/kg/day IV (AIII); or
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transparent gifgrey bulletLipid formulation of amphotericin B 5 mg/kg/day IV (AIII)
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transparent gifgrey bulletCaspofungin 70 mg IV x 1, then 50 mg IV daily (BII)
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transparent gifgrey bulletPosaconazole 400 mg bid PO (BII)
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Potential for significant pharmacokinetic interactions between PIs or NNRTIs with voriconazole; it should be used cautiously in these situations. Consider therapeutic drug monitoring and dosage adjustment if necessary.

References

647. Mylonakis E, Barlam TF, Flanigan T, Rich JD. Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Chest 1998;114:251-62.
648. Holding KJ, Dworkin MS, Wan PC, et al. Aspergillosis among people infected with human immunodeficiency virus: incidence and survival. Clin Infect Dis 2000;31:1253-7.
649. Wallace JM, Lim R, Browdy BL, et al. Risk factors and outcomes associated with identification of Aspergillus in respiratory specimens from persons with HIV disease: Pulmonary Complications of HIV Infection Study Group. Chest 1998;114:131-7.
650. Lortholary O, Meyohas MC, Dupont B, et al. Invasive aspergillosis in patients with acquired immunodeficiency syndrome: report of 33 cases. Am J Med 1993;95:177-87.
651. Kemper CA, Hostetler JS, Follansbee SE, et al. Ulcerative and plaque-like tracheobronchitis due to infection with Aspergillus in patients with AIDS. Clin Infect Dis 1993;17:344-52.
652. Mylonakis E, Paliou M, Sax PE, et al. Central nervous system aspergillosis in patients with human immunodeficiency virus infection: report of 6 cases and review. Medicine (Baltimore) 2000;79:269-80.
653. Maertens J, Verhaegen J, Lagrou K, Van Eldere J, Boogaerts M. Screening for circulating galactomannan as a noninvasive diagnostic tool for invasive aspergillosis in prolonged neutropenic patients and stem cell transplantation recipients: a prospective validation. Blood 20 01;97:1604-10.
654. Cornely OA, Maertens J, Winston DJ, et al. Posaconazole vs. fluconazole or itraconazole prophylaxis in patients with neutropenia. N Engl J Med 2007;356:348-59.
655. Segal BH, Walsh TJ. Current approaches to diagnosis and treatment of invasive aspergillosis. Am J Respir Crit Care Med 2006;173:707-17.
656. Walsh TJ, Raad I, Patterson TF, et al. Treatment of invasive aspergillosis with posaconazole in patients who are refractory to or intolerant of conventional therapy: an externally controlled trial. Clin Infect Dis 2007;44:2-12.
657. Sambatakou H, Denning DW. Invasive pulmonary aspergillosis transformed into fatal mucous impaction by immune reconstitution in an AIDS patient. Eur J Clin Microbiol Infect Dis 2005;24:628-33.
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