Johns Hopkins HIV GuidePathogensFungi

Aspergillus spp.

Dionissis Neofytos, M.D., Paul G. Auwaerter, M.D.

MICROBIOLOGY

  • Ubiquitous, saprophytic filamentous mold, hyphae (2-5 µm) usually septated with 45° angle branching.
  • Microbiologic diagnosis mainly based on colony morphology on solid media and specific microscopic features.
  • Non-invasive diagnostic tests now available:
    • Galactomannan antigen: serum and BAL (good sensitivity/specificity in the right patient population)
    • PCR (not well studied)
    • (1-3) beta-D-glucan: less specific
  • Specific species: determination important as some more virulent, more likely to cause pathological disease.
    • A. fumigatus most common (~90%) cause of human disease.
      • A. flavus next most common, followed by A. terreus, A. niger (usually a contaminant), A. versicolor, and A. nidulans.
      • Recently, new Aspergillus spp. described (e.g. A. lentulus).
    • Antifungal profiles:
      • A. terreus, A. calidoustus: may be resistant to amphotericin products.
      • A. fumigatus: azole-resistance reported.
      • A. lentulus: may be resistant to itraconazole, voriconazole, caspofungin.

CLINICAL

  • Portal of entry: respiratory tract > skin.
    • Aspergillus conidia inhaled and migrate to bronchi/lung parenchyma, germinate into hyphae, which can invade tissue. Alveolar macrophages and neutrophils important host defenses.
  • Broad spectrum of disease from non-invasive to invasive/disseminated:
  1. Colonization
  2. Allergic bronchopulmonary aspergillosis (ABPA, see module in ABX Guide)
  3. Aspergilloma in pre-exisiting cavity or aspergillus nodules (necrotic nodules with hyphae, no invasion)
  4. Invasive infections: chronic pulmonary necrotizing aspergillosis, invasive aspergillus (IA), or disseminated aspergillosis. Generally seen with immune suppression: transplant (bone marrow and organ) recipients, hematologic malignancy, neutropenia, corticosteroids, advanced AIDS, chronic granulomatous disease.
  • HIV: common risk factors include advanced disease (CD4 < 50), steroid use, prior OI and neutropenia.
  • Presentations: may present as sinusitis, tracheobronchitis, otitis or pneumonia. Note: colonization of respiratory tract common, especially if pre-exisiting chronic lung disease.
    • Frequent bronchial colonizer in pts w/ structural lung disease (eg, bronchiectasis, carcinoma, sarcoid, prior TB).
    • Acute invasive lung disease: fungal angioinvasion and thrombosis with tissue infarction may cause pleuritic chest pain, cough, hemoptysis, dyspnea.
      • CT lung imaging w/ nodular/cavitary lesions, patchy infiltrates, "halo-sign" (hemorrhage), and "crescent-sign" (necrosis).
      • In HIV patients, may be more indolent in presentation than in neutropenic/hematological malignancy populations.
  • Dx of invasive disease: often not able to conclusively prove but suspect given host factors.
    • Proven: histopathological/culture evidence of tissue invasion
    • Probable: host factors, clinical criteria and mycological criteria (microscopy/cx/galactomannan antigen)
    • Possible: absence of mycological support
    • Tests:
      • Respiratory Cx: with pulmonary disease, sensitivity of only ~ 40% from sputum or BAL fungal cultures. Isolation from respiratory specimen does have high predictive value in immunocompromised patients.
      • Blood culture: almost always negative.
      • PCR: lack of standardization has precluded widespread use.
      • Antigen detection:
        • Galactomannan EIA assay, as aspergillus-specific polysaccharides expressed with invasion of tissue.
          • Serum or BAL specimens: sensitivity >70%, specificity ~ 90% in at risk hosts
          • Cutoff: now 0.5 as standard, values ≥0.5 predictive especially BAL
        • Beta-D-glucan: less specific indicator for invasive fungal disease as may be positive also with Candida, Fusarium and other fungi (not Cryptococcus or Mucor spp.)

SITES OF INFECTION

  • Lung: spectrum ranges from allergic bronchopulmonary aspergillosis (ABPA) to tracheobronchitis w/ white plaques to aspergilloma or aspergillus nodules to chronic necrotizing aspergillosis to invasive aspergillosis
  • Sinuses: allergic, fungus ball, invasive disease.
  • CNS: abscess (contiguously through sinuses, chronic otitis/mastoiditis or hematogenously), mycotic infarction.
  • Skin: primary (inoculation, armboard-related, catheter-related) or secondary (disseminated) in heavily immunosuppressed pts.
  • Heart: endocarditis (rare, risk factors include prosthetic heart valve surgery, IV drug abuse, central line infection).
  • Eye: endophthalmitis (hematogenous or direct inoculation). Keratitis from trauma.
  • Dissemination: kidney, liver, spleen, and CNS; blood cx rarely positive.

TREATMENT

Invasive or disseminated infection

  • General comments:
    • Early institution of antifungal therapy may be helpful, often delayed due to difficulties in achieving a diagnosis or lack of suspicion.
    • Determination of Aspergillus species may be helpful to guide selection of drug due to resistance commonly seen in some species.
  • Preferred:voriconazole 6 mg/kg IV q12h x 2 then 4 mg/kg IV q12h
    • Therapeutic drug monitoring (TDM) targets:
      • C min: >1mcg/mL, some correlation with efficacy
      • C max: < 5.5mcg/mL, to avoid greater toxicities
      • Note: review for potential drug interactions. See voriconazole module for additional details.
        • Efavirenz (EFV): dose of voriconazole should be immediately doubled and TDM followed closely. EFV should be decreased or consider switch to alternative ART.
        • Rifampin: dose of voriconzole should be immediately doubled and TDM followed closely.
        • Corticosteroids: co-administration may reduce voriconazole levels, especially dexamethasone.
  • Alternatives:
    • Liposomal amphotericin 3.0-5.0 mg/kg/d IV
    • Isavuconazole
      • FDA approved for IA and invasive mucormycosis
    • Posaconazole:
      • Approved for IA prophylaxis, less data regarding primary treatment.
      • Parenteral and improved oral extended-release formulations now available.
    • Other lipid complex amphotericin products
  • Salvage therapies: only caspofungin among the echinocandins FDA approved for IA as salvage therapy.
    • Caspofungin 70 mg IV x 1 dose, then 50 mg IV q24h
    • Micafungin
    • Anidulafungin
  • Combination therapy: now often employed in serious IA as first line rather than salvage, preferred in azole-resistant IA.
    • Voriconazole + echinocandin (animal models suggest effectiveness; small study in solid organ transplant suggested improved efficacy over liposomal amB)
    • Liposomal amphotericin + caspofungin
    • Triazole (posaconazole, isavuconazole) therapy in other combinations either not studied or concern regarding antagonism (amB-triazole combinations).
  • If neutropenic, consider use of G-CSF.
  • Decrease/stop corticosteroids/other immunosuppression if possible.

Aspergilloma

  • Often requires no intervention.
    • Must be distinguished from necrotic mass in cavity due to invasive pulmonary aspergillosis.
  • May cause significant hemoptysis: consider pulmonary artery embolization, partial lung resection (if adequate PFTs).
  • Medical treatment of unclear benefit; main conundrum: is there invasive/progressive disease? Some data suggest itraconazole may be helpful, but rate of invasive disease low, despite risk factors.

Local disease (Sinus/HEENT, cutaneous) and Other

  • Medical therapy as in invasive disease.
  • Surgery to remove necrotic tissue, active infection e.g., brain, bone, heart valve, skin, sinuses.

Allergic bronchopulmonary aspergillosis

  • Treatment often using asthma medications to improve airway management, improve cough. Severe problems may require daily, systemic corticosteroids.
    • Severe disease: prednisone 0.5 mg/kg/d x 1 wk then 0.5 mg/kg every other day x 5 wks with taper.
  • Antifungal therapy:
    • Itraconazole 200 mg PO twice-daily x 16 wks leads to quicker steroid taper and improved pulmonary parameters. Role remains controversial regarding effectiveness.
    • Role of voriconazole not studied in this population.
    • Omalizumab (anti IgE therapy): may be helpful in longer-term management as steroid sparing agent in severe disease.

Selected Drug Comments

Drug

Recommendation

Amphotericin B

Prior standard therapy, now replaced by voriconazole. A. terreus may be more resistant to amphotericin B.

Amphotericin B liposomal

Now preferred over standard amphotericin B for reasons of toxicity, but no compelling data to suggest clinical superiority over standard amB.

Anidulafungin

Echinocandin with spectrum similar to caspofungin; does not have indication for aspergillosis, but should work similarly.

Caspofungin acetate

FDA approved for salvage therapy, but lack of larger clinical trials makes this a 2nd-tier choice compared to voriconazole; would not use alone. A. lentulus may be resistant to caspofungin.

Isavuconzaole

New triazole drug approved by FDA for both IA and invasive mucormycoses. Has broad spectrum of anti-fungal activities.

Itraconazole

Older azole with some activity; would not use for IA. May have a role in ABPA.

Micafungin

Echinocandin with spectrum similar to caspofungin; does not have indication for aspergillosis, but should work similarly.

Posaconazole

Good in vitro activity, FDA approved for prevention of aspergillosis in high-risk populations, but little treatment data (can use off label as salvage therapy). Extended release formulation now improves bioavailability over older oral formulation. Also available in parenteral form.

Voriconazole

Preferred drug for serious infections, but numerous drug interactions (calcineurin inhibitors, rifampin, PIs, EFV, PPIs, etc). Excellent bioavailability makes parenteral to oral switch easy. In severe invasive disease would use IV formulation. Beware of increasing azole-resistance among A. fumigatus isolates. A. lentulus may be resistant.

FOLLOW UP

Aspergillus infections

  • May transition to oral therapy once clinically stable.
    • Voriconazole 4mg/kg mg PO twice-daily
    • Isavuconazole
    • Posaconazole
    • Duration: uncertain, but usually until no clinical evidence of active disease and reduced immunosuppression.
  • Treatment failure: some define as no response within 96 hrs or persistent fever.
    • Beware of "transient" worsening of chest CT findings upon resolution of neutropenia and possibly immune reconstitution.
    • See combination therapy above. Limited data available for combination therapy.
  • Very limited data to correlate galactomannan assay titers with response.

OTHER INFORMATION

  • Serious disease remains difficult to treat. However, outcomes have improved due to a number of factors (risk factor identification, high clinical suspicion, non-invasive diagnostic tests, effective/safe antifungal agents).
  • Resistance to voriconazole may be identified in up to 8% of Aspergillus isolates.

Basis for recommendation

  1. Bassetti M et al: Current and Future Therapies for Invasive Aspergillosis. Pulm Pharmacol Ther Jun 30  [PMID:24994691]

    Comment: Well referenced review article that serves as basis for recommendations while IDSA is updating their guideline for IA.

  2. Herbrecht R et al: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med 347:408, 2002  [PMID:12167683]

    Comment: Important paper that has made voriconazole preferred treatment for aspergillosis based on randomized trial of 277 pts w/ invasive aspergillosis (most had hematological malignancies). Voriconazole response rate 53% vs. 32% for amphotericin B. Survival also superior: 71 vs. 58%.

  3. De Pauw B et al: Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group. Clin Infect Dis 46:1813, 2008  [PMID:18462102]

    Comment: Revised definitions of invasive fungal infections, including invasive aspergillosis. Important assitions: galactomannan assay in serum/BAL.

  4. Schelenz S et al: British Society for Medical Mycology best practice recommendations for the diagnosis of serious fungal diseases. Lancet Infect Dis 15:461, 2015  [PMID:25771341]

    Comment: This guideline incorporates newer data regarding diagnostics. Group recommends at least three sputum samples for detection of respiratory fungi to improve sensitivity unless validated PCR method used. Also they note that Galactomannan testing of BAL from patients at high risk of invasive aspergillosis should be considered, although the current OD index cutoff of 0·5 might change. PCR if validated method, helpful especially in if negative to help rule out IA.
    Combination testing with aspergillus PCR plus another antigen test improves the positive predictive value and diagnosis of invasive fungal disease

References

  1. Agarwal R et al: Itraconazole in chronic cavitary pulmonary aspergillosis: a randomised controlled trial and systematic review of literature. Mycoses 56:559, 2013  [PMID:23496375]

    Comment: Small study in non-HIV population suggests that clinical and radiographic improvements were seen in those with chronic cavitoary aspergillosis on the itraconazole arm.

  2. Mylonakis E et al: Invasive Aspergillus sinusitis in patients with human immunodeficiency virus infection. Report of 2 cases and review. Medicine (Baltimore) 76:249, 1997  [PMID:9279331]

    Comment: Authors only find 19 definite or probable cases in the literature but find a dismal prognosis; only early, aggressive intervention including surgical debridement (with amphotericine B therapy) is helpful.

  3. 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 24:628, 2005  [PMID:16177885]

    Comment: Case argues that aspergillosis can be added to the menu of organisms associated with IRIS following institution of ART.

  4. Cornely OA et al: Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial). Clin Infect Dis 44:1289, 2007  [PMID:17443465]

    Comment: RCT failed to show benefit with 10 mg/kg dosing vs. 3 mg/kg over a 14d period, with similar response rates measured at 12 weeks.

  5. Snelders E et al: Emergence of azole resistance in Aspergillus fumigatus and spread of a single resistance mechanism. PLoS Med 5:, 2008  [PMID:18998768]

    Comment: First organized effort to detect and describe azole-resistance among A. fumigatus isolates in Europe.
    Rating: Important

  6. Maertens J et al: Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study. Clin Infect Dis 41:1242, 2005  [PMID:16206097]

    Comment: Important study that describes importance of screening the right pt population with chest CT and serum galctomannan antigen assay for the early detection of aspergillosis.
    Rating: Important

  7. Musher B et al: Aspergillus galactomannan enzyme immunoassay and quantitative PCR for diagnosis of invasive aspergillosis with bronchoalveolar lavage fluid. J Clin Microbiol 42:5517, 2004  [PMID:15583275]

    Comment: Important study to supportutility of the galactomannan assay in BAL.
    Rating: Important

  8. Marr KA et al: Detection of galactomannan antigenemia by enzyme immunoassay for the diagnosis of invasive aspergillosis: variables that affect performance. J Infect Dis 190:641, 2004  [PMID:15243943]

    Comment: Important study to validate serum galactomannan antigen assay as diagnostic tool for aspergillosis. This study illustrates the importance of variables affecting performance of the test.
    Rating: Important

  9. Dannaoui E, Lortholary O, Dromer F: In vitro evaluation of double and triple combinations of antifungal drugs against Aspergillus fumigatus and Aspergillus terreus. Antimicrob Agents Chemother 48:970, 2004  [PMID:14982791]

    Comment: In vitro data such as this report suggest that combinations of antifungals may have some synergy with Aspergillus spp. Authors studied combinations of caspofungin with either amphotericin B or voriconazole suggesting they were additive for all isolates, and antagonism was not observed. Triple combination of caspofungin w/ 5FC and amphotericin B synergistic for all isolates tested. Triple combination of caspofungin w/ 5FC and voriconazole also mostly synergistic, but complex interactions with some isolates, with synergy or antagonism depending on concentrations of caspofungin and voriconazole. Authors suggest that activity of 5FC as part of double combination w/ caspofungin and as part of triple combination w/ caspofungin and amphotericin B against Aspergillus spp. warrants further investigations.

  10. Kankolongo, MA, Hello, K, Nawa, IN; Assessment for fungal, mycotoxin and insect spoilage in maize stored for human consumption in Zambia; Journal of the Science of Food and Agriculture; Vol. 89; pp. 1366-1375;

    Comment: Multi-site sampling of maize in Zambia for contaminants.

  11. Marukutira T et al: Clinical characteristics and outcomes in 303 HIV-infected patients with invasive fungal infections: data from the Prospective Antifungal Therapy Alliance registry, a multicenter, observational study. HIV AIDS (Auckl) 6:39, 2014  [PMID:24648769]

    Comment: Study of subset of HIV-infected patients with fungal infections in the PATH prospective trial. Aspgerillus was represented in 4.4% of these patients, with 74.1% of these patients with a CD4 count of < 50 cells/µL. Pulmonary disease accounted for 81.8% of aspergillus infections. Worst survival was seen with aspgerillus, probability of 0.58.

  12. Holding KJ et al: Aspergillosis among people infected with human immunodeficiency virus: incidence and survival. Adult and Adolescent Spectrum of HIV Disease Project. Clin Infect Dis 31:1253, 2000  [PMID:11073760]

    Comment: National study examining 35,252 HIV-infected pts reporting an incidence of aspergillosis was 3.5 cases per 1000 person-yrs. Higher incidence was noted among ages > 35 yrs, CD4 <50, prior OI and neutropenia. Median survival after Dx 3 mos w/ 26% survival >1 yr.
    Rating: Important

  13. Denning DW et al: Pulmonary aspergillosis in the acquired immunodeficiency syndrome. N Engl J Med 324:654, 1991  [PMID:1994248]

    Comment: Older paper adding use of marijuana and prior Abx use as risk factors for infection. Radiographic appearances included upper-lobe cavitary disease (confused with TB), nodules, pleural-based lesions and diffuse (usually lower lobe) infiltrates.

  14. Mylonakis E et al: Central nervous system aspergillosis in patients with human immunodeficiency virus infection. Report of 6 cases and review. Medicine (Baltimore) 79:269, 2000  [PMID:10941356]

    Comment: Paper reviews literature in 33 pts, concluding that CNS disease probably more a consequence of sinus/HEENT infection that dissemination from pulmonary sources. Medical treatment with amphotericin B unsuccessful in all cases.

  15. Marr KA et al: Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis 39:797, 2004  [PMID:15472810]

    Comment: Small study suggesting that combination voriconazole/caspofungin therapy was superior to voriconazole alone in reducing mortality. Firm recommendations in this difficult infection can only be made following randomized, prospective study.
    Rating: Important

  16. Mylonakis E et al: Pulmonary aspergillosis and invasive disease in AIDS: review of 342 cases. Chest 114:251, 1998  [PMID:9674477]

    Comment: Typical symptoms of fever, cough and dyspnea reported in >60% of pts w/ typical risk factors including advanced HIV, steroid use and neutropenia. Authors emphasize need for tissue diagnosis to discriminate from colonization/contamination. As expected, survival appeared to depend on making an early diagnosis with subsequent use of amphotericin.
    Rating: Important

  17. Addrizzo-Harris DJ et al: Pulmonary aspergilloma and AIDS. A comparison of HIV-infected and HIV-negative individuals. Chest 111:612, 1997  [PMID:9118696]

    Comment: Typically TB and sarcoidosis are among the most prevalent predisposing diseases' PCP in HIV was identified as a risk factor. Unlike HIV-negative pts, who are more likely to require intervention for hemoptysis, those with HIV and CD4 <100 appear more likely to have disease progression despite treatment.

  18. Stevens DA et al: A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med 342:756, 2000  [PMID:10717010]

    Comment: Use of oral itraconazole (200 mg PO twice-daily x 16 wks) appears to correlate w/ quicker reduction in corticosteroid dosage and better PFTs/exercise tolerance.

  19. Walsh TJ et al: Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis 46:327, 2008  [PMID:18177225]

    Comment: Revised treatment guidelines for treatment of aspergillosis.

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Last updated: June 6, 2015