MICROBIOLOGY

  • Ubiquitous mold found worldwide including in hay, compost, soil, basements, HVAC and plants (including marijuana).
    • Contamination of air in medical units can occur with construction/renovation unless preventative control measures are implemented.
  • In the environment (and on culture plates) Aspergillus grows in the vegetative state that is composed of long filamentous structures (hyphae) attached to the substrate upon which the fungus is feeding AND as aerial hyphae, which including a distinctive appearance that resembles an aspergillum (an instrument used for sprinkling holy water in Roman Catholic and Anglican traditions) with associated spores (called conidia) [ Fig] .
    • Hyphae: long tubular structures, 2-4 µm wide, usually septate, 40 degree angle branching.
    • Conidia: spherical structure, 2-5 µm wide, very easily airborne and hardy that may settle in the sinuses and lower respiratory tract.
  • If the conidia are not cleared out of the sinuses and airway, they may germinate to form hyphae, invade blood vessels and parenchymal tissue, and use the human host as a substrate for vegetative growth.
  • Dominant human pathogen species: A. fumigatus > A. flavus, A. terreus, A. niger.

CLINICAL

  • Disease types: respiratory tract most common site of infection (lung, sinuses, large airways).
  • Other sites include skin, eye, ears, CNS, bone/joint, mediastinum, heart, liver and kidneys. Infection in those cases is due to direct inoculation during a medical procedure or trauma or from disseminated disease.
    • Invasive infection:
      • The intensity and rapidity of progression often depends on the extent of immunosuppression and possibly, genetic factors. Lungs are most commonly involved sites where disease spectrum includes chronic cavitary, chronic fibrosing, subacute invasive (also called chronic necrotizing) and acute invasive variants.
    • Risk groups:
      • Patients with bone marrow failure: especially neutropenia due to hematological malignancies/chemotherapy, hematopoietic stem cell transplants before engraftment and aplastic anemia.
      • Neutrophil/phagocyte dysfunction: chronic corticosteroids are a major risk, allogeneic stem cell transplants after engraftment, solid organ transplants, AIDS with CD4 < 100 cells/ml, chronic granulomatous disease and cirrhosis.
      • ICU patients are increasingly recognized as at risk.
    • Allergic disease:
      • Allergic bronchopulmonary aspergillosis (ABPA): often seen in patients with asthma or cystic fibrosis.
      • Allergic sinusitis
    • Aspergilloma: presence of Aspergillus fungus ball in preexisting pulmonary cavity. Clinical manifestations range from single and stable aspergilloma to presence of fungus ball(s) in the context of chronic cavitary aspergillosis.
  • Diagnosis: usually by combination of host status, imaging and mycological findings. Early diagnosis and treatment is critical in management.
    • Proven: histopathology, cytopathology, or direct microscopy showing dichotomously branching, septate hyphae AND associated tissue damage AND growth of Aspergillus species from culture of normally sterile and clinically or radiologically abnormal site.
    • Probable: clinical disease + immunocompromised host + non-definitive mycological testing. Because proven disease is so difficult to establish, patients are increasingly diagnosed at the "Probable" level of proof.
      • Cytology
      • Direct microscopy and/or culture indicating presence of Aspergillus species in a lower respiratory tract specimen
      • Galactomannan antigen index ≥ 0.5 in plasma, serum or bronchoalveolar lavage fluid
      • Serum 1,3 beta D-glucan level of ≥ 80 pg/ml.
    • Possible: Clinical disease + immunocompromised host: This is often a driver for empiric therapy.
  • Notes on diagnostic tests:
    • Aspergillus spp. commonly colonize the respiratory tract and are also frequent laboratory contaminants, so positive cultures need to be interpreted carefully.
    • Negative cultures do not rule out invasive aspergillosis.
      • Blood cultures are almost never positive (when blood cultures are positive, it is typically due to laboratory contamination, not actual infection).
      • Often tissue cultures do not yield growth either despite obvious presence on histopathology.
    • Serum and BAL galactomannan testing are increasingly used to diagnose invasive aspergillosis.
      • Cross reactions can occur with other filamentous fungi and with histoplasmosis
    • 1,3-beta-D-glucan: assay has limitations due to cross reaction with other fungi (including Candida and Pneumocystis).
      • Specificity improved in:1) hematology patients; 2) with two positive serum tests; and 3) when combined with positive culture.
    • Lung CT scan:
      • In the appropriate patient (e.g., neutropenic), the presence of nodules ≥ 1 cm in diameter are suggestive of a filamantous fungal infection, usually aspergillosis.
        • Halo/crescent sign predominantly applies to neutropenic populations and is suggestive of, but not definitive evidence for aspergillosis.
        • Developing invasive pulmonary aspergillosis while neutropenic, radiographic findings may appear to progress with recovery of neutrophils. Nodules may cavitate and apparent aspergillomas may develop at sites of pulmonary infiltrates.
    • BAL galactomannan greatly facilitates early diagnosis in high-risk patients, but must be interpreted with caution due to cross reactions to other fungi and inability to differentiate airway colonization vs. invasive disease based soley on this test.

SITES OF INFECTION

  • Pulmonary (4 major subtypes): most common form seen.
    • Rapidly progressive disease: typically seen in patients with major deficiencies in neutrophil number and function (e.g. acute leukemia, aplastic anemia, allogenic stem cell transplants, solid organ transplants, AIDS with CD4 < 100 cells/ml, chronic granulomatous disease).
    • Subacute infection: necrotizing and cavitary lesions typically seen in patients with chronic structural lung diseases that also involve the airways (e.g. cystic fibrosis, bronchiectasis, sarcoidosis, emphysema).
    • Allergic bronchopulmonary (ABPA, not truly an infection but a hypersensitivity reaction)
    • Fungus ball (aspergilloma, mycetoma)
  • Sinusitis: spectrum ranges from allergic (possible role in some chronic sinusitis) to fungus ball to invasive forms.
  • Tracheobronchial or laryngeal aspergillosis: presents as large airway pseudomembranes and ulcerations in patients with advanced HIV and as infection at anastomosis sites in lung transplant recipients.
  • Otitis externa
  • CNS: abscesses, meningitis
    • CSF beta glucan and/or galactomannan levels can aid in diagnosis.
  • Bone: osteomyelitis (often vertebral)
  • Cutaneous: burns, wounds
  • Ocular: endophthalmitis, keratitis
  • Other (all rare):

TREATMENT

Pulmonary

  • Early treatment with the right agent appears critical for invasive aspergillosis.
  • Invasive pulmonary (IA):
    • Preferred: voriconazole (alone or in combination)
      • Adult voriconazole dosing:
        • Severe disease:
          • Loading dose of 6mg/kg q 12h PO/IV x 2 doses, then 4mg/kg q 12h IV/PO
        • Mild/moderate disease:
          • May consider loading dose 400 mg x 2 doses on 1st day then 200 mg twice daily.
        • Adult patients ≤ 40 kg should receive half of the oral maintenance dose.
      • Combination therapy: voriconazole AND echinocandin (anidulafungin, micafungin or caspofungin)
        • May improve outcomes in patients with hematological malignancy whose IA diagnosis was established by radiographic findings and galactomannan positivity [3].
      • Therapeutic drug monitoring:
        • Trough target levels: > 1-2 mg/L and < 5.5 mg/L.
        • Measure levels within 7 days of starting therapy.
          • Also if starting or stopping interacting drugs, unclear medication adherence, suspected toxicity or sub-optimal response to treatment.
    • Alternatives:
      • Isavuconazonium (prodrug of isavuconazole IV or oral): 372 mg of isavuconazonium sulfate (= 200 mg Isavuconazole) every 8 hours x 6 doses (48 hours) as loading dose then 372 mg/day.
      • Liposomal amB (most preferred of amB products) 5 mg/kg/d IV
      • Amphotericin B 1 mg/kg/d IV
      • Caspofungin 70 mg IV x 1 dose then 50 mg/d IV (FDA approved for salvage indication)
      • Micafungin 100-150 IV/d
      • Anidulafungin 200 mg x 1 dose then 100 mg/d IV
      • Posaconazole delayed release tablets or IV: 300 mg twice on day 1, then 300 mg daily; oral suspension 800 mg daily (in 2-4 divided doses taken with food);
    • Failure with voriconazole: consider amphotericin products, combination of voriconazole with an echinocandin, check if voriconazole levels are therapeutic .
  • Aspergilloma:
    • Single and stable aspergilloma: no consensus on whether anti-fungal treatment is effective; main concern is hemoptysis.
      • Observe (most cases)
      • Bronchial artery embolism (temporizing, especially for hemoptysis)
      • Consider systemic therapy (itraconazole, voriconazole, posaconazole).
      • Some have used intracavitary amB.
      • Surgical resection: consider if adequate pulmonary function plus if pt w/ sarcoidosis, immunocompromise, increasing IgG or recurrent hemoptysis.
    • Aspergillomas in context of chronic cavitary pulmonary aspergillosis: long term antifungal therapy (e.g. with voriconazole, itraconazole, posaconazole).
  • Allergic bronchopulmonary aspergillosis (ABPA): since hypersensitivity reaction, unclear whether antifungal therapy truly needed or helpful.
    • Prednisone 0.5mg/kg/d x 1wk then 0.5mg/kg every other day x 5wks
    • Antifungal agent (e.g. itraconazole, voricaonzole, posaconazole) +/- prednisone

ENT Infections

  • Sinonasal
    • Acute invasive (typically affects immunocompromised patients): considerations for therapy include.
      • Antifungal therapy as for invasive pulmonary aspergillosis (e.g. voriconazole +/- echinocandin, amphotericin B, isavuconazonium, and posaconazole)
      • Surgical evaluation and possible debridement
      • Correction of immune compromise to extent feasible
      • Possible AmB sinus lavage (unclear benefit in patients already receiving systemic antifungal therapy)
    • Chronic invasive (typically affects non-immunocompromised patients living in climates with dry air).
      • Treatment includes surgical debridement + systemic antifungal therapy (e.g. voriconazole, posaconazole, isavuconazonium or amphotericin.
    • Fungus ball: surgical removal.
    • Sinusitis, allergic fungal: surgical drainage + corticosteroids (inhaled or systemic) +/- antibacterial (role of antifungals controversial).
  • Otic infection
    • Immunocompetent (typically affects the external auditory canal):
      • Topical therapy, e.g., otic azole, tolnaftate, nystatin, cresylate, boric acid, acetic acid.
      • Avoid potentially ototoxic agents as well as creams, gels and ointments in patients with perforated tympanic membrane.
    • Immunocompromised host:
      • Infection may be associated with bacterial otitis and can extend to involve deeper structures (e.g. mastoid).
      • Topical therapy, systemic therapy (e.g. voriconazole, posaconazole, isavuconazonium) and surgical debridement may be required depending on situation and extent of infection.

Other Infections

  • Central nervous system (brain, spinal cord and/or meninges)
    • Medical management:
      • Voriconazole (adult dosing): 6 mg/kg IV every 12 hours x 2 doses followed by 4 mg/kg every 12 hours (goal trough levels of 2-5), or liposomal AmB 5-7.5 mg/kg/day.
      • Role of dual therapy with an echinocandin unclear in CNS infections.
      • Posaconazole may have a role as second line therapy. CSF penetration poor, but parenchymal penetration may be adequate when there is inflammation.
    • Surgery: as dictated by lesion size, location, characteristic, impact on intracranial pressure and acuity.
      • Options include surgical decompression, stereotactic drainage, placement of extraventricular drainage (EVD) catheter and hemicraniectomy.
  • Bone: surgical debridement + voriconazole.
    • Role of combination with echinocandin unclear.
    • May alternatively use AmB product, posaconazole or an echinocandin, but not as first line therapy.
  • Endocarditis: valve replacement + voriconazole (+/- echinocandin).
    • Alternate therapy is AmB product.
  • Hepatosplenic: voriconazole (+/- an echinocandin).
    • Alternate therapy is AmB product.
  • Peritoneal catheter-associated: remove catheter, intraperitoneal dialysis with AmB and IV AmB.
  • Cutaneous: determine if due to dissemination from primary focus, should be treated with systemic voriconazole (+/- echinocandin) or alternatively, AmB product, isavuconazole, posaconazole or echinocandin.
    • If due to primary cutaneous process (e.g. following trauma), may require surgical debridement in addition to antifungal therapy.

Selected Drug Comments

Drug

Recommendation

Voriconazole

(Vfend) Preferred drug for aspergillus infections based on improved mortality compared to AmB in the treatment of invasive aspergillosis. Advantages are PO and IV formulations, good tolerance, Good CNS penetration and good in vitro and in vivo activity. Drug interactions may be troublesome especially in transplant populations. Parenteral form might be problematic in renal failure, but recent data more reassuring regarding safety. Therapeutic drug monitoring (serum trough levels) seems to be important for improving efficacy and reducing toxicity.

Anidulafungin

Well tolerated parenteral drugs; however, exact role as monotherapy in the treatment of serious aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes.

Caspofungin acetate

Well tolerated parenteral drugs; however, exact role as monotherapy in the treatment of serious aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes.

Micafungin

Well tolerated parenteral drugs; however, exact role as monotherapy in the treatment of serious aspergillus infection is unclear. Use in combination therapy with voriconazole and may result in improved outcomes.

Isavuconazonium (prodrug of isavuconazole)

(Cresemba) Azole antifungal agent FDA approved for invasive aspergillosis and invasive mucormycosis. Available as IV and oral formulations. Drug interactions with immunosuppressant (e.g. cyclosporine, tacrolimus, sirolimus) and digoxin. Isavuconazole levels impacted by CYP3A4 inhibitors and inducers.

Liposomal amphotericin B

(Ambisome) The lipid formulations of amphotericin B were initially compared w/ conventional AmB in pts with aspergillosis. Results of these studies show an advantage for the lipid amphotericin formulations, but only for reduction in adverse reactions. The clinical outcome compared to conventional has generally been the same, but the side effects are substantially reduced with the lipid preparations. The cost differential is large.

Amphotericin B lipid complex (ABLC)

The lipid formulations of amphotericin B were initially compared w/ conventional AmB in pts with aspergillosis. Results of these studies show an advantage for the lipid amphotericin formulations, but only for reduction in adverse reactions. The clinical outcome compared to conventional has generally been the same, but the side effects are substantially reduced with the lipid preparations. The cost differential is large.

Amphotericin B deoxycholate

Used for severe disease (invasive aspergillosis). In one of the most common forms, invasive pulmonary in compromised hosts especially with neutropenia +/- reduced cell mediated immunity, initial reports showed almost 100% mortality. Now there is substantial survival due to rapid dx and if very high doses of amphotericin are used, though voriconazole has now supplanted as first-line therapy.

Posaconazole

(Noxafil) Alternative azole available in oral solution, dealyed release tablet and IV formulation that is FDA approved for the prevention of Aspergillus and Candida as invasive fungal infections in patients at risk. An alternative to voriconazole for patients with aspergillosis. Time to steady state levels can be nearly a week for the tablet and even longer for the solution formulations.

Itraconazole

The clinical experience is extensive and reasonably good, but serious invasive disease requires voriconazole, isavuconazole, posaconazole or amphotericin B.

Flucytosine

Cannot be used as a single agent for aspergillus infections. It is sometimes combined with amphotericin B as a desperation maneuver, especially with CNS infections due to the more favorable penetration of 5FC across the blood-brain barrier.

Basis for recommendation

  1. 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: 2008 IDSA Guidelines for treatment of aspergillosis. This is the source document used here.

  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: Large multicenter study of 144 patients with invasive aspergillosis randomized to receive voriconazole or amphotericin B. Voriconazole was superior in rates of success (53% vs 32%), survival (71% vs 58%) and reduced adverse effects.

  3. Marr KA et al: Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med 162:81, 2015  [PMID:25599346]

    Comment:

    Randomized study of voriconazole +/-anidulafungin in patients with hematological malignancy or hematopoietic stem cell transplant and invasive aspergillosis. Key findings: a. Overall mortality was same in monotherapy and combination group, b. Survival was better in combination therapy than monotherapy for those whose aspergillosis diagnosis was established by radiographic findings and galactomannan positivity.

  4. Pascual A et al: Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis 46:201, 2008  [PMID:18171251]

    Comment: This study is based on 181 measurements of voriconazole levels and showed, despite standard dosing, 31% showed levels considered potentially toxic and 25% showed levels considered subtherapeutic.

References

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

    Comment: A double-blind, placebo-controlled trial for allergic bronchopulmonary aspergillosis using itraconazole 200mg PO twice daily x 16wks. Benefits included reduction in steroid dose, improved exercise tolerance, improved pulmonary function and decreased IgE.
    Rating: Important

  2. Soubani AO, Khanchandani G, Ahmed HP: Clinical significance of lower respiratory tract Aspergillus culture in elderly hospitalized patients. Eur J Clin Microbiol Infect Dis 23:491, 2004  [PMID:15141337]

    Comment: A review of 66 cases with positive cultures for aspergillus indicated 61 were presumed contaminants

  3. Judson MA: Noninvasive Aspergillus pulmonary disease. Semin Respir Crit Care Med 25:203, 2004  [PMID:16088463]

    Comment: Allergic form is associated with Type I, II and IV allergic responses to Aspergillus antigens. Clinical presentation is bronchiectasis, and airway destruction. May be asymptomatic. Treatment is corticosteroids; surgery may be definitive in some cases but many have inadequate lung reserve.

  4. Schubert MS: Allergic fungal sinusitis: pathophysiology, diagnosis and management. Med Mycol 47 Suppl 1:S324, 2009  [PMID:19330659]

    Comment: Allergic fungal sinusitis is a non-invasive form of sinusitis that accounts for 6-9% of surgeries for rhinosinusitis. Major pathogens: aspergillus, Bipolaris and Curvularia species.
    Rating: Important

  5. Bowden R et al: A double-blind, randomized, controlled trial of amphotericin B colloidal dispersion versus amphotericin B for treatment of invasive aspergillosis in immunocompromised patients. Clin Infect Dis 35:359, 2002  [PMID:12145716]

    Comment: Amphotec 6mg/kg/d compared to Ampho B 1.0-1.5 mg/kg/d. Rates of therapeutic response were the same (52% vs 51%), but Amphotec was less nephrotoxic (25% vs 49%, p = 0.002).

  6. Wark PA et al: Anti-inflammatory effect of itraconazole in stable allergic bronchopulmonary aspergillosis: a randomized controlled trial. J Allergy Clin Immunol 111:952, 2003  [PMID:12743557]

    Comment: Argues that anti-fungal drugs may exert benefit by mechanisms other than anti-infective effect.

  7. Ashbee HR et al: Therapeutic drug monitoring (TDM) of antifungal agents: guidelines from the British Society for Medical Mycology. J Antimicrob Chemother 69:1162, 2014  [PMID:24379304]

    Comment: Review of literature and recommendations for therapeutic drug monitoring of antifungal agents
    Rating: Important

  8. Parize P et al: Antifungal therapy of Aspergillus invasive otitis externa: efficacy of voriconazole and review. Antimicrob Agents Chemother 53:1048, 2009  [PMID:19104029]

    Comment: Authors show clinical response with voriconazole treatment of Aspergillus causing invasive otitis externa.
    Rating: Important

  9. Odds FC et al: Interlaboratory comparison of results of susceptibility testing with caspofungin against Candida and Aspergillus species. J Clin Microbiol 42:3475, 2004  [PMID:15297486]

    Comment: Comparison of results in 17 expert labs with 20 Aspergillus strains showed good correlation for itraconazole but poor correlation for caspofungin.

  10. Rosenberg M et al: Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med 86:405, 1977  [PMID:848802]

    Comment: Criteria are: 1) episodic asthma; 2) eosinophilia, 3) immediate scratch test reaction to Aspergillus antigen, 4) precipitating antibodies + aspergillus antigen, 5) elevated serum IgE, 6) hx of pulmonary infiltrates, and 7) central bronchiectasis

  11. Denning DW; Aspergillus species; Chapter 248 IN: Principles & Practice of Infectious Diseases. Mandell G, Bennett J, Dolin R (Eds), Churchill Livingston, 5th Ed; 2000; pp. 2674;

    Comment: Classification: ALLERGIC: bronchopulmonary aspergillosis, aspergillus sinusitis; SAPROPHYTIC: pulmonary aspergilloma, fungus ball in sinuses; SUPERFICIAL: otomycosis, onychomycosis, cutaneous aspergillosis immunocompromised; INFECTION 2ND ANY TISSUE DAMAGE/FOREIGN BODY: Keratitis or endophthalmitis, cutaneous, burn wound aspergillosis, OP SITE AND/OR FOREIGN BODY: prosthetic valve, CNS shunt, Hickman, other catheters; IMMUNOCOMPROMISED: Primary cutaneous or mucocutaneous, PULMONARY: acute or chronic necrotizing, AIRWAY: obstructing bronchial or invasive bronchial, sinusitis, disseminated.

  12. Felton TW et al: Efficacy and safety of posaconazole for chronic pulmonary aspergillosis. Clin Infect Dis 51:1383, 2010  [PMID:21054179]

    Comment: Treatment results of 79 patients with chronic pulmonary aspergillosis treated with posaconazole (400 mg bid). Response rate was 61% at 6 months and 46% at 12 months.

  13. Messer SA et al: Activity of contemporary antifungal agents, including the novel echinocandin anidulafungin, tested against Candida spp., Cryptococcus spp., and Aspergillus spp.: report from the SENTRY Antimicrobial Surveillance Program (2006 to 2007). J Clin Microbiol 47:1942, 2009  [PMID:19386851]

    Comment: In vitro studies of 49 strains of Aspergillus fumigatus showed all were sensitive to caspofungin, itraconazole, posaconazole and voriconazole.
    Rating: Important

  14. Kontoyiannis DP et al: Prospective surveillance for invasive fungal infections in hematopoietic stem cell transplant recipients, 2001-2006: overview of the Transplant-Associated Infection Surveillance Network (TRANSNET) Database. Clin Infect Dis 50:1091, 2010  [PMID:20218877]

    Comment: Transplant Surveillance Network with 23 US centers reviewed invasive fungal infections in hemtopoietic stem cell transplant recipients -- 983 cases: aspergillus -- 43%, candidiasis -- 28%, zygomyces (8%). Cumulative incidence in 16,200 HSCT was 7.7-8.1 invasive fungal infections/100 cases for matched and mismatched-related, respectively.
    Rating: Important

  15. Lopes da Silva R et al: Early Diagnosis of Invasive Aspergillosis in Neutropenic Patients. Comparison between Serum Galactomannan and Polymerase Chain Reaction. Clin Med Insights Oncol 4:81, 2010  [PMID:20703324]

    Comment: Comparison of serum PCR and galactomannan in patients with hematological malignancies and chemotherapy. Results: sensitivity GM 88%, PCR 75%; specificity GM 93%, PCR 92%. BAL was sometimes positive by either method when serum was negative. Two or more positive tests improved specificity of both.
    Rating: Important

  16. Lu Y et al: Diagnosis of invasive fungal disease using serum (1→3)-β-D-glucan: a bivariate meta-analysis. Intern Med 50:2783, 2011  [PMID:22082890]

    Comment: Meta-analysis of 15 studies to evaluate the use of (1-3)-B-D-Glucan (BG). Sensitivity and specificity were 0.76 and 0.85, respectively. Subset analysis showed better specificity with positive results with two positive tests in patients with hematologic malignancies and when combined with galactomannan.
    Rating: Important

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

    Comment: Retrospective analysis with 47 patients with AmB failure failures showed voriconazole and caspofungin was a good salvage regimen and was superior to voriconazole alone.
    Rating: Important

  18. McCarthy M et al: Mold infections of the central nervous system. N Engl J Med 371:150, 2014  [PMID:25006721]

    Comment: Comprehensive review of diagnosis and management of filamentous fungal infections of the CNS
    Rating: Important

  19. Patterson TF: Clinical utility and development of biomarkers in invasive aspergillosis. Trans Am Clin Climatol Assoc 122:174, 2011  [PMID:21686223]

    Comment: Author is major authority on aspergillus. For galactomannan the sensitivity for detecting invasive aspergillosis is best in high risk in patients. It is reported as high as 92%, but more recent studies show 40-50% sensitivity. Specificity in high risk patients is >90%. The 1, 3 beta-D-glucan test is somewhat early in development and nonspecific since other fungi including Candida have this cell wall constituent.
    Rating: Important

  20. Maschmeyer G et al: A prospective, randomised study on the use of well-fitting masks for prevention of invasive aspergillosis in high-risk patients. Ann Oncol 20:1560, 2009  [PMID:19451183]

    Comment: Randomized study showed that use of masks for preventing aspergillosis in high risk patients did not work.

  21. Diekema DJ et al: Activities of caspofungin, itraconazole, posaconazole, ravuconazole, voriconazole, and amphotericin B against 448 recent clinical isolates of filamentous fungi. J Clin Microbiol 41:3623, 2003  [PMID:12904365]

    Comment: Results show in vitro activity vs aspergillus as follows: AmB -91% sensitive, caspofungin -98%, itraconazole -83%, posaconazole -98%, ravuconazole -97% and voriconazole -95%.

  22. Herbrecht R et al: Invasive pulmonary aspergillosis. Semin Respir Crit Care Med 25:191, 2004  [PMID:16088462]

    Comment: Review concludes the drug of choice is voriconazole. Alternatives are caspofungin, micafungin, posaconazole and amphotericin.

  23. Marr KA, Leisenring W: Design issues in studies evaluating diagnostic tests for aspergillosis. Clin Infect Dis 41 Suppl 6:S381, 2005  [PMID:16108003]

    Comment: Review from Seattle on the utility of the assay for Aspergillus galactomannan. The controversial concern regards the performance of the test. Now that the test is widely available it is assumed that there will be large trials with definitive answers.

  24. Steinbach WJ et al: Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis 39:192, 2004  [PMID:15307028]

    Comment: Review of 83 cases showed mortality in 19/34 (56%) given voriconazole compared to 36/49 (73%) given other antifungals.

  25. Riscili BP, Wood KL: Noninvasive pulmonary Aspergillus infections. Clin Chest Med 30:315, 2009  [PMID:19375638]

    Comment: Review of non-invasive pulmonary aspergillosis that includes: 1) bronchoallergic form; 2) fungus ball and 3) "chronic pulmonary aspergillosis". The latter has also been called "semi-invasive aspergillosis.
    Rating: Important

  26. Miceli MH et al: Strong correlation between serum aspergillus galactomannan index and outcome of aspergillosis in patients with hematological cancer: clinical and research implications. Clin Infect Dis 46:1412, 2008  [PMID:18419445]

    Comment: Serum galactomannan is a non-invasive, widely available, reproducible test that is FDA cleared for use as a surrogate marker of invasive aspergillosis. This paper is a correlation between serum aspergillus galactomannan levels and outcome.
    Rating: Important

  27. Sun W et al: Evaluation of PCR on bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis: a bivariate metaanalysis and systematic review. PLoS One 6:, 2011  [PMID:22164295]

    Comment: Review of PCR to detect aspergillus in blood samples to facilitate diagnosis of invasive aspergillus. Summary of 17 studies with 1,191 at risk patients showed sensitivity of 0.91 and specificity of 0.92. However, authors concluded that the technique still needs to be standardized.
    Rating: Important

  28. Allo MD et al: Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med 317:1105, 1987  [PMID:3657878]

    Comment: The authors present a case and a graphic picture of aspergillosis at a Hickman catheter insertion site. The lesion showed concentric plaque lesions of diverse colors. Therapy required removal of the catheter and antifungals.

  29. Caillot D et al: Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 15:139, 1997  [PMID:8996135]

    Comment: The authors show the value of CT scans to indicate probable aspergillosis in neutropenic patients and then employ surgical resection as a method of management

  30. Morgan J et al: Incidence of invasive aspergillosis following hematopoietic stem cell and solid organ transplantation: interim results of a prospective multicenter surveillance program. Med Mycol 43 Suppl 1:S49, 2005  [PMID:16110792]

    Comment: The cumulative incidence from 19 sites in the US with 4621 HSCT at 12 months was 0.5% after autologous transplant, 2.3% with an HLA matched donor and 3.9% with an unrelated donor. For 410 organ transplant recipients it was at 12 months it was: lung-2.4%, heart 0.8%, liver 0.3%, kidney -0.1%. The 3 month mortality ranged from 20% for lung transplants to 67% for heart and kidney. The dominant species were A fumigatus -56%, A flavus -19%, A. terreus-16% and A. niger-8%.

  31. White MH et al: Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis 24:635, 1997  [PMID:9145737]

    Comment: The initial trials for drug registration for the 3 commercially available lipid formulations of amphotericin B were done with aspergillosis. The initial FDA approval was consequently for aspergillosis. These trials showed the lipid formulations were not clinically superior to conventional amphotericin B, but they were less toxic.

  32. Jewkes J et al: Pulmonary aspergilloma: analysis of prognosis in relation to haemoptysis and survey of treatment. Thorax 38:572, 1983  [PMID:6612647]

    Comment: The operative mortality for surgical resection of aspergillus fungus balls was 7%, and post-op complications included B-P fistulae and hemorrhage. The recommendation is to reserve surgery for cases that show severe hemoptysis and show adequate pulmonary reserve.

  33. 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: This is the NIH Mycosis Study Group criteria for the diagnosis of invasive aspergillosis which combines host factors, radiologic findings and mycotic criteria.
    Rating: Important

  34. Kuhlman JE et al: Invasive pulmonary aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management. Chest 92:95, 1987  [PMID:3595255]

    Comment: This is the original description of the "halo sign" (nodular lung lesion with surrounding area of low attenuation) as an early sign, and the later "crescent sign" (air crescent at periphery of lung nodule).

  35. Stevens DA, Lee JY: Analysis of compassionate use itraconazole therapy for invasive aspergillosis by the NIAID Mycoses Study Group criteria. Arch Intern Med 157:1857, 1997  [PMID:9290545]

    Comment: This report showed the potential efficacy of itraconazole as the best and then currently only available azole for aspergillosis. The "cure/improve" rate in these studies was 63%. Diagnostic criteria for study purposes were defined as: histopathology showing septate hyphae measuring 2-4u in width with acute angle branching + culture yielding aspergillus. This fungus is difficult to distinguish histologically from Fusarium and P. boydii.

  36. Levy H et al: The value of bronchoalveolar lavage and bronchial washings in the diagnosis of invasive pulmonary aspergillosis. Respir Med 86:243, 1992  [PMID:1620912]

    Comment: Use of bronchoscopy is reasonably good for detecting aspergillus in compromised patients with invasive aspergillosis.

  37. Weiler S et al: Human tissue distribution of voriconazole. Antimicrob Agents Chemother 55:925, 2011  [PMID:21078931]

    Comment: Voriconazole penetrates well into tissue based on autopsies from patients: lung (median level 6.3 ug/gm), brain (3.4 ug/gm), liver (6.9 ug/gm), kidneys (6.2 ug/gm), spleen (11.5 ug/gm) and myocardium (16.6 ug/gm).

  38. Wingard JR et al: Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood 116:5111, 2010  [PMID:20826719]

    Comment: Randomized blinded trial of prophylactic fluconazole vs. voriconazole to prevent invasive aspergillosis in patients undergoing myeloablative allogeneic hematopoietic cell transplant. With intensive monitoring (serum galactomannan twice weekly x 60 days, then once weekly x 40 days). Aspergillosis occurred in 7.3% recipiens of voriconazole vs. 11% for fluconazole (p=0.09).
    Rating: Important

Media

Aspergillus hyphae and conidiaSource: CDC

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Last updated: January 15, 2016