Aspergillus

Shmuel Shoham, M.D.

MICROBIOLOGY

  • Ubiquitous group of molds 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 species grow 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.
  • Major species: A. fumigatus (most common), A. flavus, A. niger, A. terreus, A. versicolor, A. calidoustus, and A. nidulans
    • A. fumigatus complex has multiple subspecies, including:
      • A. fumigatus (by far the most common) tends to be susceptible to mold active azoles, Amphotericin B (AmB) and echinocandins.
      • A. lentulus has decreased susceptibility to azoles, AmB and echinocandins.
      • A. fischeri and A. thermomutatus have decreased susceptibility to azoles.
      • A. viridinutans and A. felis have decreased susceptibility to voriconazole.
      • A. udagawae has decreased susceptibility to AmB and voriconazole.
    • A. flavus, A. versicolor and A. terreus:
      • Tend to be resistant to AmB, but susceptible to voriconazole, posaconazole and isavuconazole.
    • A. niger: Often a colonizer rather than an invasive fungus.
    • A. ustus and A. calidoustus:
      • Tend to be resistant to multiple antifungal agents.
    • A. nidulans: Tends to be resistant to echinocandins.
  • Susceptibility testing should be performed in patients with invasive disease occurring in areas with known resistance, patients previously exposed to azoles, those who are non-responsive to therapy, and when there is a concern for infection with resistant Aspergillus species.

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 depend on the extent of immunosuppression and possibly, genetic factors.
      • Lungs are the most commonly involved sites where disease spectrum includes chronic cavitary, chronic fibrosing, subacute invasive (also called chronic necrotizing) and acute invasive variants.
    • Risk groups (may often overalp)
      • Abnormalities in neutrophil/phagocyte number: neutropenia (< 500 neutrophils/mm3) for >10 days, hematologic malignancy (e.g. leukemia, lymphoma, multiple myeloma), stem cell transplant prior to neutrophil recovery, aplastic anemia, HIV infection with CD4 count < 100 cells/ml.
      • Abnormalities in neutrophil/phagocyte function: heavy corticosteroid use (e.g. ≥ 0.3 mg/kg prednisone for ≥3 weeks), advanced grades of graft vs. host disease, active CMV infection, cirrhosis, treatment with ibrutinib, treatment with a T-cell immunosuppressant (e.g. calcineurin inhibitor, TNF-α blocker, anti-lymphocyte- Ab, nucleoside analog), solid organ transplants (especially lung and liver), inherited severe immunodeficiency (e.g. chronic granulomatous disease, STAT 3 deficiency, severe combined immunodeficiency).
      • Severe abnormalities in lung function (e.g. cystic fibrosis, bronchiectasis, sarcoidosis), ICU patients, including those with respiratory failure due to severer influenza.
    • Allergic disease:
      • Allergic bronchopulmonary aspergillosis (ABPA): often seen in patients with asthma or cystic fibrosis.
      • Allergic sinusitis
    • Aspergilloma: the presence of Aspergillus fungus ball in a preexisting pulmonary cavity. Clinical manifestations range from single and stable aspergilloma to the presence of fungus ball(s) in the context of chronic cavitary aspergillosis.
  • Diagnosis: usually by a combination of host status, imaging and microbiological findings. Early diagnosis and treatment are critical in management.
    • Techniques:
      • Microscopy
        • Fluorescent dyes (e.g. Calcofluor White): Rapid turnaround, increased sensitivity, not specific for Aspergillus.
        • Histopathology: Gomori’s methenamine silver stain (GMS) and periodic acid-Schiff (PAS) stains are key.
      • Culture: Sabouraud dextrose agar, potato dextrose agar, brain heart infusion (with gentamicin plus chloramphenicol for non-sterile site specimen) at 30°C and 37°C for 72 hours.
      • Radiography: particularly high-resolution CT scan of the chest (see additional information below)
    • Clinical likelihoods:
      • Proven: histopathology, cytopathology, or direct microscopy showing dichotomous branching, septate hyphae AND associated tissue damage AND growth of Aspergillus species from the culture of a normally sterile and clinically or radiographically abnormal site.
      • Probable: clinical disease + immunocompromised host + non-definitive microbiological testing. Because the proven disease is so difficult to establish, patients are increasingly diagnosed at the "Probable" level of proof.
        • Aspergillus recovered by culture from sputum, BAL, bronchial brush, or non-sterile site aspirate (e.g., sinuses).
        • Galactomannan index:
          • Single measurement of ≥ 1.0 from blood, BAL fluid or CSF.
          • Single measurement of ≥ 0.7 from blood AND of ≥0.8 from BAL fluid.
            • Caveats:
              • Exposure to mold active antifungals reduces the sensitivity of the GM index assay.
              • Using a lower threshold (e.g. ≥ 0.5) increases sensitivity, but reduces specificity for actual infection. Many centers have therefore chosen a cutoff of 0.5 for positivity.
        • PCR: Two or more positive measurements from blood, BAL fluid or combination of both.
        • β-d-Glucan: A single level of >80 pg/mL in the appropriate clinical context is suggestive, but not specific for aspergillosis (or even a fungal infection at all).
      • 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).
      • Tissue cultures will often fail to yield growth despite the obvious presence of fungi in histopathology.
    • Serum and BAL galactomannan testing are increasingly used to diagnose invasive aspergillosis.
      • Cross-reactions can occur with other filamentous fungi and with histoplasmosis.
      • A positive result may be due to airway colonization rather than invasive disease so it must be taken in the context of the clinical situation.
    • Lung CT scan:
      • In the appropriate patient, the presence of nodules ≥ 1 cm in diameter are suggestive of a filamentous fungal infection, usually aspergillosis.
      • Halo sign: a nodule surrounded by a halo of ground-glass attenuation. In a neutropenic patient, it is suggestive of aspergillosis.
      • Radiographic findings can evolve due to angioinvasion (wedge-shaped pulmonary infarct) and with the recovery of neutrophils (air crescent at the periphery of lung nodule and cavitation).
      • Aspergillomas may develop at sites of pulmonary infiltrates.
      • Less specific CT findings: alveolar and ground glass consolidations, pleural effusion, bronchoinvasive disease with the appearance of tracheal or bronchial wall thickening, centrilobular nodules with tree in bud appearance in a patchy distribution, predominant peribronchial areas of consolidation, and bronchopneumonia.

SITES OF INFECTION

  • Pulmonary most common form seen (4 main subtypes with overlaps between groups):
    • Rapidly progressive disease: typically seen in patients with major deficiencies in neutrophil number and function (e.g. acute leukemia, aplastic anemia, allogeneic 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: the 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 the first day then 200 mg twice daily.
          • Adult patients ≤ 40 kg should receive half of the oral maintenance dose.
          • 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 suboptimal response to treatment.
        • 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[5].
        • Isavuconazole: 200 mg (given as 372 mg of isavuconazonium) IV TID x 2 days then 200 mg/day (given as 372 mg of isavuconazonium) daily thereafter.
    • Alternatives:
      • 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); Not approved for treatment, but clinically used. A trough of >1 mg/L recommended for the treatment of invasive disease.
      • Itraconazole (only for mild cases, intolerant of other therapies): 200 mg PO 3 times daily for the first 3 d of therapy, followed by 200‐400 PO mg/d. Target trough level >0.5‐1 mg/L.
    • Failure with voriconazole consider:
      • Amphotericin products
      • Combination of voriconazole with an echinocandin
      • Check if the voriconazole level is therapeutic.
    • Approach to treatment based on susceptibility testing results and for intrinsically resistant species
      • Voriconazole MIC = 2 mg/mL, A. tubingensis (part of A. niger complex), A. lentulus (part of A. fumigatus complex): voriconazole AND an echinocandin OR Lipid AmB alone
      • Voriconazole MIC ≥ 2 mg/mL, A. calidoustus: Lipid AmB
      • A. niger: consider avoiding isavuconazole
      • AmB MIC ≥ 1 mg/L, A. terreus, A. alliaceus (part of the A. flavus complex):
        • Use voriconazole or isavuconazole (if susceptible)
  • Aspergilloma:
    • Single and stable aspergilloma: no consensus on whether anti-fungal treatment is effective; the 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 the 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. Steroids are the cornerstone of therapy.

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 the 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 a 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 the 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 poorly, 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 an AmB product.
  • Hepatosplenic:voriconazole (+/- an echinocandin).
    • Alternate therapy is an AmB product.
  • Peritoneal catheter-associated: remove catheter, intraperitoneal dialysis with AmB and IV AmB.
  • Cutaneous: determine if due to dissemination from a 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. The 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, the exact role of 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, the exact role of 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, the exact role of 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 immunosuppressants (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. The results of these studies show an advantage for the lipid amphotericin formulations, but only for a 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. The results of these studies show an advantage for the lipid amphotericin formulations, but only for a 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 is available in oral solution, delayed-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

It 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.

OTHER INFORMATION

Prevention:

  • Target groups for prophylaxis
    • Hematological malignancies with prolonged and profound neutropenia: (e.g. leukemia/MDS receiving induction therapy, stem cell transplant prior to neutrophil recovery, stem cell transplant with GVHD requiring steroids ( >1 mg/kg/day of prednisone for >2 weeks) and/or the use of other systemic anti-GVHD therapies
    • Lung transplant recipients, especially if high risk (e.g. known to be colonized with Aspergillus, single-lung transplant, early airway ischemia, CMV infection, IgG level < 400 mg/dL, treatment of rejection with anti-T cell antibody or high dose steroids).
      • If galactomannan in BAL ≥ 1 (i.e. preemptive therapy): posaconazole or voriconazole x 3-4 months (see below for doses)
      • Prophylaxis: targeted toward high-risk groups or universal
        • Inhaled AmB: frequency duration vary (e.g. deoxycholate D‐AmB 20 mg three times a day to 25 mg/d; ABLC 50 mg every other day, L‐AmB 25 mg three times/week)
        • Posaconazole 300 mg/day tablet, voriconazole 6 mg/kg for two doses followed by 4 mg every twice-daily, itraconazole 200 mg twice-daily
    • Liver transplant recipients with high-risk features (e.g. re-transplantation, fulminant hepatic failure, ICU or steroids prior to transplant, massive blood transfusion requirement at transplant, dialysis, re-operation involving thoracic or intra‐abdominal cavity).
      • Echinocandin preferred for 2-3 weeks. Lipid AmB 3-5 mg/day as an alternative.
    • Heart transplant: Targeted prophylaxis for high-risk patients (Aspergillus colonization, presence of airborne Aspergillus spores in the ICU, thoracic re‐operation, CMV disease, hemodialysis, suspected outbreak). Posaconazole, itraconazole, voriconazole or an echinocandin. Duration ranges from 50-150 days
    • Secondary prophylaxis should be considered for patients with a history of invasive aspergillosis who undergo T‐cell depletion, receive high‐dose steroids or have neutropenia.

Basis for recommendation

  1. Husain S, Camargo JF. Invasive Aspergillosis in solid-organ transplant recipients: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice. Clin Transplant. 2019;33(9):e13544.  [PMID:30900296]

    Comment: Clinical guidelines for management and prevention of aspergillosis in solid organ transplant recipients. Source of recommendations for such patients in this module

  2. Donnelly JP, Chen SC, Kauffman CA, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2019.  [PMID:31802125]

    Comment: Updated and revised formal definitions for invasive fungal infections. Useful as a guide, but patients with conditions not fulfilling the requirements of these definitions may still have an invasive fungal infection.

  3. Ullmann AJ, Aguado JM, Arikan-Akdagli S, et al. Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018;24 Suppl 1:e1-e38.  [PMID:29544767]

    Comment: Multinational guidelines for diagnosis and management of aspergilliosis.

  4. Patterson TF, Thompson GR, Denning DW, et al. Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016;63(4):e1-e60.  [PMID:27365388]

    Comment: Practice guidelines published by IDSA for aspergillosis. Source for recommendations in this module

  5. Marr KA, Schlamm HT, Herbrecht R, et al. Combination antifungal therapy for invasive aspergillosis: a randomized trial. Ann Intern Med. 2015;162(2):81-9.  [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 the 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.

  6. Pascual A, Calandra T, Bolay S, et al. Voriconazole therapeutic drug monitoring in patients with invasive mycoses improves efficacy and safety outcomes. Clin Infect Dis. 2008;46(2):201-11.  [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.

  7. Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6):408-15.  [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. Few infectious diseases studies have ever shown the superiority of a particular drug.

References

  1. Gautier M, Normand AC, Ranque S. Previously unknown species of Aspergillus. Clin Microbiol Infect. 2016;22(8):662-9.  [PMID:27263029]

    Comment: Comprehensive review of newly recognized microbiology of Aspergillus species. Multiple newly discovered species are detailed

  2. Lamoth F. Aspergillus fumigatus-Related Species in Clinical Practice. Front Microbiol. 2016;7:683.  [PMID:27242710]

    Comment: Review highlighting clinical and microbiological features of newly discovered species within the Aspergillus fumigatus species complex.
    Rating: Important

  3. McCarthy M, Rosengart A, Schuetz AN, et al. Mold infections of the central nervous system. N Engl J Med. 2014;371(2):150-60.  [PMID:25006721]

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

  4. Weiler S, Fiegl D, MacFarland R, et al. Human tissue distribution of voriconazole. Antimicrob Agents Chemother. 2011;55(2):925-8.  [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).

  5. Lu Y, Chen YQ, Guo YL, et al. Diagnosis of invasive fungal disease using serum (1→3)-β-D-glucan: a bivariate meta-analysis. Intern Med. 2011;50(22):2783-91.  [PMID:22082890]

    Comment: A 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

  6. Patterson TF. Clinical utility and development of biomarkers in invasive aspergillosis. Trans Am Clin Climatol Assoc. 2011;122:174-83.  [PMID:21686223]

    Comment: The author is a major authority on aspergillus. For galactomannan, the sensitivity for detecting invasive aspergillosis is best in a high-risk patient. 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

  7. Sun W, Wang K, Gao W, et al. Evaluation of PCR on bronchoalveolar lavage fluid for diagnosis of invasive aspergillosis: a bivariate metaanalysis and systematic review. PLoS One. 2011;6(12):e28467.  [PMID:22164295]

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

  8. Lopes da Silva R, Ribeiro P, Abreu N, et al. Early Diagnosis of Invasive Aspergillosis in Neutropenic Patients. Comparison between Serum Galactomannan and Polymerase Chain Reaction. Clin Med Insights Oncol. 2010;4:81-8.  [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 the specificity of both.
    Rating: Important

  9. Felton TW, Baxter C, Moore CB, et al. Efficacy and safety of posaconazole for chronic pulmonary aspergillosis. Clin Infect Dis. 2010;51(12):1383-91.  [PMID:21054179]

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

  10. Wingard JR, Carter SL, Walsh TJ, et al. Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation. Blood. 2010;116(24):5111-8.  [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% recipients of voriconazole vs. 11% for fluconazole (p=0.09).
    Rating: Important

  11. Kontoyiannis DP, Marr KA, Park BJ, 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. 2010;50(8):1091-100.  [PMID:20218877]

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

  12. Maschmeyer G, Neuburger S, Fritz L, et al. A prospective, randomised study on the use of well-fitting masks for prevention of invasive aspergillosis in high-risk patients. Ann Oncol. 2009;20(9):1560-4.  [PMID:19451183]

    Comment: A randomized study showed that the use of masks for preventing aspergillosis in high-risk patients did not work.

  13. Parize P, Chandesris MO, Lanternier F, et al. Antifungal therapy of Aspergillus invasive otitis externa: efficacy of voriconazole and review. Antimicrob Agents Chemother. 2009;53(3):1048-53.  [PMID:19104029]

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

  14. Messer SA, Moet GJ, Kirby JT, 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. 2009;47(6):1942-6.  [PMID:19386851]

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

  15. Riscili BP, Wood KL. Noninvasive pulmonary Aspergillus infections. Clin Chest Med. 2009;30(2):315-35, vii.  [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

  16. Schubert MS. Allergic fungal sinusitis: pathophysiology, diagnosis and management. Med Mycol. 2009;47 Suppl 1:S324-30.  [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

  17. Miceli MH, Grazziutti ML, Woods G, 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. 2008;46(9):1412-22.  [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

  18. Marr KA, Boeckh M, Carter RA, et al. Combination antifungal therapy for invasive aspergillosis. Clin Infect Dis. 2004;39(6):797-802.  [PMID:15472810]

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

  19. Steinbach WJ, Benjamin DK, Kontoyiannis DP, et al. Infections due to Aspergillus terreus: a multicenter retrospective analysis of 83 cases. Clin Infect Dis. 2004;39(2):192-8.  [PMID:15307028]

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

  20. Judson MA. Noninvasive Aspergillus pulmonary disease. Semin Respir Crit Care Med. 2004;25(2):203-19.  [PMID:16088463]

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

  21. Stevens DA, Schwartz HJ, Lee JY, et al. A randomized trial of itraconazole in allergic bronchopulmonary aspergillosis. N Engl J Med. 2000;342(11):756-62.  [PMID:10717010]

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

  22. Caillot D, Casasnovas O, Bernard A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol. 1997;15(1):139-47.  [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

  23. White MH, Anaissie EJ, Kusne S, et al. Amphotericin B colloidal dispersion vs. amphotericin B as therapy for invasive aspergillosis. Clin Infect Dis. 1997;24(4):635-42.  [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.

  24. Allo MD, Miller J, Townsend T, et al. Primary cutaneous aspergillosis associated with Hickman intravenous catheters. N Engl J Med. 1987;317(18):1105-8.  [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.

  25. Kuhlman JE, Fishman EK, Burch PA, et al. Invasive pulmonary aspergillosis in acute leukemia. The contribution of CT to early diagnosis and aggressive management. Chest. 1987;92(1):95-9.  [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).

  26. Jewkes J, Kay PH, Paneth M, et al. Pulmonary aspergilloma: analysis of prognosis in relation to haemoptysis and survey of treatment. Thorax. 1983;38(8):572-8.  [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.

  27. Rosenberg M, Patterson R, Mintzer R, et al. Clinical and immunologic criteria for the diagnosis of allergic bronchopulmonary aspergillosis. Ann Intern Med. 1977;86(4):405-14.  [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

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Aspergillus hyphae and conidia

Source: CDC

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Last updated: February 9, 2020