Aspergillus

Shmuel Shoham, M.D.

MICROBIOLOGY

A ubiquitous group of molds found worldwide includes hay, compost, soil, basements, HVAC and plants (including marijuana).
- Air contamination 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, which is composed of long filamentous structures (hyphae) attached to the substrate upon which the fungus is feeding AND as aerial hyphae. These hyphae have 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.
- For example, in A. fumigatus, azole susceptibility varies by geographical region. Voriconazole susceptibility rates are as low as 22.2% in the Netherlands and 76% in Brazil but exceed 94% in Korea, India, China, and the UK.
- Cross-resistance to other azole is common.

CLINICAL

Disease types: The respiratory tract (lung, sinuses, and large airways) is the most common site of infection.
Other sites include skin, eyes, 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, and the disease spectrum includes chronic cavitary, chronic fibrosing, subacute invasive (also called chronic necrotizing) and acute invasive variants.
- Risk groups (may often overlap)
  - Abnormalities in neutrophil/phagocyte number: neutropenia (< 500 neutrophils/mm3) for >10 days, hematologic malignancy (e.g., leukemia, lymphoma, multiple myeloma), stem cell transplant before 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, therapy with a T-cell immunosuppressant (e.g., a 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: reflecting hypersensitivity responses to the fungus from the host.
  - Allergic bronchopulmonary aspergillosis (ABPA): often seen in patients with diagnoses of asthma or cystic fibrosis.
  - Allergic sinusitis
- Aspergilloma: The presence of Aspergillus fungus ball in a preexisting pulmonary cavity.
  - Clinical manifestations in chronic cavitary aspergillosis range from a single and stable aspergilloma to fungus ball(s).
Diagnosis: usually, a combination of host status, imaging and microbiological findings is used to diagnose. 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 ≥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 an 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 a 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).
  - Possible: clinical disease + immunocompromised host: This is often a driver for empiric therapy.
Important notes on diagnostic testing:
- Aspergillus spp. commonly colonize the respiratory tract and are also frequent laboratory contaminants, so positive cultures must be interpreted carefully.
- Negative cultures do not rule out invasive aspergillosis.
  - Blood cultures are rarely positive (when they are positive, it is typically due to laboratory contamination, not actual infection).
  - Tissue cultures will often fail to yield growth despite the apparent 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, nodules ≥ 1 cm in diameter suggest a filamentous fungal infection, usually aspergillosis.
  - Halo sign: a nodule surrounded by a halo of ground-glass attenuation.
    - In neutropenic patients, 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 a tree-in-bud appearance in a patchy distribution, predominant peribronchial areas of consolidation, and bronchopneumonia.
- Diagnosis of ABPA relies on a combination of clinical, radiographic, hematologic and serologic data.
  - Predisposing clinical conditions (e.g., asthma, cystic fibrosis, bronchiectasis, COPD)
  - Compatible clinical and radiological presentation
  - Labs:
    - Elevated serum total IgE
    - Aspegillus-specific IgE,
    - Elevated eosinophil count
    - Anti-Aspergillus IgG

SITES OF INFECTION

Pulmonary most common form seen (4 main subtypes with overlaps among groups):
- Rapidly progressive disease: typically seen in patients with significant 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 involving 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 (which may play a 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
- Seen in patients with poorly controlled diabetes or host immune deficiencies.
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):
- Catheter and CSF shunt infections
- Urinary tract infection
- Endocarditis

TREATMENT

Pulmonary

Early treatment with the right agent appears critical for invasive aspergillosis, and for immunocompromised patients recovery of immune function.
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:
        Consider loading 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[6].
    - 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.
    - 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 FDA-approved for treatment, but clinically used.
      - A trough of >1 mg/L is recommended to treat invasive disease.
- Alternatives:
  - Liposomal amB (most preferred of amB products) 5 mg/kg/d IV. Improtant role in azole resistant aspergillosis.
  - Amphotericin B 1 mg/kg/d IV: use is limited by toxicities
  - Caspofungin 70 mg IV x 1 dose, then 50 mg/d IV (FDA approved for salvage indication). Use of any of the echinocandins alone is not recommended as first-line therapy
  - Micafungin 100-150 IV/d
  - Anidulafungin 200 mg x 1 dose then 100 mg/d IV
  - Itraconazole (only for mild cases, intolerant of other therapies): 200 mg PO 3 times daily for the first 3 d of treatment, 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.
- The approach to treatment is based on susceptibility testing results and for intrinsically resistant species if culture-positive specimens are available.
  - 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 chronic cavitary pulmonary aspergillosis: long-term antifungal therapy (e.g., with voriconazole, itraconazole, posaconazole).
Allergic bronchopulmonary aspergillosis (ABPA): Steroids are the cornerstone of therapy. Antifungal agents can have steroid-sparing properties
- Prednisone 0.5 mg/kg/day for 2 weeks, followed by 0.5 mg/kg/day every other day x 8 weeks, then taper by 5 mg every 2 weeks and discontinue over 3–5 months
- Alternate: prednisone 0.5 mg/kg/day x 4 weeks, then 0.25 mg/kg/day x 4 weeks, then 0.125 mg/kg/day, for 4 weeks each; then taper by 5 mg every 2 weeks till discontinuation
- Antifungal agent (e.g. itraconazole, voriconazole, posaconazole) +/- prednisone
- Nebulized inhaled amphotericin B: May reduce exacerbations
- Biologic agents: These drugs may be used for ABPA when they are needed to treat concomitant asthma. They may have steroid-sparing effect
  - Anti-IL-5: mepolizumab and Benralizumab
  - Anti-Il4: Dupilumab
  - anti-IgE: Omalizumab:
  - Other: Tezepelumab

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 and 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).
  - Depending on the situation and extent of the infection, topical therapy, systemic therapy (e.g., voriconazole, posaconazole, isavuconazonium), and surgical debridement may be required.

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.
    - The role of dual therapy with an echinocandin is unclear in CNS infections.
  - Posaconazole may have a role as second-line therapy.
    - CSF penetration is poor, but parenchymal penetration may be adequate for 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.
- The role of combination with echinocandin is unclear.
- Alternatively, AmB products, posaconazole, or echinocandin may be used, 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 the catheter and do intraperitoneal dialysis with AmB and IV AmB.
- Alternate: voriconazole
Cutaneous: determine if it is due to dissemination from a primary focus other than the skin.
- 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), it 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 treating 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 are more reassuring regarding safety. Therapeutic drug monitoring (serum trough levels) seems important for improving efficacy and reducing toxicity.
Anidulafungin	They are well-tolerated parenteral drugs; however, monotherapy’s exact role in treating severe Aspergillus infection is unclear. Use in combination therapy with voriconazole may result in improved outcomes.
Caspofungin acetate	They are well-tolerated parenteral drugs; however, monotherapy’s exact role in treating serious Aspergillus infection is unclear. Use in combination therapy with voriconazole may result in improved outcomes.
Micafungin	They are 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 may result in improved outcomes.
Isavuconazonium (prodrug of isavuconazole)	(Cresemba) The FDA-approved azole as an antifungal agent 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 with conventional AmB in patients 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 significant.
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, voriconazole has now been supplanted as first-line therapy.
Posaconazole	(Noxafil) This alternative azole is available in an oral solution, delayed-release tablet and IV formulation. It is FDA-approved for the prevention of Aspergillus and Candida invasive fungal infections in patients at risk. It is 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 invasive severe disease requires voriconazole, isavuconazole, posaconazole or amphotericin B.
Flucytosine	It cannot be used as a single agent for Aspergillus infections. However, it is sometimes combined with amphotericin B as a desperation maneuver, especially with CNS infections, due to 5FC’s more favorable penetration 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 before 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
  - Posaconazole (preferred) 300 mg x 2, then daily tablet/IV (200 mg three times a day solution), voriconazole 200 mg twice-daily or itraconazole 200 mg twice-daily.
  - Echinocandin (e.g., micafungin 50–100 mg/day, caspofungin 50 mg/day) if azole is contraindicated.
  - Isavuconazole is increasingly used as prophylaxis due to the reduced potential for toxicities and drug/drug interactions with some chemotherapeutic agents.
    - This use is not approved, and data from randomized controlled trials are currently lacking.
- 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 varies (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 before transplant, massive blood transfusion requirement at transplant, dialysis, re-operation involving thoracic or intra‐abdominal cavity).
  - Echinocandin is preferred for 2-3 weeks.
  - Lipid AmB 3-5 mg/day as an alternative.
- Heart transplant: Targeted prophylaxis for high-risk patients (Aspergillus colonization, 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

Agarwal R, Sehgal IS, Muthu V, et al. Revised ISHAM-ABPA working group clinical practice guidelines for diagnosing, classifying and treating allergic bronchopulmonary aspergillosis/mycoses. Eur Respir J. 2024;63(4). [PMID:38423624]
Comment: Practice guidelines for diagnosis and management of ABPA.
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. 2020;71(6):1367-1376. [PMID:31802125]
Comment: Updated and revised formal definitions for invasive fungal infections. Helpful as a guide, but patients with conditions not fulfilling the requirements of these definitions may still have an invasive fungal infection.
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. The source of recommendations for such patients is in this module.
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.
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.
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 the monotherapy and combination groups, b. Survival was better in combination therapy than monotherapy for those whose aspergillosis diagnosis was established by radiographic findings and galactomannan positivity.
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: A large multicenter study of 144 patients with invasive aspergillosis randomized them 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 disease studies have ever shown the superiority of a particular drug.

References

Thompson GR, Chen SC, Alfouzan WA, et al. A global perspective of the changing epidemiology of invasive fungal disease and real-world experience with the use of isavuconazole. Med Mycol. 2024;62(9). [PMID:39138063]
Comment: Review article that describes the real-world use of isavuconazole as treatment and prophylaxis of aspergillosis.
Morrissey CO, Kim HY, Duong TN, et al. Aspergillus fumigatus-a systematic review to inform the World Health Organization priority list of fungal pathogens. Med Mycol. 2024;62(6). [PMID:38935907]
Comment: This is a systemic literature review regarding Aspergillus fumigatus infections in multiple countries. This paper reports on variability in azole susceptibility by geographic region. For example, in the Netherlands) voriconazole susceptibility for A. fumigatus is 22.2%. By contrast, the susceptibility rates in Brazil, Korea, India, China, and the UK were 76%, 94.7%, 96.9%, 98.6%, and 99.7%, respectively.
Maertens JA, Rahav G, Lee DG, et al. Posaconazole versus voriconazole for primary treatment of invasive aspergillosis: a phase 3, randomised, controlled, non-inferiority trial. Lancet. 2021;397(10273):499-509. [PMID:33549194]
Comment: This article reports on a randomized clinical trial demonstrating the efficacy of posaconazole for treating invasive pulmonary aspergillosis. Outcomes with posaconazole were similar to those with voriconazole but with fewer side effects.
.
Rating: Important
Maertens JA, Raad II, Marr KA, et al. Isavuconazole versus voriconazole for primary treatment of invasive mould disease caused by Aspergillus and other filamentous fungi (SECURE): a phase 3, randomised-controlled, non-inferiority trial. Lancet. 2016;387(10020):760-9. [PMID:26684607]
Comment: This article reports on a randomized clinical trial demonstrating the efficacy of isavuconazole for treating invasive pulmonary aspergillosis. Outcomes with isavuconazole were similar to those with voriconazole but with fewer side effects.
Rating: Important
Gautier M, Normand AC, Ranque S. Previously unknown species of Aspergillus. Clin Microbiol Infect. 2016;22(8):662-9. [PMID:27263029]
Comment: A comprehensive review of newly recognized microbiology of Aspergillus species. Multiple freshly discovered species are detailed.
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
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
Weiler S, Fiegl D, MacFarland R, et al. Human tissue distribution of voriconazole. Antimicrob Agents Chemother. 2011;55(2):925-8. [PMID:21078931]
Comment: Based on autopsies from patients, voriconazole penetrates well into tissue: 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).
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
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 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
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. The summary of 17 studies with 1,191 at-risk patients showed a sensitivity of 0.91 and a specificity of 0.92. However, the authors concluded that the technique still needs to be standardized.
Rating: Important
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
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.
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
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
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):1560-1564. [PMID:19451183]
Comment: A randomized study showed that the use of masks for preventing aspergillosis in high-risk patients did not work.
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 a clinical response with voriconazole treatment of Aspergillus, which can cause invasive otitis externa.
Rating: Important
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
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 are Aspergillus, Bipolaris, and Auricularia.
Rating: Important
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 about the correlation between serum aspergillus galactomannan levels and outcomes.
Rating: Important
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 shows that, despite standard dosing, 31% showed levels considered potentially toxic, and 25% showed levels considered subtherapeutic.
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: A retrospective analysis of 47 patients with AmB failure failures showed that voriconazole and caspofungin were a good salvage regimen and superior to voriconazole alone.
Rating: Important
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.
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.
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 16 weeks. Benefits included reduced steroid dose, improved exercise tolerance, improved pulmonary function and decreased IgE.
Rating: Important
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.
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. Consequently, the initial FDA approval was for aspergillosis. These trials showed the lipid formulations were not clinically superior to conventional amphotericin B, but they were less toxic.
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 the removal of the catheter and antifungals.
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 the surrounding area of low attenuation) as an early sign and the later "crescent sign" (air crescent at the periphery of lung nodule).
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 with severe hemoptysis and adequate pulmonary reserve.
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.

Media

Aspergillus hyphae and conidia

Source: CDC