Aspergillus species

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Aspergillus /
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Background

Microbiology

  • Aspergillus is a mold with hyaline (lightly-pigmented) hyphae, septated, and usually branched at acute angle (45º)
  • Named for the appearance of the sporulating head, which looks like an aspergillum used to sprinkle holy water (in 1729)
  • Most species reproduce asexually, although A. fumigatus and a few others have teleomorphs (sexual form with fruiting body)
  • Culture is important, but molecular methods are often required to identify the particular species
    • Pathogenic species grow quickly on common media
    • Can grow at 37º C, and A. fumigatus can grow up to 50º C
  • Organized into complexes, which cannot be differentiated phenotypically, but rather need molecular methods
    • Fumigatus: A. fumigatus, A. lentulus, A. udagawae
    • Ustus: A. calidoustus (often resistant to ampho B)
    • Niger: A. tubingensis and A. niger
    • Versicolor: A. versicolor and A. sydowii
Species Colonies Conidiophore Phialides Other
A. flavus Yellow green, yellow, brownish Rough colourless Uniseriate and biseriate Sclerotia sometimes present
A. fumigatus complex Grey-green, blue green, yellowish Smooth, colourless or greenish Uniseriate Good growth at 48ºC
A. glaucus Green and yellow, yellowish, brown Smooth, colourless Uniseriate Yellow to orange cleistothecia present
A. nidulans Green buff, purplish red, olive Smooth, brown Biseriate Round hülle cells and cleistothecia with purple ascospores usually present
A. niger Black, white, yellowish Smooth, colourless or brown Biseriate
A. terreus Brown cinnamon, yellowish brown Smooth, colourless Biseriate Round, solitary aleurioconidia produced directly on hyphae
A. ustus Light brown, grayish brown, yellowish brown Smooth, brown Biseriate Long, brown-walled conidiophores, small vesicles, rough-walled conidia
A. versicolor White, buff, yellow, pink, pale green, white, yellow, purplish red Smooth, colourless Biseriate Round hülle cells sometimes present

Epidemiology

  • Ubiquitous worldwide, found in soil, water, food, air, and decaying vegetation
  • There is increasing antifungal resistance worldwide
  • Outbreaks can occur with construction
  • May also be possible to have activation of latent infecton or colonization, making infection control more difficult

High-Risk Populations

  • The major risk factor is defective function or decreased number of neutrophils
  • Highest risk, in order, are: CGD, allogeneic hematopoietic stem cell transplantation with GVHD, AML with induction or (worse) reinduction, everyone else
  • Hematopoitic stem cell transplantion is high risk (7% allo, 1% auto)
    • Peaks <40 days and >100 days
    • With or without neutropenia, most likely related to steroid use
  • Hematologic malignancies
    • Usually following induction chemotherapy, or refractory or recurrenct disease (50% mortality)
    • 3+7 AML induction usually 14-21 days of neutropenia
  • Solid organ transplantation
    • Highest among lung transplantation recipients (6%) due to ongoing environmental exposure, decreased ciliary clearance, and common concomitant Aspergillus colonization
    • Followed by liver (4%), heart (2%), and kidney (0.5%)
    • Usually diagnosed at 6 to 12 months
  • Therapeutic immunosuppression, including prednisone and TNF-α inhibitors
  • GVHD increases the risk, due to the additional immune suppression
    • Highest risk within GVHD is with gut involvement
  • Solid maligancies are relatively low risk due to the short courses of neutropenia, but increasing risk with newer chemotherapies

Pathophysiology

  • Initially acquired by inhalation of conidia into lungs or sinuses, or rarely from local tissue invasion
  • The conidia grow and germinate, transforming into hyphae and invading the vasculature
    • Hydrocortisone appears to be a growth factor for Aspergillus
    • Vascular invasion is typical of invasive aspergillosis
    • May cause pulmonary infarction
  • This can be followed by hematogenous dissemination
  • The host immune response begins with ciliary clearance to prevent the conidia from reaching the alveoli
  • Once in the alveoli, the response depends on pulmonary macrophages to phagocytose the conidia
  • Following germination and growth of hyphae, PMNs act to kill hyphae and swollen conidia
    • This is helped by opsonization of conidia by complement
    • Antibodies are common, given the mold's ubiquity, but not protective
  • A. fumigatus has small conidia, allowing it to reach the alveoli more easily, and also produces a complement inhibitor

Clinical Manifestations

Colonization and Superficial Infections

Aspergilloma (Fungal Ball)

  • Ball of hyphae growing in a preexisting cavity, often in bullous emphysema, sarcoidosis, tuberculosis, histoplasmosis, congenital cysts, bacterial lung abscesses, or Pneumocystis bleb
  • Often asymptomatic, but the most common symptom is hemoptysis, which can be fatal
  • Can also occur in the sinuses

Other Superficial Infections

Allergic syndromes

Allergic Bronchopulmonary Aspergillosis (ABPA)

Allergic Fungal Sinusitis

  • Can be Aspergillus or other molds
  • Mangement is mostly surgical

Chronic Cavitary Pulmonary Aspergillosis (CCPA)

  • One or more cavities that can contain solid or liquid material or a fungal ball, usually following creation of multiple cavities from another process
  • May present with pulmonary or constitutional symptoms, including hemoptysis, dyspnea, and productive cough
    • Weight loss and fatigue are common and profound, while fevers are less common
    • May mimic TB
  • Diagnosis requires:
    • 3 months of symptoms or chronic illness or progressive radiological abnormalities with cavitation, pleural thickening, perivacitary infiltrates +/- fungal ball
    • Aspergillus IgG antibodies
    • No or minimal immunocompromise
  • Must rule out other causes of symptoms, including other causes of weight loss

Invasive Aspergillosis

  • aka. angioinvasive, invading the vasculature

Subacute Invasive Aspergillosis

  • Previously called chronic necrotizing pulmonary aspergillosis
  • Occurs in mildly immunocompromised or very debilitated patients
    • Risk factors include diabetes mellitus, malnutrition, alcoholism, advanced age, prolonged corticosteroids or other immunosuppressive agents, chronic obstructive lung disease, connective tissue disorders, radiation therapy, non-tuberculous mycobacterial infection, or HIV infection
  • Similar clinical and radiological findings as chronic cavitary pulmonary aspergillosis, but progresses more rapidly into frank invasive pulmonary aspergillosis

Invasive Pulmonary Aspergillosis

  • Usually after 10 to 12 days of severe neutropenia
  • Non-productive cough, dyspnea, pleuritic chest pain, and fever with pulmonary infiltrates despite broad-spectrum antibiotics
    • Symptoms may be less prominent in patients with defective immunity
    • Fever dampened by high dose steroids
  • Also hemoptysis, pleural effusion, and pneumothorax
    • Can mimic a pulmonary embolism
  • Imaging may show multiple dense nodular pulmonary infiltrates without air bronchograms, suggesting extensive infection
    • Classic, though, is pleural-based wedge-shaped densities or cavitary lesions
    • Pleural effusions are common
    • A nodular lesion wth a halo is suggestive of early aspergillosis, followed by cavitation in later disease

Other Sites of Invasive Respiratory Aspergillosis

  • Ulcerative tracheobronchitis, a high concern in lung transplant
    • May mimic graft rejection
  • Invasive rhinosinusitis, with mortality of 10-20%
  • Hematogenous dissemination to any organ, associated with 90% mortality

Other Sites of Invasive Aspergillosis

  • Cerebral aspergillosis, which may explain half of all CNS lesions in HSCT
    • Presents >100 days after transplant, usually with concomitant pulmonary disease
    • Presents with focal neurological signs, altered mental status, and headache
  • Osteomyelitis
    • Vertebral osteomyelitis may result from extension of empyema, but is also the most common site of hematogenous dissemination
  • Skin and soft tissue infection
    • Either from hematogenous spread or local invasion
    • Often around IVs or adhesive dressings
    • Neutropenic patients as well as burns and surgical sites

Specific Risk Groups

  • For CGD, AML induction, and SOT, it tends to be isolated pulmonary aspergillosis
  • In HSCT with GVHD, you tend to see more CNS aspergillosis and disseminated aspergillosis

Diagnosis

  • Culture positive for Aspergillus and histology with invasive hyphae
    • Only 10-30% of patients with IA have a positive BAL culture, improved with use of fungal media
  • Serology
    • Antibodies is unhelpful, given that the mold is ubiquitous
    • Galactomannan by EIA
      • Best-studied and most sensitive in HSCT patients
      • It is a meleased from the fungal cell wall on growth
      • Cutoff of 0.5 is good, 80% Sn and Sp (up to 90% in HSCT patients' serum)
      • BAL is more sensitive, but prophylaxis decreases sensitivity
      • Can be done from CSF
      • False-positives may occur with pip/tazo and other beta-lactams (though mostly of historical interest now)
    • 1,3-beta-D-glucan (BDG): can detect Candida and Pneumocystis as well, so less specific. May be useful in combination with GM.
    • Combination serologies: GM (BAL) Sn 43-56% and Sp 97%; BDG (blood) Sn 56-65% and Sp 97%; combination of either test positive Sn 78-92%% and Sp 93%, while PCR did not have any additional benefit (source).
  • Molecular testing
    • Fungal PCR possible, but not routinely done; may not be helpful since the fungus is ubiquitous and wouldn’t differentiate invasive disease vs. colonization.
    • Microarray DNA: Microbiologic diagnostics are often combined with imaging to diagnose probable invasive fungal infection.
  • Imaging can be helpful
    • Halo sign on CT is present for about the first 7 days of disease in neutropenic patients
    • Can also have nodules, pleural-based infarctions, or vacitation, as well as non-specific consolidation

Management

Antifungal Resistance

  • Broth microdilution is the main method for determining Aspergillus susceptibility recommended by CLSI and EUCAST. Microdilution results are affected by a number of factors (shape of the microdilution well, inoculum concentration, temperature and length of incubation time), so testing must be rigorously standardized.
  • Antifungal mechanisms
    • Polyenes (amphotericin): binds ergosterol to create pores within the cell membrane.
    • Triazoles (except fluconazole): inhibit sterol synthesis of ergosterol by disrupting 14-alpha demethylase. The mechanisms of resistance are myriad: modification of target enzymes, an increased expression of drug efflux mechanisms, an overexpression of target enzymes, an incorporation of exogenous cholesterol, an overexpression of HSP90 and of a sterole-regulatory element binding protein.
    • Echinocandins (the fungins): disrupt synthesis of beta-glucan in the cell wall by inhibiting 1,3-beta glucan synthase.
  • Resistance patterns
    • All species are resistant to fluconazole. Historically, amphotericin has been the most reliable anti-Aspergillus antifungal; now, voriconazole is the standard.
    • Resistance to amphotericin is seen in A. terreus, A. flavus, and other less common species.
    • A. niger has variable susceptibility to azoles. There is increasing A. fumigatus resistance to azoles, with reports being most common from Europe. A. calidoustus (within A. ustus complex) is a growing cause, with late presentation, intrinsic antifungal resistance, and high mortality.
Organism AmB Fluc Itra Vori Posa Anidula Caspo Mica Flucyt
Aspergillus spp. + – + + + + + + –
 A. flavus ± – + + + + + + –
 A. fumigatus + – + + + + + + –
 A. terreus – – + + + + + + –
 A. niger + – ± + + + + + –

Aspergilloma

  • If asymptomatic and single aspergilloma, monitor
  • If symptoms, especially hemoptysis, surgical resection (if possible)
  • No role for antifungals

Allergic Bronchopulmonary Aspergillosis (ABPA)

Allergic Fungal Rhinosinusitis

  • Polypectomy and sinus washout
  • Topical nasal steroids
  • Oral antifungal therapy can be tried if above does not work, but rarely effective

Chronic Cavitary Pulmonary Aspergillosis (CCPA)

  • If asymptomatic, monitor every 3-6 months, with investigations every 3-12 months including
    • Low-dose CT chest or CXR
    • ESR/CRP
    • Aspergillus IgG titres
    • Annual PFTs
  • If pulmonary symptoms, constitutional symptoms, or worsening lung function, treat with 6+ months of antifungal therapy
  • If hemoptysis, treat with tranexamic acid, pulmonary artery embolization, or antifungal therapy
  • May need surgical resection if localized disease refractory to medical management

Invasive Aspergillosis

Breakthrough Infection

  • Base empiric treatment on local epidemiology
  • Probably fewer breakthroughs in HSCT patients with posaconazole prophylaxis

Therapeutic Drug Monitoring

Antifungal When to Measure Trough Level Target for Treatment Target for Prophylaxis Target for Safety
Itraconazole day 5 of therapy 1-4 mg/L by HPLC

3-17 mg/L by bioassay

0.5-4 mg/L by HPLC

3-17 mg/L by bioassay

≤~4 mg/L by HPLC

≤17.1 mg/L by bioassay

Voriconazole after 2 to 5 days of therapy, and 4 days after any change 1-5.5 mg/L 1-5.5 mg/L
Posaconazole day 5 of therapy >1 mg/L >0.7 mg/L ≤3.75 mg/L
Isavuconazole day 5 of therapy, but not clearly needed

Failure

  • Technically should be assessed at 6 weeks (2 weeks at a minimum, based on pharmacokinetics)

Prevention

  • For high-risk patients in hospital (e.g. HSCT), use air filters, frequent air exchanges, and positive-pressure ventilation

Antifungal Prophylaxis

Further Reading

  • Practice Guidelines for the Diagnosis and Management of Aspergillosis: 2016 Update by the IDSA. Clin Infect Dis. 2016;63(4):e1-e60. doi: 10.1093/cid/ciw326
  • Diagnosis and management of Aspergillus diseases: executive summary of the 2017 ESCMID-ECMM-ERS guideline. Clin Microbiol Infect. 2018. doi: 10.1016/j.cmi.2018.01.002
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