- Rapid Reference
- Overall approach to diagnosis
- Special situations
- Questions & discussion
evaluation: getting started
evaluation: integrating data
- Aspergillus is a ubiquitous fungus. We are all exposed to it, but our immune systems generally resist it. However, as an opportunistic infection, it can cause disease in specific situations. Invasive pulmonary aspergillosis occurs in roughly two situations:
- (1) Primary pneumonia in a patient with profound immunocompromise (e.g., most commonly prolonged neutropenia). This is the classic form of invasive pulmonary aspergillus which has been recognized for decades.
- (2) Secondary nosocomial pneumonia which occurs among patients who are admitted to the ICU for another reason (e.g., ARDS due to influenza). This is fairly common, yet is an extremely challenging diagnosis. Critically ill patients super-infected with aspergillus usually aren't profoundly immunosuppressed. This superinfection can mimic bacterial pneumonia or simply ARDS, with a tendency to blend in among the numerous other issues which the patient has.
- Neutropenia >10 days
- Allogeneic stem-cell transplantation
- Prolonged steroid use (at least 0.3 mg/kg/day prednisone equivalents for >3 weeks)
- Treatment with recognized T-cell immunosuppressant
- Inherited severe immunodeficiency (e.g., chronic granulomatous disease)
- Severe influenza (and possibly COVID-19??)
- Intermediate risk
- Neutropenia <10 days
- Steroid use (less than 0.3 mg/kg/day prednisone equivalents for >3 weeks)
- Malignancy treated with cytotoxic chemotherapy
- Lung transplant, small bowel transplant, autologous stem cell transplantation
- Advanced AIDS (e.g., CD4 count <50, or neutropenia due to antiviral therapy)
- Low risk
- Non-lung solid organ transplantation (heart, kidney, liver, pancreas)
- Short course steroid (e.g., <7 days)
- Prolonged ICU stay
- Renal failure, hemodialysis
- Malnutrition, alcoholism
Invasive pulmonary aspergillosis tends to present differently in neutropenic and non-neutropenic patients. However, there may be overlap between these two presentation types. Overall, patients generally develop severe respiratory failure leading to intubation. (31361683)
neutropenic patients: angioinvasion mimics pulmonary embolism + pneumonia
- Infection may initially center on the pulmonary arteries and behave a bit like a pulmonary embolism.
- Refractory fever is a central finding (may persist even despite anti-fungal therapy).
- Signs of pulmonary infarction
- Dry cough
- Pleuritic chest pain
- Hemoptysis (which can be massive).
- Metastatic infection may extend beyond the lungs
- Abscesses in brain, liver, spleen, kidney
- Skin lesions can be diagnostically helpful if present.
non-neutropenic patients: mimics pneumonia
- Course is overall slower and with less prominent fever, making diagnosis more difficult. (32140409)
- Dyspnea is a prominent symptom.
- Copious sputum production is often seen.
- Fever and chest pain are less frequent than in neutropenic patients.
- This frequently occurs in the context of an intubated patient with ARDS. It may present as either a ventilator-associated pneumonia or simply “refractory ARDS.”
- Most common cutoff is >0.5. In severely immunosuppressed patients, this cutoff yields a sensitivity of ~75% and a specificity of ~85%. (ATS guideline 2019)
- Sensitivity is lower in non-neutropenic patients (perhaps ~50%), because circulating neutrophils will clear the galactomannan antigen.(30299367) Anti-fungal prophylaxis or therapy may likewise decrease sensitivity.
- Specificity is very good, but not perfect (~90%):
- Galactomannan cross-reacts with some other fungal antigens (e.g., penicillium species now renamed talaromycosis, histoplasmosis, fusarium species).
- False-positive results may also be caused by materials contaminated with galactomannan (e.g., some blood transfusion bags, some manufactures of plasmalyte, and in one case ingestion of ice-pops).
- Historically, piperacillin-tazobactam has caused false-positive results, but currently this doesn't seem to be an issue. (ATS guideline 2019)
bronchoalveolar lavage (BAL) galactomannan
- The most commonly used cutoff is >0.5 optical density index. This yields a sensitivity of 79% with specificity of 84%. (ATS guideline 2019) BAL galactomannan can be somewhat elevated in patients with aspergillus colonization.(32572532)
- In non-neutropenic patients, BAL galactomannan may be superior to serum galactomannan, since the infection is centered on the airways. (32140409; 31361683) In one series of patients with post-influenza aspergillosis, sensitivity was 94%. (30299367)
- Beta-D-glucan is a cell wall component of nearly all fungi (except for: Cryptococcus spp., Mucorales spp. including Mucor and Rhizopus, and the yeast phase of Blastomyces dermatitidis).
- This shouldn't be used as the sole serum test, but may be useful in combination with galactomannan. (ESCMID18)
sensitivity for invasive aspergillus
- Sensitivity ~75%. (31970725)
- Sensitivity is not reduced by the use of antifungal agents. Beta-D-glucan might have superior sensitivity compared to galactomannan in patients who aren't neutropenic.
specificity for invasive aspergillus
- Beta-D-glucan is less specific than galactomannan, perhaps ~80%. (31970725)
- (1) False-positive results may occur due to hemodialysis with cellulose membranes, wound packing with gauze, albumin, or intravenous immunoglobulin.
- (2) Positive results can also result from other fungal infections (e.g., Pneumocystis Jiroveci, histoplasmosis, blastomycosis, Candida colonization or invasive infection) or certain bacteria which contain beta-glucans (e.g., Pseudomonas aeruginosa).
sputum culture & fungal stain
- Aspergillus overall is difficult to culture, with sputum culture sensitivity in the 30-50% range.
- BAL culture sensitivity is 30-60%. (ATS guideline 2019)
- The specificity may be on the order of ~50% among intubated patients, where the rate of colonization is fairly high. Overall, the significance of a positive result varies greatly depending on the clinical context (e.g., degree of immunosuppression and background rate of colonization).
- Another limitation is that the culture usually takes 1-3 days to grow. Furthermore, speciation requires sporulation to occur, which can take even longer.
sputum evaluation with fungal stain
- Sputum should be evaluated for fungal organisms using a cytological stain to identify them (e.g., Gomori methenamine silver). Aspergillus species have septated hyphae with acute angle branching (with a similar appearance compared to Scedosporium species and Fusarium species).
- The combination of positive culture plus positive fungal staining may be more suggestive of true infection (rather than colonization).
- Sensitivity is ~80%, with specificity of ~75%. (ATS guidelines 2019)
- This is probably less useful in non-neutropenic patients, among whom Aspergillus is less likely to spread hematogenously.
bronchoalveolar lavage PCR
- Sensitivity is 90%. (ATS guidelines 2019)
- A positive bronchoalveolar PCR doesn't distinguish between colonization versus invasive infection. Thus, the specificity will depend on the clinical context (as with a sputum culture).
- A positive PCR doesn't prove invasive aspergillosis, but a negative PCR argues strongly against this diagnosis.
- PCR can also be performed using a tracheal aspirate in intubated patients unable to undergo bronchoscopy, although the precise yield is unclear. (32343223)
CT scan is the modality of choice
- CT scan is superior to chest X-ray in patients with immunosuppression and possible invasive aspergillosis. (ESCMID18)
neutropenic patients may present with a classic fungal pattern
- In neutropenia, infection often initially centers on the blood vessels. This leads to pulmonary infarction, with subsequent necrosis of infarcted tissue leading to cavitation.
- Initial finding is often nodular infiltrates.
- Patchy, nodular opacities reflect infarction. These can be pleural-based and wedge-shaped.
- Nodular infiltrates may be surrounded by ground-glass opacification due to hemorrhage, generating a “halo sign.”
- Later on, cavitation occurs. In neutropenic patients, this may coincide with recovery of the bone marrow and an increase in neutrophil count.
- Necrosis of lung tissue creates cavities in the lung. The initial cavitation process yields an air-crescent sign (where there is a sliver of air within a forming cavity).
- Clinically, cavitation often correlates with the development of hemoptysis.
non-neutropenic patients often have nonspecific imaging
- In non-neutropenic patients, infection often centers on bronchi and alveolar tissue (bronchoinvasion).
- This leads to a pattern of bronchopneumonia with airspace consolidation, which may look like other forms of pneumonia.
- A “tree in bud” pattern may result from infection of bronchioles.
- Thickening of trachea or bronchial walls may be seen.
- Classic features of aspergillosis can be seen in non-neutropenic patients (e.g., nodular infiltrates with halo sign, cavitation, and air-crescent signs). If present, these can be useful diagnostic clues, but they are infrequently seen.
Bronchoscopy should be considered if the patient is stable enough to tolerate this (especially among patients who are already intubated).
tests which may be obtained include:
- Culture and fungal stain (more on this above)
- Galactomannan (more on this above)
- PCR (more on this above)
airway examination for Aspergillus plaques
- Invasive pulmonary aspergillosis may be accompanied by Aspergillus tracheobronchitis in up to 15% of patients. (30299367)
- Aspergillus tracheobronchitis is diagnosed on the basis of characteristic-appearing lesions seen in the trachea and large bronchi (findings may include ulceration, nodule, pseudomembrane, or plaque). Visualization of these lesions strongly supports invasive disease.
- Definitive diagnosis requires tissue biopsy showing invasion of tissue. There are roughly three different ways to obtain lung tissue, each of which carries substantial risks:
- (1) Surgical biopsy (i.e., wedge biopsy).
- (2) Bronchoscopy with trans-bronchial biopsy.
- (3) Interventional radiology trans-thoracic needle biopsy.
- Most critically ill patients are too unstable to undergo these procedures (due to risks of bleeding and pneumothorax).
approach to diagnosis
 Suspicion for pulmonary aspergillosis
A trigger to evaluate for pulmonary aspergillosis is typically one of the following:
- Sputum culture or smear reveals Aspergillus.
- Imaging findings are highly suggestive of a fungal infection (e.g., nodular infiltrates with cavitation).
- Patient has a very high risk for aspergillosis (e.g., prolonged neutropenia) with persistent fevers or lung infiltrates.
- “Refractory pneumonia” marked by a combination of the following features:
- i) Lung infiltrates with respiratory failure
- ii) Refractory to antibiotics
- iii) Underlying risk factors for aspergillosis
- Investigation of ventilator-associated pneumonia
 Diagnostic workup for aspergillosis
This will vary depending on clinical context and the index of suspicion. Typical elements include the following:
- CT scan of the chest
- Serum galactomannan antigen and beta-D-glucan
- Sampling of the lung if possible:
- Endotracheal aspirate for culture, PCR, and fungal stain (if the patient is intubated and too unstable for bronchoscopy)
- Bronchoalveolar lavage for culture & fungal stain, PCR, and galactomannan (if it can be accomplished safely)
 Integration of data
Having collected several data points, the next step is to integrate this information to reach a clinical decision. Key factors to consider are mycology, imaging, epidemiology, and clinical presentation:
when to treat?
- This is unclear. Especially in the ICU, precise guidelines regarding how to diagnose invasive aspergillosis and when to initiate therapy are lacking.
- Treatment initiation depends on overall clinical judgement and risk assessment. Treatment initiation shouldn't wait for definitive diagnosis (which is often impossible in critically ill patients). Furthermore, many lab tests are send-outs which take days to return. When in doubt, it may be reasonable to initiate treatment with voriconazole or isavuconazonium while simultaneously obtaining additional diagnostic tests.
voriconazole is traditionally the front-line agent
- Typical dose is 6 mg/kg q12hr for one day followed by 2-4 mg/kg q12hr. It may be administered intravenously or orally (with excellent absorption).
- Voriconazole is metabolized in the liver by CYP2C19 and CYP3A4 systems, leading to numerous drug-drug interactions.
- Major side-effects include visual disturbance, hepatotoxicity, skin rash, neurological symptoms, and QT prolongation.
- Intravenous voriconazole is contraindicated in renal dysfunction, due to its formulation in a cyclodextrin vehicle. However, enteral voriconazole is safe in this situation.
- Therapeutic drug monitoring
- Check 3-5 days after treatment initiation and consider repeating the following week (or more frequently PRN). (ESCMID18)
- The target serum trough is 1-5.5 mg/L for most patients. Higher trough levels (2-6 mg/L) are recommended in multifocal disease, disseminated disease including CNS involvement, or resistant strains.(ESCMID18)
- This is an alternative front-line treatment. Isavuconazole could be preferred in patients when the specific diagnosis of aspergillosis is unclear, because it covers a broader range of fungal species.
- Isavuconazole was non-inferior to voriconazole in the SECURE trial, yet with better tolerance. (26684607)
- The regimen used was 372 mg IV q8hr for two days, followed by 372 mg IV/PO once daily (note: 372 mg isavuconazonium sulfate is equivalent to 200 mg isavuconazonium base; different countries use different units).
- Advantages of isavuconazole over voriconazole:
- (1) Broader spectrum of activity (including mucorales and endemic fungi).
- (2) More favorable safety profile (especially regarding renal dysfunction and QT prolongation).
- (3) Reduced risk of drug-drug interactions. (31102782)
- Close attention is still needed for co-administration with medications that affect the CYP3A4 system. (31970725)
- Not generally a front-line therapy, due to nephrotoxicity.
- May be indicated in selected situations:
- (1) Hepatic failure
- (2) Azole-resistant Aspergillus
echinocandins (e.g., micafungin, caspofungin)
- These are not usually recommended for monotherapy.
- Echinocandins exert synergistic activity when combined with triazoles (e.g., voriconazole). Combination antifungal therapy isn't usually recommended as primary treatment, but can be used in the following situations:
- (1) Salvage therapy due to clinical failure of an azole
- (2) Known azole-resistance (ESCMID18)
- (3) High regional rates of azole-resistance
- (4) Treating a species with higher rates of resistance (e.g., Aspergillus calidoustus).
reduction of immunosuppression
- Depending on the context, immunosuppression should be limited as much as possible.
sensitivity testing & infectious disease consultation
- Determination of species and their drug sensitivities should be performed if possible.
- Some PCR-based tests offer the ability to detect azole resistance very rapidly.
- Infectious disease specialists will generally be involved at this point. Patients will require long-term therapy with antifungal agents and infectious disease follow-up.
invasive aspergillosis complicating COVID-19
- Data regarding COVID-19 is rapidly emerging and still incomplete. As in other contexts, it is challenging to distinguish between colonization versus invasion. Nonetheless, several reports suggest that COVID-19 patients are susceptible to invasive pulmonary aspergillosis in a similar fashion to severe influenza patients (section above). (32517166, 32503617, 32396381, 32488446, 32339350, 32445626, 32395423)
- Different series of critically ill COVID-19 patients in Europe have found invasive aspergillosis in 5/19, 7/20, and 6/31 patients, respectively. (32339350, 32488446, 32396381) Aspergillus was detected an average of one week following intubation. (32488446) Nodular infiltrates on CT scan were often reported. (32339350)
- There should be a high index of suspicion for invasive aspergillosis among intubated COVID-19 patients who aren't responding to conventional therapies.
- When evaluating for superinfection among intubated COVID-19 patients, respiratory specimens should be tested for Aspergillus in addition to bacterial pathogens (e.g., using PCR, fungal stains, and galactomannan). Serum galactomannan may also be helpful.
- One center instituted prophylactic nebulized amphotericin B among intubated COVID-19 patients. This concept may bear further investigation. (32488446)
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questions & discussion
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- Failure to recognize that invasive aspergillosis can manifest in different ways among different patient populations (e.g., angioinvasion with lung necrosis and high-grade fevers is common in neutropenia, but less common in non-neutropenic invasive aspergillosis).
- When testing for ventilator-associated pneumonia in the ICU, consider adding sputum analysis for Aspergillus in at-risk patients (especially patients with influenza or COVID-19).
- Angioinvasive aspergillus (Radiopaedia, Mostafa El-Feky and Frank Gaillard et al.)
- Airway invasive aspergillus (Radiopaedia, Naim Qaqish and Yuranga Weerakkody et al.)
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