CONTENTS

• Invasive pulmonary aspergillosis:
  • Overall approach to the diagnosis 🚀
  • Presentation
  • Investigations
    • Radiology
    • Galactomannan ➡️
    • Beta-D-Glucan ➡️
    • Culture & fungal stain
    • Bronchoscopy
    • Tissue diagnosis
  • Treatment
• Other forms of Aspergillus infection:
  • Aspergillus tracheobronchitis
  • Aspergilloma
  • Chronic cavitary pulmonary aspergillosis
• Other mold infections:
  • Invasive pulmonary mucormycosis
• Related topics
  • PCR for invasive pulmonary aspergillosis
• Podcast
• Questions & discussion
• Pitfalls

---

guide to the diagnosis of invasive pulmonary aspergillosis

(back to contents)

---

---

tests for invasive pulmonary aspergillosis

• Chest CT scan.
• Blood tests:
  • Galactomannan level.
  • Beta-D glucan level.
• Bronchoscopy:
  • Fungal culture & stain.
  • BAL Galactomannan.
  • Endobronchial biopsy for any airway involvement.
• If unable to tolerate bronchoscopy: Endotracheal aspirate for fungal stain & culture.

---

diagnosis usually involves integrating three dimensions of risk

Diagnosing invasive pulmonary aspergillosis centers around radiology, mycology, and epidemiology. Reaching a definitive diagnosis is frequently impossible. The decision to initiate antifungal therapy is a clinical judgment regarding risks and benefits guided by individual patient specifics.  

#1/3: radiology

• High risk: Imaging suggests fungal infection:
  • Dense nodules +/- halo sign.
  • Air-crescent sign.
  • Cavity formation.
• Moderate risk: CT scan is nonspecific yet consistent with fungal infection:
  • Wedge-shaped opacities.
  • Areas of consolidation.
• Low risk:
  • A chest radiograph is nonspecific yet consistent with fungal infection.
• Unlikely:
  • Normal imaging (especially a normal CT scan). (31361683)

#2/3: mycology

• High risk:
  • Serum Galactomannan positive.
  • BAL Galactomannan is strongly positive (OD >1.0).
• Moderate risk:
  • BAL Galactomannan weakly positive (OD 0.5-1)
  • BAL/ET aspirate: culture-positive and microscopy-positive (showing branching hyphae).
  • Serum beta-D glucan is positive without an alternative explanation.
• Low risk:
  • BAL/ET aspirate: culture-positive or microscopy-positive.
• Unlikely:
  • Multiple sputum samples are negative by culture and fungal stain. (31361683)

#3/3: epidemiology

high-risk epidemiology

• Neutropenia >10 days. This often occurs in the course of therapy for acute myeloid leukemia or myelodysplastic syndromes. (36836246)
• Steroid use, high intensity (pulse-dose steroid & prolonged high-dose steroid regimens).
• Transplantation: Allogeneic stem-cell transplantation. This often occurs as either an early complication (associated with neutropenia) or as a late complication (associated with therapy for graft-versus-host disease). (Fishman 2023)
• Severe influenza: Retrospective series have found that invasive aspergillosis may complicate ~5-10% of ICU patients with influenza. Aspergillus infection may be diagnosed relatively soon in the ICU course (a median of 3-5 days after admission). (34366041) Risk factors include influenza H1N1, more severe influenza, steroid use, and underlying asthma/COPD. (37641513)
• Severe COVID-19: Aspergillosis is diagnosed a median of a week following intubation (later than influenza-associated pulmonary aspergillus).  Risk factors include prolonged intubation and anti-IL6 therapies. (37022291)
• Inherited severe immunodeficiency (e.g., chronic granulomatous disease).

moderate-risk epidemiology

• Neutropenia <10 days.
• Steroid use: >20 mg/day prednisone for >3 weeks.
• Malignancy plus:
  • Cytotoxic chemotherapy.
  • Treatment with Bruton's Tyrosine Kinase inhibitors, including ibrutinib. (Murray 2022)
• Treatment with T-cell immunosuppressant, e.g.: (38211628)
  • Calcineurin inhibitors.¹
  • TNF-inhibitors.
  • Lymphocyte-specific monoclonal antibodies.
  • Immunosuppressive nucleoside analogs (e.g., azathioprine, mycophenolate, fludarabine, cladribine, cytarabine).
• Transplantation: lung, small bowel, or allogeneic stem cells.¹
• COPD. Aspergillus often colonizes the lungs of patients with COPD, which may create a setup for invasive infection following steroids. (36210108) The rate of invasive pulmonary aspergillosis could be as high as 2% of COPD admissions. (38211628)
• Cirrhosis (especially Child-Pugh class C cirrhosis 🧮).
• HIV with CD4<50 or neutropenia. Invasive aspergillosis is an uncommon infection in HIV patients. Risk factors include CD4 count <50-100/uL, neutropenia due to antiviral therapy, steroid use, and exposure to broad-spectrum antibiotics. (Murray 2022)

low-risk epidemiology

• Steroid use: short course (<7 days) or low intensity.
• Transplantation: kidney, heart, liver, or pancreas.¹
• Malnutrition.
• Alcoholism without cirrhosis.
• Diabetes.
• Renal failure, hemodialysis.
• Prolonged ICU stay.

unlikely epidemiology

• No underlying conditions.
• Cystic fibrosis patients may be colonized with Aspergillus. (31361683)

notes

• [1] Transplantation risk:
  • Lung transplant (2.4% in 1st post-transplant year).
  • Heart transplant (0.8% in 1st post-transplant year).
  • Liver transplant (0.3% in 1st post-transplant year).
  • Kidney transplant (0.1% in 1st post-transplant year). (16110792)

---

presentation

(back to contents)

---

Invasive pulmonary aspergillosis tends to present differently in neutropenic and non-neutropenic patients. However, these two presentation types may overlap. (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 the brain, liver, spleen, and kidney.
  • Skin lesions can be diagnostically helpful if present.

non-neutropenic patients: mimics bacterial pneumonia

• The course is slower overall and has a 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 ventilator-associated pneumonia or simply “refractory ARDS.”

---

radiology

(back to contents)

---

CT scan is the modality of choice

• CT scan is superior to a chest radiograph 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.
• Nodular infiltrates are often the initial finding.
  • Infarction may cause patchy nodular opacities. These can be pleural-based and wedge-shaped.
  • Nodular infiltrates may be surrounded by ground-glass opacification due to hemorrhage, generating a “halo sign.”
• Cavitation occurs later on. 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.
• Vascular occlusion on CT angiography may be more sensitive and specific for aspergillus than the halo sign. (Fishman 2023)

non-neutropenic patients often have nonspecific imaging

• In non-neutropenic patients, infection often centers on bronchi and alveolar tissue (broncho-invasion). This leads to a bronchopneumonia pattern 📖 which, unfortunately, is relatively nonspecific.
  • A “tree in bud” pattern may result from an infection of the bronchioles.
  • Thickening of the 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.

---

galactomannan

(back to contents)

---

Please see the chapter on approaching pulmonary infectious diseases: 📖

---

beta-D-glucan

(back to contents)

---

Please see the chapter on approaching pulmonary infectious diseases: 📖

---

culture & fungal stain

(back to contents)

---

culture of either sputum or BAL fluid

• Sensitivity:
  • Aspergillus is difficult to culture, with sputum culture sensitivity in the 30-50% range.
  • BAL culture sensitivity is 30-60%. (ATS guideline 2019)
• Specificity:
  • Aspergillus is ubiquitous in the environment.
  • The rate of airway colonization is fairly high.
  • Among intubated patients, the specificity might be on the order of ~50%.
  • Overall, the significance of a positive result varies greatly depending on the clinical context (e.g., degree of immunosuppression and background rate of colonization).
• Culture usually takes 1-3 days to grow. Speciation requires sporulation to occur, which can take even longer.

fungal stain of sputum or BAL fluid

• Sputum or BAL fluid should be evaluated for fungal organisms using a cytological stain to identify them (e.g., Gomori methenamine silver).
• Aspergillus morphology is notable for:
  • Septate, narrow hyphae (3-6 uM wide).
  • Acute angle branching (45-degree).
  • (Similar appearance compared to Scedosporium and Fusarium species, but not Mucor).
• The combination of positive culture plus positive fungal staining is more suggestive of true infection (rather than colonization).

(Blood cultures are almost never positive, even in disseminated invasive aspergillosis). (38211628)

---

bronchoscopy

(back to contents)

---

Bronchoscopy should be considered if the patient is stable enough to tolerate this (especially among patients who are already intubated).

tests to obtain include:

• Cytology.
• Culture and fungal stain.
• BAL Galactomannan.

airway examination for Aspergillus plaques

• Aspergillus tracheobronchitis might be seen in ~25% of patients (depending on the underlying etiology). If encountered, this may be a very useful diagnostic feature.
• Endobronchial biopsies may be obtained from tracheobronchial plaques, ulcers, or pseudomembranes. (38228164)
• See the section on invasive tracheobronchial aspergillosis below: 📖

---

tissue diagnosis

(back to contents)

---

•  There are roughly four different ways to obtain tissue:
  • [1] Surgical biopsy.
  • [2] Bronchoscopy with transbronchial biopsy of the lung parenchyma.
  • [3] Interventional radiology transthoracic needle biopsy.
  • [4] Bronchoscopy with endobronchial forceps biopsy of aspergillus tracheobronchitis. Although this doesn't diagnose aspergillus pneumonia directly, it provides evidence of invasive aspergillus and may imply the presence of invasive aspergillus in the lungs.
• With the exception of an endobronchial biopsy, most critically ill patients are too unstable to undergo these procedures (due to risks of bleeding and pneumothorax).

---

treatment

(back to contents)

---

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 judgment and risk assessment. Treatment initiation shouldn't wait for a 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 an azole (voriconazole, isavuconazonium, or posazonazole) while simultaneously obtaining additional diagnostic tests. Note that these are generally well-tolerated medications, some of which are used for antifungal prophylaxis.

---

initial therapy 

triazole is usually the backbone

• Voriconazole 💉 is traditionally the front-line agent for the treatment of aspergillus (given evidence of superiority over amphotericin). (12167683)
• Isavuconazole:
  • Isavuconazole 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.
  • In the SECURE trial, Isavuconazole was non-inferior to voriconazole yet was better tolerated. (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, QT prolongation, and hepatic impairment). (36836246)
    • (3) Reduced risk of drug-drug interactions. (31102782)
• Posaconazole:
  • Posaconazole is another alternative front-line treatment. An RCT in 2021 found equivalent outcomes from posaconazole versus voriconazole. (33549194) The dose of posaconazole studied was 300 mg twice daily for the first day, followed by 300 mg daily. This is the same dose that is often utilized for antifungal prophylaxis, which underlines that it is generally well tolerated. Common adverse effects include QTc prolongation, abnormal liver function tests, or drug-drug interactions due to the CYP system.  
  • Posaconazole hasn't yet been recommended as a front-line agent by guidelines (which preceded the 2021 trial).
  • Posaconazole may have the advantage of fewer side effects than voriconazole (e.g., reduced risk of adverse neurological events) as well as activity against Mucorales. (38286175, 36836246)
  • Therapeutic dose monitoring is recommended with a target trough of 1 mg/L. (36836246)

adjunctive echinocandin? 💉 

• Echinocandins are not recommended for monotherapy.
• Echinocandins exert synergistic activity when combined with triazoles. Caspofungin seems to be more effective than either micafungin or anidulafungin. (36836246)
• One RCT compared voriconazole monotherapy versus voriconazole plus anidulafungin.  Combination therapy showed a trend toward mortality reduction that didn't reach statistical significance. Posthoc analysis shows a mortality benefit among patients with elevated serum galactomannan. (25599346)
• 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 (>10%).
  • [4] Treating a species with higher rates of resistance (e.g., Aspergillus calidoustus).
  • [5] Severe disease (e.g., hematologic malignancy and/or prolonged neutropenia). (27365388)

liposomal amphotericin B

• Amphotericin is not generally a front-line therapy due to nephrotoxicity.
• Situations where amphotericin may be indicated:
  • [1] Hepatic failure.
  • [2] Inability to tolerate azole therapy.
  • [3] Azole-resistant Aspergillus.
  • [4] Breakthrough infection despite azole prophylaxis. (36836246)
  • [5] Coinfection with both aspergillus plus mucormycosis.

reduction of immunosuppression

• Depending on the context, immunosuppression should be limited as much as possible.
• For patients with neutropenia, granulocyte or granulocyte-macrophage colony-stimulating factor (G-CSF, GM-CSF) might be beneficial.

---

refractory disease & salvage therapy

• Potential causes of treatment failure:
  • Immune reconstitution.
  • Medication nonadherence or low therapeutic drug levels.
  • Drug resistance.
  • Alternative or superimposed diagnosis (see: section on community-acquired pneumonia with treatment failure 📖).
• Diagnostic evaluation may include:
  • Azole serum levels.
  • Review all available microbiological data (including fungal species and any drug-sensitivity data that is available).
  • Blood cultures.
  • Serum beta-D-glucan and galactomannan antigens.
  • Serum cryptococcal antigen.
  • Urine antigen for histoplasma/blastomycosis.
  • Bronchoscopy.
  • CT scan, including CT angiography, to exclude PE.
• Therapeutic considerations:
  • Adjust the azole dose as appropriate based on drug levels.
  • Transition to a parenteral azole if there is concern about drug absorption.
  • Transition to a different azole in efforts to evade drug resistance (one proposed rotation is voriconazole to posaconazole, posaconazole to isavuconazole, or isavuconazole to posaconazole). (38286175)
  • Add an echinocandin for synergic effects (e.g., azole/amphotericin backbone + echinocandin).
  • Transition to liposomal amphotericin 5 mg/kg/day (this may cover coinfection with mucormycosis or alternative infections such as fusariosis). (38286175)

---

Aspergillus tracheobronchitis

(back to contents)

---

Tracheobronchial aspergillosis may be divided into roughly three different presentations, although these may overlap to a certain extent. 

#1/3) obstructive Aspergillus tracheobronchitis (OATB)

• Basics:
  • Mucus plugs occur without underlying inflammation of the airways.
• Symptoms vary considerably:
  • Some patients may be found to have asymptomatic focal atelectasis.
  • Patients may present with cough, dyspnea, and fever. (26437820)
  • Patients may expectorate fungal airway casts (somewhat similar to allergic bronchopulmonary aspergillosis).
  • Lobar atelectasis may cause substantial hypoxemia.
• Epidemiology:
  • Obstructive Aspergillus tracheobronchitis is uncommon (it was first reported in 1991).
  • This may occur in patients with relatively less immunocompromise than patients who develop invasive aspergillosis (e.g., solid organ transplant recipients, HIV).
• Radiology:
  • Chest radiograph may reveal lobar atelectasis.
  • A CT scan may show atelectasis without air bronchograms, reflective of endobronchial obstruction.
• Diagnosis is suggested by: (26437820)
  • (1) Presence of aspergillus and mucus plugs in the airways.
  • (2) Absence of asthma, pulmonary infiltrates, or bronchiectasis (i.e., exclusion of allergic bronchopulmonary aspergillosis).
• Treatment:
  • Aggressive removal of mucus plugs.
  • Antifungal therapy is usually utilized.
  • Among patients who seem to have an allergic component (e.g., peripheral eosinophilia or elevated IgE antibodies against Aspergillus), steroids may be considered as well. (26437820)

#2/3) pseudomembranous Aspergillus tracheobronchitis

• Plaques of pseudomembranes occur without obstruction or deeper tissue invasion. (28693782)
• Diagnosis:
  • Diagnosis is based largely on a typical bronchoscopic appearance combined with microbiological evidence of aspergillosis.
  • The differential diagnosis of pseudomembranes may include: viral infection (e.g., HSV, CMV, influenza B) or bacterial tracheitis (e.g., Staphylococcus aureus or Haemophilus influenza). (28693782)

#3/3) ulcerative Aspergillus tracheobronchitis

• Basics:
  • Invasion of the bronchial mucosa and underlying cartilage. In severe cases, the entire bronchial wall may be involved with necrotizing tracheobronchitis, which may invade the surrounding tissue. (Murray 2022)
• Epidemiology:
  • Invasive bronchial aspergillosis may be associated with many of the same risk factors as invasive pulmonary aspergillosis.
  • Invasive tracheobronchial aspergillosis is especially associated with lung and heart-lung transplant patients, often involving the site of surgical anastomosis. Infection usually occurs within the first three months following transplantation.
• Diagnosis:
  • Serum galactomannan antigen has a sensitivity of only ~60% (with variability depending on the severity of the disease). (Fishman 2023)

management of aspergillus tracheobronchitis

• Systemic antifungal therapy is similar to the management of invasive aspergillosis, as discussed above. (However, note that voriconazole interacts with some anti-rejection medications.)
• The addition of aerosolized amphotericin may also be considered.
• Bronchoscopic debridement may be needed to relieve obstruction. This can cause significant bleeding, so it may be best performed by an interventional pulmonologist in a context where any bleeding could be immediately managed. Occasional patients may require additional interventional pulmonology therapies such as serial dilation and airway stenting. (Murray 2022)

---

aspergilloma

(back to contents)

---

basics

• Aspergilloma refers to the growth of Aspergillus in pulmonary cavities without tissue invasion (“fungal balls”).
• The natural history is variable:
  • The aspergilloma may increase or decrease in size.
  • In some patients, this may transition into a more invasive infection.
  • Spontaneous resolution may occur ~10% of the time, often associated with bacterial superinfection of the cavity. (Fishman 2023)

epidemiology of aspergilloma

• Aspergilloma usually occurs in patients with pre-existing cavitary lung disease (and a normal immune system). More common causes include:
  • Cavitating infection (tuberculosis, histoplasmosis, bacterial abscess, pneumocystis jirovecii pneumonia).
  • Fibrocystic sarcoidosis.
  • Cavitary carcinoma.
  • Emphysema.
  • Bronchiectasis (including cystic fibrosis).

symptoms of aspergilloma

• Aspergilloma is often an asymptomatic radiological finding.
• Recurrent hemoptysis is the primary symptom:
  • Seen in most patients.
  • Hemoptysis is typically infrequent and mild but can be massive. (Fishman 2023)
• Cough and dyspnea may also occur.
• Usually, there aren't any systemic features (e.g., weight loss, fever, lethargy). The absence of constitutional symptoms may help differentiate aspergilloma from CCPA (chronic cavitary pulmonary aspergillosis).

laboratory studies in Aspergilloma

• Sputum may reveal hyphal fragments on microscopy. Cultures may be positive for Aspergillus.
• Serum IgG against Aspergillus is present in virtually all patients with aspergilloma (>95%). The absence of antibodies suggests an alternative type of fungus ball (e.g., scedosporium).

imaging in aspergilloma

• (1) Air-crescent sign:
  • Soft-tissue mass is seen within the cavity. This may shift when the patient changes position.
  • Mass is usually 3-5 cm in size.
• (2) Cavity may often be thin-rimmed, which may help establish that the cavitary process has already resolved.

treatment of aspergilloma

• Who needs therapy?
  • Treatment is not necessarily indicated for an asymptomatic patient with a stable aspergilloma (e.g., detected incidentally on imaging studies). As noted above, some aspergillomas will resolve spontaneously or decrease in size over time.
  • Potential indications for treatment include poor prognostic features:
    • Significant hemoptysis, especially if recurrent.
    • Increase in size or number of aspergillomas.
    • Immunosuppression (e.g., HIV).
    • Severe underlying lung disease with poor pulmonary reserve.
• Bronchial artery embolization:
  • Embolization is effective for the management of hemoptysis, but patients tend to develop collateral arteries. Thus, hemoptysis may recur in about half of patients (and may be more difficult to treat in the future).
  • Bronchial artery embolization is ideally utilized as a bridge to more definitive therapy (e.g., surgery – if feasible).
• Systemic antifungal therapy:
  • May be beneficial in selected patients.
  • Chronic itraconazole therapy has been reported in non-controlled studies. Results seem to be favorable, with clinical and radiographic improvement in about two-thirds of patients. Unfortunately, recurrence often occurs after discontinuation. (Fishman 2023)
• Surgery:
  • Surgery is the definitive treatment option, but it is often high-risk.
  • The IDSA strongly recommends surgery for a patient with an isolated aspergilloma, a history of significant hemoptysis, and no contraindication to surgery (i.e., favorable pulmonary function tests). (27365388)
• Radiotherapy: May be considered for patients with severe hemoptysis who aren't favorable surgical candidates.

---

chronic cavitary pulmonary aspergillosis

(back to contents)

---

basics

• Chronic cavitary pulmonary aspergillosis (CCPA) is one subtype of chronic pulmonary aspergillosis. It is also known as “semi-invasive pulmonary aspergillosis” or “chronic necrotizing aspergillosis.”
• CCPA is a chronic, indolent infection that leads to cavity formation. An aspergilloma may occur, with local invasion of lung tissue at the interface of the fungus ball and normal lung.

epidemiology

• Patients are often middle-aged.
• (1) Patients usually have some degree of immunosuppression, e.g.:
  • Diabetes.
  • Alcoholism.
  • Debilitation, advanced age.
  • Low-dose steroid use.
• (2) There is often some sort of underlying structural lung disease, e.g.:
  • Fibrocystic sarcoidosis.
  • COPD with centrilobular emphysema.
  • Bronchiectasis (including allergic bronchopulmonary aspergillosis).
  • Status post thoracic radiotherapy.
  • Lung cancer.
  • Chronic lung cavities (e.g., prior tuberculosis).

symptoms

• CCPA follows an indolent course over months to years.
• Constitutional symptoms:
  • Low-grade fever (high fever may suggest superinfection or invasive aspergillosis).
  • Weight loss.
  • Fatigue.
• Pulmonary symptoms:
  • Chronic productive cough.
  • Hemoptysis.
  • Dyspnea.

laboratory studies

• Lab abnormalities seen in CCPA:
  • Inflammatory markers are usually elevated (but this is nonspecific).
  • Aspergillus may be isolated repeatedly from the sputum. However, sputum culture is often negative for Aspergillus. (27365388) PCR may have a higher yield. 
  • Beta-D-glucan and galactomannan levels can be mildly elevated.
  • Serum IgG against Aspergillus has high sensitivity (~90%). However, serology may be negative among Aspergillus species other than the most common one, Aspergillus fumigatus.
• Tests to order in a patient with suspected CCPA:
  • Sputum for AFB culture/smear, fungal culture/smear, and possibly TB PCR and Aspergillus PCR.
  • Serum IgG against Aspergillus.
  • Serum beta-D-glucan level and galactomannan level.
  • Antigen tests for other fungal pathogens (e.g., urine histoplasma antigen).

radiology

• Serial imaging may be needed to establish the progressive nature of the disorder and thereby differentiate CCPA from aspergilloma. (Fishman 2023) One typical pattern of evolution of the disease process is as follows:
• (#1) May begin as a nodule or mass-like consolidation:
  • Tends to involve the upper lobes.
  • Often associated with pleural thickening.
• (#2) Usually progresses over weeks-months to cavitation:
  • The cavity is initially thick-walled, with an irregular internal wall (but over time may eventually become thin-walled). (27365388)
  • Infiltrates adjacent to the cavity seem to correlate with disease activity. (Fishman 2023)
• (#3) Mycetoma formation (fungus ball) can be present, but usually it is not. (27365388)
• (#4) The cavity may continue to grow slowly over time.
• (#5) Eventually, fibrosis may occur.
• Surrounding tree-in-bud abnormalities may be seen, creating a pattern that closely mimics post-primary tuberculosis.

differential diagnosis

• Differential diagnosis includes:
  • Tuberculosis.
  • Non-tuberculous mycobacteria.
  • Malignancy (e.g., necrotizing lung cancer may be superinfected with aspergillosis). (27365388)
  • Endemic fungal infection (e.g., chronic cavitary pulmonary histoplasmosis).
  • Other forms of aspergillosis:
    • Isolated aspergilloma.
    • Invasive aspergillosis, subacute invasive aspergillus.
  • Lung abscess.
• This is challenging because chronic pulmonary aspergillosis may coexist with other pathologies – especially atypical mycobacterial infections or malignancy. Bacterial superinfection may also occur (occasionally due to Pseudomonas aeruginosa and Staphylococcus aureus). (27365388)

diagnostic criteria

• Key components of the diagnosis include: (31422416, 27365388)
• (1) Compatible radiology (e.g., cavitation, pleural thickening, pericavitary infiltrates, and sometimes a fungal ball).
• (2) Microbiological evidence of Aspergillus, such as:
  • (i) Positive serum Aspergillus IgG antibody (aka precipitins test).
  • (ii) Culture data showing Aspergillus.
• (3) Chronic, progressive process:
  • Illness duration should generally be >3 months.
  • Radiographic progression supports the diagnosis of CCPA (e.g., new cavities, increased pericavitary infiltrates, or increasing pleural thickening). (27365388)
• (4) Compatible epidemiology (e.g., mild immunosuppression and/or underlying pulmonary disease). Alternatively, if the patient is severely immunosuppressed, the diagnosis of acute invasive aspergillosis should be considered instead.
• (5) Pulmonary and/or constitutional symptoms.
• (6) Absence of an alternative diagnosis (see differential diagnosis above).

treatment

• Systemic antifungal therapy is indicated for patients with constitutional symptoms, pulmonary symptoms, progressive loss of lung function, or radiographic progression. (Alternatively, asymptomatic patients who seem to have stable disease may undergo meticulous observation without treatment.) (27365388, 32249630)
  • Itraconazole has traditionally been used, with the greatest bulk of supporting evidence. (32249630) Therapeutic dose monitoring should be utilized to ensure compliance and efficacy.
  • Voriconazole may be more effective against Aspergillus, but chronic use may cause some safety concerns (e.g., skin cancers). In retrospective comparisons, voriconazole and itraconazole appeared to have similar efficacy. (32249630)
  • Isavuconazole may be better tolerated than voriconazole and has fewer drug-drug interactions. (30570179)
  • IV micafungin may be an option if azole therapy is ineffective (e.g., due to azole resistance). Due to their synergic efficacy, echinocandins may also be combined with azoles as salvage therapy. (32249630)
• Surgery:
  • Surgery generally isn't a desirable option, given that most patients with chronic pulmonary aspergillosis are poor surgical candidates (e.g., due to underlying lung disease). By definition, patients have poor immunologic containment of aspergillosis, so they are at significant risk of postoperative complications (e.g., pleural aspergillosis, disseminated Aspergillus, or bronchopleural fistula). Additionally, the relapse rate of CCPA following surgery is up to 25%. (27365388)
  • Potential indications for surgery:
    • Persistent hemoptysis, despite bronchial artery embolization.
    • Medication-refractory disease (e.g., pan-azole-resistant Aspergillus fumigatus).
• Immunosuppression should be avoided (especially steroids).

treatment monitoring & duration

• Monitoring of the following parameters may be helpful:
  • Symptoms.
  • Weight (ideally, lost weight will be regained; any weight loss at six months suggests deterioration).
  • Radiologic stabilization or improvement (noting that cavity size may increase in patients with a favorable treatment response). (32249630)
• Parameters that may not track with the clinical response: (32249630)
  • Aspergillus IgG levels.
• Causes of treatment failure:
  • Azole-resistant Aspergillus.
  • Inadequate drug level attainment.
  • Secondary bacterial infection or underlying tuberculosis.
  • Uncontrolled underlying disease (e.g., bronchiectasis, COPD, allergic bronchopulmonary aspergillosis). (32249630)
• Duration of therapy:
  • The duration of therapy should be six months at least. (27365388)
  • Relapse following treatment discontinuation is common (~25%). (32249630)

prognosis

• Chronic cavitary pulmonary aspergillosis may progress to chronic fibrotic pulmonary aspergillosis (defined by marked fibrosis and irreversible destruction of at least two lobes of the lung). (Murray 2022)

---

invasive pulmonary mucormycosis

(back to contents)

---

basics

• Invasive pulmonary mucormycosis is generally similar to invasive pulmonary aspergillosis.
• Mucormycosis refers to infection by members of the order Mucorales and the family Mucoraceae, which includes several genera as listed below:(35000717; 35396054)
  • Rhizopus spp.
  • Mucor spp.
  • Lichtheimia spp.
  • Apophysomyces spp.
  • Cunninghamella spp.
  • Rhizomucor spp.
  • Saksenaea spp.

---

epidemiology – risk factors 

• Mucor species are widely distributed in the environment (e.g., on decaying food, soil, and animal excrement). (32196429) Mucormycosis affects a smaller group of patients than invasive pulmonary aspergillosis, especially patients with more profound immunosuppression:
• (1) Hematological malignancy (~70% cases), especially associated with: (36983475)
  • Acute leukemia.
  • Prolonged neutropenia.
  • Voriconazole or echinocandin prophylaxis.
• (2) Organ transplantation (~15% cases). (36983475)
  • Mucormycosis may cause a breakthrough infection in stem cell transplant recipients on voriconazole for treatment or prophylaxis against an invasive fungal infection. Graft-versus-host disease is a risk factor. (33965160)
• (3) Diabetes, especially diabetic ketoacidosis (DKA):
  • Mucor spp. grow best in an acidic, high-glucose medium. (33678281) 
  • Patients with DKA may develop rapidly progressive or indolent mucor infections. Sinus disease is more common in DKA, but pulmonary infection can also occur.
  • Diabetes is the only risk factor in up to a third of patients with pulmonary mucormycosis. (31042090)
• (4) Steroid use
  • Covid-associated mucormycosis: (35000717)
    • Major risk factors may include poorly controlled diabetes and steroid use.
    • Mucormycosis usually occurs 2-3 weeks after initial diagnosis of COVID. (35396054) 
• (5) Deferoxamine therapy.

---

clinical features

general aspects

• Overall, clinical features are similar to pulmonary aspergillosis. Illness severity may range from an acute and fulminant respiratory infection to a more indolent infection (among patients with less severe immunosuppression). (26317272) 
  • ~20% of patients present with subacute or chronic symptoms which began more than a month prior to admission. (31042090)
• High fevers may occur, which may persist despite broad-spectrum antibiotics.

pulmonary manifestations:

• These include cough, dyspnea, and pleuritic chest pain.
• Hemoptysis (~20% of patients): (36983475)
  • Invasion of blood vessels may cause infarction and pulmonary hemorrhage (especially among patients with neutropenia).
  • Invasion of blood vessel walls may lead to aneurysm formation, with subsequent rupture and massive hemoptysis. (35396054)
• Endobronchial involvement may occur (which may cause atelectasis, airway wall invasion, fistula formation, and severe hemoptysis).

dissemination to extrapulmonary sites:

• CNS involvement.
• Skin involvement is seen in ~10-14%. (36884326)
• Liver, spleen.
• Kidneys.

---

radiology

• Nodular lesions without air bronchograms are the most common finding on CT scans. (Fishman 2023) The following progression may occur, especially in patients who are recovering from neutropenia: (32196429) 
  • (#1) Halo sign occurs around a nodule, mass, or consolidation (reflecting intrapulmonary hemorrhage).
  • (#2) Reverse-halo sign develops.
  • (#3) An air-crescent sign occurs (due to central necrosis).
• Airspace consolidation may occur.
  • Necrosis may occur due to the tendency to invade vasculature. (32196429)
  • There is usually a paucity of air bronchograms, but cavitation can occur. (32196429)
• Other potential findings:
  • Pleural effusion.
  • Lymphadenopathy. (31042090)
  • Pulmonary artery pseudoaneurysm. (26317272)
  • Infection may traverse tissue planes (e.g., bronchomediastinal fistula formation). (33965160)

clues suggesting mucormycosis rather than aspergillosis: 

• >10 nodular lesions suggest a diagnosis of mucormycosis (odds ratio of 20). (Murray 2022)
• Reverse-halo sign is more common in mucormycosis (especially if there is a >1 cm outer consolidation rim). 📖 (Fishman 2023)
• Pleural effusion (odds ratio of 5). (33965160)
• Concurrent sinus infection (odds ratio of 25). (32196429)
• Prior voriconazole therapy (odds ratio of 7). (32196429)

---

diagnostic tests

diagnostic basics

• Fungal biomarkers are unhelpful. Mucorales spp. lack significant quantities of galactomannan or beta-D-glucan, so neither of these tests is useful.
• Diagnosis requires isolation of the organism (cytology/pathology and/or culture). Potential specimens may include:
  • Sputum, tracheal aspirates, or bronchoalveolar lavage.
  • Skin biopsy.
  • Transthoracic lung biopsy.
  • Pleural fluid analysis.

bronchoscopy

• Bronchoalveolar lavage should be sent for fungal cytology and culture.
• Bronchoscopic airway examination reveals endobronchial involvement in about a third of patients. Potential findings may include: (33965160, 36983475)
  • Stenosis, or obstruction of the airway.
  • Gelatinous or mucoid secretions.
  • Polypoid mass.
  • Airway necrosis.
  • Ulcerative and pseudomembranous tracheobronchitis.

transthoracic lung biopsy

• May be useful for patients with masses or nodules that are peripherally located.

morphological characteristics

• Hyphae are broad (5-25 uM), ribbon-like, with thin walls.
• Nonseptate or pauci-septated.
• Irregular branching at right angles.

---

treatment

getting started

• Staging evaluation: A CT scan of the sinuses, brain, abdomen, and pelvis may help evaluate for metastatic sites of infection that may alter management. MRI is preferable if there is concern regarding involvement of the sinus, brain, or eye. (36983475)
• Reverse immunosuppression if possible, for example:
  • Neutropenia may be treated by granulocyte colony-stimulating factor (G-CSF) or granulocyte/monocyte cell stimulating factor (GM-CSF).
  • Hyperglycemia should be managed appropriately (hyperglycemia has been especially associated with mucormycosis).
  • Steroids should be weaned or discontinued as soon as possible.

antibiotic therapy

• Liposomal amphotericin is generally regarded as front-line therapy. Patients with mucormycosis might benefit from higher doses of amphotericin than usual (discussed further here: 📖)
• Isavuconazole appeared to be effective in a single-arm trial compared to historic controls. (26969258) Consequently, isavuconazole was FDA-approved for first-line therapy of mucormycosis and has been endorsed by recent guidelines. (Fishman 2023) European guidelines recommend intravenous isavuconazole as front-line therapy among patients with renal dysfunction. (36983475)
• Dual therapy with both liposomal amphotericin plus isavuconazole has been reported, but its benefit is unclear. This may be reasonable for patients who are unable to undergo surgery. Animal models have found improved survival with dual therapy. (36983475)
• Agents that do not seem effective:
  • Echinocandins (e.g., caspofungin) might exert synergistic efficacy when combined with amphotericin, but this remains unclear. Recent guidelines by the European Confederation for Medical Mycology recommended against the use of echinocandins for the treatment of mucormycosis. (31699664)
  • Voriconazole is ineffective against mucormycosis.

surgical resection

• Surgery should be considered if the infection is anatomically amenable.
• Retrospective series suggest a correlation between surgical resection and improved survival, but this is almost certainly confounded by selection bias (surgery is selectively offered to patients with a more favorable prognosis and a higher commitment to intensive therapies). (33678281) 

---

PCR for invasive pulmonary aspergillosis

(back to contents)

---

PCR seems to be utilized more widely in Europe than in the United States.  

serum PCR for Aspergillus

• 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.

BAL PCR for Aspergillus

• Sensitivity is 90%. (ATS guidelines 2019)
• A positive bronchoalveolar PCR doesn't distinguish between colonization and 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.
• Cycle threshold may provide some additional information regarding specificity. A cycle threshold >35 is more consistent with colonization or contamination, whereas lower cycle thresholds suggest disease. (38228164)
• PCR can also be performed using a tracheal aspirate in intubated patients unable to undergo bronchoscopy, although the precise yield is unclear. (32343223)

---

podcast

(back to contents)

---

Follow us on iTunes

---

questions & discussion

(back to contents)

---

To keep this page small and fast, questions & discussion about this post can be found on another page here.

• 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).
• A respiratory culture positive for mold shouldn't be immediately dismissed as reflective of airway colonization. (34246387)

Guide to emoji hyperlinks

• = Link to online calculator.
• = Link to Medscape monograph about a drug.
• = Link to IBCC section about a drug.
• = Link to IBCC section covering that topic.
• = Link to FOAMed site with related information.
• = Link to supplemental media.