CONTENTS
- Invasive pulmonary aspergillosis:
- Other forms of aspergillus infection:
- Other mold infections:
- Podcast
- Questions & discussion
- Pitfalls
#1/3: some red flags for possible aspergillosis
- Data review shows:
- Sputum culture reveals Aspergillus or unknown mold.
- CT scan reveals nodules, cavitation, or halo signs.
- Suggestive epidemiology:
- Neutropenia for >10 days.
- Chronic steroid use.
- Stem cell transplantation.
- Nosocomial pneumonia following severe influenza or COVID-19.
- Pneumonia refractory to antibiotics.
#2/3: investigation for possible aspergillosis
- Chest CT scan:
- Nodules or cavitation support aspergillosis.
- Nonspecific infiltrates can be seen as well (especially in non-neutropenic patients).
- Blood tests:
- Galactomannan level.
- Beta-D glucan level.
- PCR for Aspergillus, if immunocompromised.
- Endotracheal aspirate if unable to tolerate bronchoscopy:
- Fungal culture & stain.
- PCR for Aspergillus.
- Bronchoscopy with bronchoalveolar lavage (if safe to do so):
- Fungal culture & stain.
- PCR for aspergillus.
- Galactomannan level in bronchoalveolar lavage fluid.
#3/3: data integration
- 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 aspergillosis 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.
immunosuppression
- Neutropenia (especially >10 days).
- Steroid use:
- Highest risk: >0.3 mg/kg/day prednisone equivalents for >3 weeks, or high-dose steroid pulses (e.g., 500-1,000 mg methylprednisolone/day).
- Intermediate risk: <0.3 mg/kg/day prednisone equivalents for >3 weeks.
- Lower risk: Steroid at lower doses and shorter courses.
- Transplantation:
- Allogeneic stem-cell transplantation:
- (i) Early complication, in association with neutropenia.
- (ii) Late complication, as a community-acquired infection in the context of therapy for graft versus host disease.(Fishman 2023)
- Autologous stem cell transplantation.
- Lung transplant (2.4%*).
- Heart transplant (0.8%*).
- Liver transplant (0.3%*).
- Kidney transplant (0.1%*).
- *Risk during first post-transplantation year.(16110792)
- Allogeneic stem-cell transplantation:
- Malignancy:
- Treated with cytotoxic chemotherapy.
- Treated with ibrutinib (inhibitor of Bruton tyrosine kinase).(Murray 2022)
- BTK (Bruton's Tyrosine Kinase) inhibitors.
- Inherited severe immunodeficiency (e.g., chronic granulomatous disease).
- HIV:
- 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)
aspergillus following severe viral pneumonia
- 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, and additional risk factors (as listed below).
- COVID-19:
- Aspergillosis is diagnosed a median of a week following intubation.
additional risk factors
- Structural lung disease (severe COPD or bronchiectasis). Aspergillus often colonizes the lungs of patients with COPD, which may create a setup for invasive infection following the addition of immunosuppressive medications.(36210108)
- Cirrhosis.
- Prolonged ICU stay.
- Diabetes.
- 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 bacterial 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.”
serum galactomannan
- The 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)
- Antifungal 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, blastomycosis, fusarium species, Alternaria, Geotrichum, Paecilomyces, and Penicillium).
- 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 or Penicillium 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)
basics
- 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 is ~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
- Sensitivity
- 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).
- Culture usually takes 1-3 days to grow. 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 morphology is notable for:
- Septate, narrow hyphae (3-6 uM wide).
- Acute angle branching (45-degree).
- (Similar appearance compared to Scedosporium and Fusarium species).
- The combination of positive culture plus positive fungal staining may be more suggestive of true infection (rather than colonization).
serum PCR
- 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.
- 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 as compared to the halo sign.(Fishman 2023)
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
- See the section on invasive tracheobronchial aspergillosis below: 📖
- 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.
- (2) Bronchoscopy with transbronchial biopsy.
- (3) Interventional radiology transthoracic needle biopsy.
- Most critically ill patients are too unstable to undergo these procedures (due to risks of bleeding and pneumothorax).
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 +/- echinocandin
- Voriconazole 💉 is traditionally the front-line agent for treatment of aspergillus (given evidence of superiority over amphotericin). (12167683)
- Echinocandins 💉 (e.g., micafungin, caspofungin) 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 (>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)
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.
- 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)
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.
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.
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.
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 x-ray may reveal lobar atelectasis.
- 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 with seem to have an allergic component (e.g., peripheral eosinophilia, or elevated IgE antibodies against Aspergillus), steroid 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 influenzae).(28693782)
#3/3) ulcerative Aspergillus tracheobronchitis
- Basics:
- Invasion of 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 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)
basics
- Aspergilloma refers to 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). 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%). Absence of antibody 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 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, 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.
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). Echinocandins may also be combined with azoles as salvage therapy, due to their synergic efficacy. (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 as able (especially steroid).
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 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:
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)
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
- (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 seen in ~10-14%. (36884326)
- Liver, spleen.
- Kidneys.
radiology
- Nodular lesions without air bronchograms are the most common finding on CT scan. (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.
- Other potential findings:
clues suggesting mucormycosis, rather than aspergillosis:
- >10 nodular lesions suggests 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 are 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: 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).
- Steroid should be weaned or discontinued as able.
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 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)
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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).
- Respiratory culture positive for mold shouldn't be immediately dismissed as reflective of airway colonization.(34246387)
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Books:
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