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We discuss invasive aspergillosis, with a focus on when to consider and how to make this difficult diagnosis in the general ICU population—with Dr. Shmuel Shoham (@ShohamTxID), Associate Professor of Medicine at Johns Hopkins, transplant infectious disease physician, and an extensively published expert in invasive fungal infections as well as host of the Transplant ID Cast.
- Invasive aspergillosis is among the most common diseases identified on autopsy studies of ICU patients that was not recognized prior to death. Not all of these deaths are attributable to the aspergillosis, but some likely were.
- Infection in the ICU patient arises when there are abnormalities in the flow of fluid, anatomical barriers, and/or the immune defenses (particularly neutrophil function).
- When infection occurs, what organism caused it? Generally, whatever the patient is colonized by. This is influenced by the local antibiogram, environmental exposures, and the hospital or ICU course to date.
- In the majority of critically ill patients, it is reasonable to treat acute signs of infection with broad-spectrum antibiotics using a standard, protocolized approach. However, pick a metric or two to follow, and if not improving, consider further workup and/or modifications in coverage.
- Tricky diagnoses like this are best made by multiple specialists in close discussion, such as ID, critical care, pulmonology, etc. The best clue is aberrancy—features of the presentation that do not seem to match the expected disease script of a “regular” infection—and this often requires the specific knowledge of specialists brought together through collaboration. This is particularly important when approaching a “normal” ICU patient without high pre-test probability for fungal infection; start by treating regular things and look for discordant notes.
- Risk factors for invasive fungal infection include any immunosuppression that inhibits neutrophil or T-cell function, ranging from high-dose steroids, DMARDs (mycophenolate, methotrexate), neutropenia (e.g. transplant patients, leukemia), and bronchiectatic disease (cystic fibrosis, COPD, etc), but can include anything from low-dose steroids to general critical illness. HIV is not a common risk.
- Recent serious bacterial or viral pneumonia is also an important risk for fungal superinfection (e.g. a week or two later), commonly seen after H1N1 and nowadays COVID.
- Invasive candidiasis should be considered in patients with invasive devices.
- Invasive filamentous fungal infections are not a common finding in routine ICU patients (generally ill, intubated, in the ICU for some time, etc.) with no specific risk factors… but it does occur.
- When considering fungal infection, serum galactomannan and beta-D-glucan levels should be done. If looking at the lungs, bronchoscopy with BAL should be performed, and galactomannan tested on the BAL specimen as well along with both bacterial and fungal stains/cultures. An undifferentiated patient should also have BAL mycobacteria, modified AFB/nocardia, legionella, and possible PCR for pneumocystis sent.
- Bronchoscopy is maybe… probably… better for this than blind suctioning via the ETT tube. Maybe.
- Fungal infections that may occur in ICU patients are most often invasive candidiasis (anywhere), aspergillosis (usually lungs although potentially elsewhere), and rarely other filamentous fungi like histoplasmosis or cryptococcus.
- B-d glucan is a nonspecific test with many confounders, although a reasonable screen for fungal infections, many of which can elevate it. Galactomannan, particularly in the airway, is quite specific for aspergillosis. However, galactomannan in the airway may still reflect colonization, not necessarily invasive infection.
- Aspergillosis exposure can occur from smoking marijuana (it is often found in the crop), moldy buildings (e.g. basements), and gardening or mulching. Some fungi are particularly geographic, such as coccidiomycosis or histoplasmosis, so infection is unlikely in a patient with no exposure to those regions. However, aspergillus is found everywhere, and ultimately, no explanation is needed to explain colonization.
- Aspergillemia proven on blood cultures is extremely rare; it is just not a high enough concentration to pop a positive blood culture and tends to localize in thrombi anyway. Many positive cultures are lab contaminants, with the possible exception of Aspergillus terreus. Fungal isolator bottles are not necessarily needed. Sputum cultures are much more useful, although still insensitive, and could still reflect airway colonization, not necessarily infection; its significance must be considered in the clinical context.
- Candida in the sputum is similarly unhelpful when positive, but blood cultures are much more sensitive for candida and should always be considered true candidemia. However, they are still only around 50% sensitive. (B-d glucan can help here as well.)
- Imaging, generally CT of the chest, can contribute to the diagnosis. Several classic findings for filamentous fungi can occur, such as a “halo” sign (edema around a nodule), or macronodules (>1 cm). However, most ICU patients have non-specific imaging findings.
- Elevated galactomannan in both BAL and blood, in a patient with reasonable pre-test probability, and imaging consistent with the diagnosis, allows a presumptive diagnosis of probable invasive pulmonary aspergillosis. Most diagnoses are never more certain than this, which would require positive cultures from a sterile site (e.g. blood) or biopsy. Such patients should usually be treated.
- Histoplasmosis can elevate galactomannan plus some other much less common fungi, but in most general ICU patients it should be considered specific to aspergillosis.
- Treatment involves antifungals, usually a mold-active -azole or occasionally amphotericin B, and improving the patient’s immune substrate, such as removal of immunosuppression. Specific drug toxicities play an important role; infectious disease consultation should be pursued.
- The undifferentiated septic shock patient usually does not have pulmonary aspergillosis (or other filamentous fungi), as it usually does not cause that presentation, but rather respiratory or other local organ failure. If aspergillosis coverage is desired in the initial antimicrobial regimen, caspofungin is most reasonable based on its side effect profile (and provides some coverage of invasive candidiasis, which does cause septic shock).
- Overall, the key to diagnosis of aspergillosis in the ICU is a reasonable threshold to consider the diagnosis, recognizing the “skipping record” of a patient who doesn’t fit the normal stereotyped disease scripts (e.g. bacterial infections), intelligent workup particularly with biomarkers (b-d glucan, galactomannan), and multi-disciplinary collaboration.