Infectious Disease Compendium

Aspergillus

Microbiology

2016 IDSA Guideline (Pubmed)

A mold (or mould). Includes A. fumigatus (90% of disease) A. amstelodami, A. avenaceus, A. caesielius, A. felis, A. flavus, A. nidulans, A. niger, A. terreus, A. viridinutans, and a dozen other that appear in case reports.

If it looks like aspergillus but doesn’t respond to therapy, spreads across tissue planes it could be Neosartorya udagawae (PubMed).

The galactomannan assay is the best non-invasive test especially in neutropenics (27-77% sensitivity; 77-94% specificity);and stem cell transplant patients, positive if > 0.5. However, do NOT use it for chronic pulmonary aspergillus (PubMed).

For lung disease, consider doing the galactomannan assay on bronchoalveolar lavage, slightly over 91% sensitivity (PubMed) (BMJ).

A rising galactomannan on day seven likely means failure and a change in anti-fungal increases survival (PubMed).

In non-neutropenics, the galactomannas is more senstive on BAL than in serum(PubMed).

False positive galactomannan occur in liver transplants, dietary galactomannan, dialysis, bifidobacterium bacteremia, Listeria bacteremia (PubMed), decreased clearance in diabetics, and piperacillin/tazobactam and amoxicillin./clavulanate. There is a cross reaction with Blastomyces dermatitidis, Fusarium (PubMed), Nigrospora oryzae, Paecilomyces lilacinus, Penicillium chrysogenum, and Trichothecium roseum. Culture and biopsy showing invasion still the gold standard.

Epidemiologic Risks

Part of the environment, it grows in and on everything. The black stuff on your air conditioning duct? The crap on the coffee that was left out for a week? The stuff on the cheese? Your bread? Often Aspergillus. Populations at risk include heme malignancies esp. with cytotoxic chemotherapy and neutropenia, AIDS, cirrhosis (PubMed), steroid use; ie anything that messes with WBC function.

Depressing, but azole resistant Aspergillus can be found in the home. (PubMed).

It can occur in about 5% of ICU patients, especially with ventilation and liver failure. Was also seen as a complication of severe influenza (Pubmed).

Genetic PTX3 deficiency increases the risk of invasive disease in stem cell transplant (PubMed).

Mannose binding lectin deficiency (< 500 ng/ml) increases risk (as it does for other infections).

A. nidulans is uniquely a pathogen in Chronic Granulomatous Disease (PubMed).

A. felis comes from cats and dogs and is often resistant to azoles (PubMed).

Syndromes

Allergic sinusitis and bronchopulmonary allergic aspergillosis.

Sinusitis in AIDS patients; it often invades into brain and kills (Pubmed).

Cutaneous abscesses after trauma like tattoo (PubMed).

Fungus balls in sinus and lung: It can colonize old lung cavities (often old Coccidioides immitis cavities) and cause local inflammation and hemoptysis.

Chronic pulmonary aspergillosis (CPA): slowly progressive lung cavitation with an untreated one year survival rate of ∼50%; CPA usually occurs in patients with preexisting structural lung disease.

Invasive: primarily in the immunoincompetent, both focal and disseminated disease. Primary presentation is cavitary lung disease, but in the bad host it an occur anywhere.

In the neutropenic host the best way to make the diagnosis may be a CT of the chest where you look for a halo sign (62% of patients) or macronodules (94% of patients) (PubMed). However, a halo sign is useful if there, if not it does not exclude aspergillus (PubMed). Pulmonary moulds may best be found early with a chest CT (PubMed) that demonstrates a halo (Aspergillus) or reverse halo sign (Mucormycosis).

TB can mimic aspergillus in transplant patients radiographically: "Infarct-shaped consolidations and smooth bronchial wall thickening were more frequent in IPA, and mass-shaped consolidations and centrilobular nodules ( < 10 mm, clustered) were more frequent in tuberculosis (PubMed)".

If the CT is negative in a high risk patient, computed tomographic pulmonary angiography may be the test to order; vessel obstruction very senstive (PubMed) (PubMed).

The serum or bronchoscopic aspergillus galactomannan assay is also a reasonable test to send if worried about invasive disease (piperacillin/tazobactam with give a false positive). The findings of invasive mould in biopsy is still the gold standard of diagnosis.

An index > 2 on a BAL, as well as cirrhosis, bodes ill for survival in the the non-neutropenic (PubMed).

Screening asymtomatic neutropenics on prophylactic therapy with a galactomannan a waste of time (PubMed).

Serial (1-3)-Beta-D-glucan has good diagnostic parameters in cancer patients (PubMed):

"the diagnostic performance of the BG assay in proven or probable IFI was better with 2 consecutive positive test results... For 2 consecutive tests, sensitivity and specificity were 49.6% (95% CI, 34.0%–65.3%) and 98.9% (95% CI, 97.4%–99.5%), respectively. Estimated positive and negative predictive values for an IFI prevalence of 10% were 83.5% and 94.6%, respectively (PubMed)."

Prevention is key in the neutropenic with antifungals amphotericin B = voriconazole and amphotericin B = caspofungin.The big problem with voriconazole and caspofungin is no mucormycosis coverage. So guess what these patients get when placed on caspofungin or voriconazole? Mucor. No good deed ever goes unpunished. Currently I am leaning towards voriconazole unless the patient has extensive prior exposure to azole antibiotics.

But there is an nice review of the NEJM studies that cast doubt on the validity of the voriconazole use instead of amphotericin B (Online text).

To prevent pulmonary aspergillosis, inhaled lipid amphotericin at a dose of 2.5 mL of a 5-mg/mL solution of liposomal amphotericin B is effective (PubMed).

In the non-neutropenic ICU patients, respiratory cultures have 50% sensitivity (50%) and 20%–70% specificity. Perhaps the galactomannan in bronchoalveolar lavage fluid specimens may be the way to go. A negative galactomannan in high risk hematology patients probably excludes invasive aspergillus (PubMed)

The mortality rate exceeds 50% (PubMed).

A. terreus is less likely to respond to an azole and more likely to die (PubMed).

"A. viridinutans can cause a distinct form of aspergillosis, characterized by chronicity, propensity to spread in a contiguous manner across anatomical planes, and relative refractoriness to antimycotic drugs (EID)".

A. felis: a human with chronic pulmonary aspergillosis, domestic cats with fungal rhinosinusitis and a dogs with disseminated aspergillosis.

Treatment

For details go to IDSA treatment guidelines for guidelines. NEJM review (PubMed).

If you can, send it for susceptibility testing. Resistance to voriconazole and other azoles can occur in the wild as a response to environmental fungicides (PubMed) as well as from prior exposure to azoles (Pubmed).  It is alwuas the case in ID: Use it and lose it.

Allergic: steroids; in pulmonary disease itraconazole is effective in controlling disease. In CF patients prior exposure to itraconazole leads to azole resistance (PubMed). Perhaps the newer but more expensive azoles like isavuconazole would be better. (PubMed). Voriconazole, with skin cancer and fluoride toxicity, may not be the best choice from long term therapy.

Fungus balls: debated; surgery, itraconazole, and intracavitary amphotericin or 6 months of po voriconazole (PubMed).

Chronic pulmonary aspergillosis (CPA): chronic necrotizing or fungus ball can be treated with 6 months of po voriconazole (PubMed) or posaconazole (PubMed); it may take a year to respond. Failures occurred in patients with resistant aspergillus, so send for susceptibility. Long term therapy is of benefit, preventing progression and improving quality of life (PubMed).

Invasive: debridement if possible then an azole is the treatment of choice voriconazole (probably the drug of choice, its use has resulted in a decrease in mortality by about half in some populations) (PubMed)(PubMed)) >> caspofungin is reserved for salvage therapy (Pubmed) (the others do not yet have clinical trials to support use in aspergillus) OR amphotericin B (maybe should not use amphotericin for aspergillus in this day and age, but debated. If using a lipid amphotericin, 3 mg/kg is no better than higher dose (PubMed)). Posaconazole may have efficacy as well (PubMed) as does Isavuconazole.

Combination therapy? I remain uncertain.

People always want to give combination therapy, as of 2014 "From our point of view, the use of ACT has not proven to be more effective than monotherapy and is not justified for the treatment of IA (PubMed)." That being said you an find no end of studies, all with suboptimal methodology, to suggest efficacy of combination therapy is better.

For example, compared to voriconazole monotherapy, combination therapy with anidulafungin led to higher survival in subgroups of patients with invasive disease (PubMed), but subgroup post hoc analysis is always suspect.

Surgery may be the last ditch treatment, but has a high mortality rate (PubMed).

Invasive disease can occur in critically ill COPD patients with respiratory failure and can be a bitch to diagnose (PubMed).

For vertebral osteomyelitis, itraconazole or voriconazole plus debridement cured 80% (PubMed).

In neutropenics, there may be greater breakthrough when treated with caspofungin (PubMed).

A. nidulans and A. terreus are usually less like to respond to amphotericin B, azoles and echinocandins (PubMed).

Notes

Azole resistance can be present or develop on therapy. A risk for resistance is prior exposure, aka evolution in action. A problem in neutropenics, the only group that gets lots of exposure to azoles.