OVERVIEW: What every clinician needs to know

Pathogen name and classification

Aspergillus species belong to a genus that is comprised of several hundred species of medical, environmental, and commercial importance. The most common cause of human infection is A. fumigatus. Considered once to be one species based on morphologic typing, this species has recently been discovered to contain numerous different species based on genetic analysis and toxin profiling (“polyphasic taxonomy”). Different Aspergillus species may vary with regards to toxin and metabolite production, temperature of growth, and other parameters that dictate pathogenicity.

What is the best treatment?

  • Treatment of invasive aspergillosis, whether that involves the lungs, sinuses, and/or dissemination to other sites, requires use of a polyene (amphotericin B) formulation or a broad-acting azole antifungal. The “best” treatment suggested in recent consensus groups is voriconazole. Alternatives include lipid formulations of amphotericin B and echinocandins. The latter have not been studied for primary treatment, but they may have a role as secondary treatment and possibly in combination regimens.

  • Enthusiasm for combination treatment using voriconazole and an echinocandin has been generated in a recent randomized trial that showed a trend to better survival in patients who received voriconazole and anidulafungin compared to voriconazole alone.

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  • There are Aspergillus species that innately vary in their susceptibility to different antifungal drugs. Aspergillus terreus tends to have relative resistance to amphotericin B, and outcomes of infection are poor. Aspergillus ustus tends to have relatively lower susceptibility to multiple different antifungal agents, and susceptibility testing should be performed for this organism. Some of the more recently recognized species in the A. fumigatus group, such as A. lentulus, variably demonstrate relatively low susceptibilities to multiple antifungal drugs. For infection with this species, susceptibility testing should be performed, particularly in a patient with complicated infection.

  • Acquisition of azole resistance has been reported among A. fumigatus isolates; this is associated with mutations in the target enzyme, Cyp51. Although susceptibility testing is not yet standard practice, there may become a role for it in the future, as the scope of azole resistance becomes well defined.

How do patients contract this infection?

  • Epidemiology

    These organisms are ubiquitous in the environment and acquired most frequently through inhalation of airborne conidia (spores).

    Although it is difficult to determine exactly where this infection comes from, studies have shown that certain geographies do have higher airborne spore counts during specific times of the year; there do appear to be some geographic and weather-related variables that impact infection rates.

    Studies performed in the 1990s stressed an increase in the incidence of infection in numerous at-risk populations, particularly in allogeneic stem cell transplant recipients. More recent multicenter surveillance studies have shown quite a lot of variability between different centers. It is not clear how much of this variability is related to a true difference in epidemiology versus diagnostic bias, as the aggressiveness of diagnostic modalities, such as bronchoscopy, versus empirical antifungal therapy differs.

    There are spikes in infection rates during periods of hospital construction; however, as most people develop infection later after immunosuppression, it is not clear how much of this infection is truly hospital-acquired. It is, none-the-less, a good idea to be aware of potential nosocomial exposure during construction periods, triggering implementation of environmental monitoring and barrier precautions.

    The utility of masks is not well demonstrated in randomized trials; one small study showed no apparent effect in decreasing rates of infection.

    Mold-active drugs, particularly posaconazole, itraconazole, and voriconazole, have been evaluated for prophylaxis in high-risk stem cell transplant recipients and in people with leukemia (or myelodysplastic syndrome). They appear to be active in reducing the incidence of invasive aspergillosis, although findings of studies have been variable because of differences in patients enrolled and efficacy endpoints measured. Posaconazole has been approved for prophylaxis based on results of two multicenter randomized trials.

What host factors protect against this infection?

  • Historically, the people at highest risk for invasive aspergillosis have been considered to be patients with neutropenia or long-term neutrophil dysfunction because of agents, such as corticosteroids. More recently, it has been appreciated that there are multiple levels of immune responses important in dictating risks for infection, ranging from airway protective mechanism(s) to cellular defense.

  • It appears that people are inherently “wired” differently to have different risks for infection based on polymorphisms in innate immune genes. Examples include Toll-like receptor (TLR) 4, TLR1, and dectin 1.

  • Clinical and histopathological findings differ based on host immune response. In severely neutropenic patients, these organisms can show angioinvasion, with local pulmonary hemorrhage and potential spread to extrapulmonary organs. A more robust inflammatory response, characterized by monocytic cells, and less robust fungal burden is the more typical finding in a non-neutropenic host.

What are the clinical manifestations of infection with this organism?

  • Diseases caused by Aspergillus species range from primarily allergic manifestations (fungal sinusitis, allergic bronchopulmonary aspergillosis [ABPA]) to more invasive sinus and/or pulmonary infections, with a propensity to spread hematogenously.

  • Treatment of these different syndromes differs, both with regards to antifungal agents and utility of anti-inflammatory agents. ABPA and allergic diseases are not discussed here.

How should I identify the organism?

  • There is a great deal written in the literature regarding the “classic” radiographic appearance of pulmonary aspergillosis, which is typically described as nodular infiltrates with or without a halo sign, and subsequent cavitation. In reality, this is an appearance that has been described in neutropenic patients; other patients who acquire infection may exhibit focal or multifocal consolidation that can have a nodular appearance or be less characteristic.

  • Culture of bronchoalveolar lavage (BAL) is the most reliable (and typically safe) mechanism to establish the diagnosis. More recent studies have shown that detection of galactomannan antigen in BAL adds to the diagnostic yield, increasing sensitivity of lavage.

  • Biopsy is still performed, either by a transbronchial route or an open surgical procedure; however, the sensitivity of detecting the organism is variable. Essentially, a positive finding is meaningful, but a negative finding cannot rule out involvement of Aspergillus species.

  • Culture techniques are only approximately 50% sensitive, so a negative culture does not rule out infection, regardless of what specific tissue is sampled.

  • Adjunctive diagnostic tests available for use involve detection of fungal antigens, specifically those that characterize the cell wall. The most widely employed test detects galactomannan, and it is applied either on serum or BAL. The test is useful in different high-risk patients, both applied as an adjunct to diagnosis in people with clinical findings of disease and when used as a screening test to detect early infection.

  • Other diagnostic test evaluations in different centers detect beta-D-glucan, which is not specific for Aspergillus species, and tests that detect nucleic acids using polymerase chain reaction (PCR). Use of some type of adjunct diagnostic test is a good idea when the diagnosis is suspected, as culture sensitivity is so poor.

How does this organism cause disease?

  • There are multiple different microbial factors produced by Aspergillus species that allow it to cause disease in immunosuppressed people. These are best studied for A. fumigatus, which causes the bulk of disease (>90% in most centers). The organism secretes multiple toxins and metabolites that protect it from host defenses, and it has specific cell wall components that can serve to promote survival in the host as well. These are not listed here for the sake of brevity.

WHAT’S THE EVIDENCE for specific management and treatment recommendations?

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Camps, SM, Rijs, AJ, Klaassen, CH. “Molecular epidemiology of isolates harboring the TR34/L98H azole resistance mechanism”. J Clin Microbiol. vol. 50. 2012. pp. 2674-80.

Cornely, OA, Maertens, J, Bresnik, M. “Liposomal amphotericin B as initial therapy for invasive mold infection: a randomized trial comparing a high-loading dose regimen with standard dosing (AmBiLoad trial)”. Clin Infect Dis. vol. 44. 2007. pp. 1289-97.

Cornely, OA, Maertens, J, Winston, DJ. “Posaconazole vs fluconazole or itraconazole prophylaxis in patients with neutropenia”. N Eng J Med. vol. 356. 2007. pp. 348-59.

D’Haese, J, Theunissen, K, Vermeulen, E. “Detection of galactomannan in bronchoalveolar lavage fluid samples of patients at risk for invasive pulmonary aspergillosis: analytical and clinical validity”. J Clin Microbiol. vol. 50. 2012. pp. 1258-63.

Herbrecht, R, Denning, DW, Patterson, TF. “Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis”. N Eng J Med. vol. 347. 2002. pp. 408-15.

Marr, KA, Patterson, T, Denning, D. “Aspergillosis. Pathogenesis, clinical manifestations and therapy”. Infect Dis Clin North Amer. vol. 16. 2002. pp. 875-94.

Marr, KA, Schlamm, H, Rottinghaus, ST. “A randomized, double-blind study of combination antifungal therapy with voriconazole and anidulafungin versus voriconazole monotherapy for primary treatment of invasive aspergillosis”. ECCMID. 2012.

Maschmeyer, G, Neuburger, S, Fritz, L. “A prospective, randomized study on the use of well-fitting masks for prevention of invasive aspergillosis in high-risk patients”. Ann Oncol. vol. 20. 2009. pp. 1560-4.

Ok, M, Einsele, H, Loeffler, J. “Genetic susceptibility to Aspergillus fumigatus infections”. Int J Med Microbiol. vol. 301. 2011. pp. 445-52.

Panackal, AA, Li, H, Kontoyiannis, DP, Mori, M, Perego, CA, Boeckh, M, Marr, KA. “Geoclimatic influences on invasive aspergillosis after hematopoietic stem cell transplantation”. Clin Infect Dis. vol. 50. 2010. pp. 1588-97.

Segal, BH. “Aspergillosis”. N Eng J Med. vol. 360. 2009. pp. 1870-84.

Ullmann, AJ, Lipton, JH, Vesole, DH. “Posaconazole or fluconazole for prophylaxis in severe grafts-versus-host disease”. N Eng J Med. vol. 356. 2007. pp. 335-47.

Walsh, TJ, Anaissie, EJ, Denning, DW. “Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America”. Clin Infect Dis. vol. 46. 2008. pp. 327-60.

Wingard, JR, Carter, SL, Walsh, TJ. “Randomized, double-blind trial of fluconazole versus voriconazole for prevention of invasive fungal infection after allogeneic hematopoietic cell transplantation”. Blood. vol. 116. 2010. pp. 5111-18.