OVERVIEW: What every practitioner needs to know

Are you sure your patient has aspergillosis? What are the typical findings for this disease?

Infection with Aspergillus species can manifest as allergic or invasive disease. Invasive aspergillosis often presents as fever despite antibacterial therapy in the immunocompromised patient, especially in the setting of abnormal lung radiographs. The leading symptoms of pulmonary disease are hemoptysis, pleural pain and, rarely, hypoxemia, although normal oxygen saturation does not exclude pulmonary aspergillosis. Invasive sinusitis is also common and presents as brownish discharge from the nose as well as facial and sinus pain. Allergic pulmonary disease is essentially an allergic reaction to the Aspergillus spores and can present with clinical findings similar to those seen in reactive airways disease.

What other disease/condition shares some of these symptoms?

Several other nonfungal infections, as well as invasive mold infections, can mimic the presentation of invasive aspergillosis. Most of the other invasive mold infections are generally treated in a fashion similar to treatment of aspergillosis; however, mucormycosis (formerly called zygomycosis) can present with similar findings but is resistant to voriconazole therapy, which is often used to treat aspergillosis. Mucormycosis also has a greater likelihood of presenting with concurrent sinusitis and pulmonary nodules, whereas invasive aspergillosis is more likely to be one or the other.

Allergic bronchopulmonary aspergillosis (ABPA) can be mistaken for chronic asthma.

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What caused this disease to develop at this time?

Aspergillus conidia (spores) are ubiquitous in nature and everyone inhales them throughout the day. Certain situations cause greater exposure, including gardening, composting, and landscaping. The key to development of invasive aspergillosis is inhalation of these ubiquitous spores by an immunocompromised patient who is not able to clear them.

ABPA is caused by a hypersensitivity response to environmental exposure to aspergillus organisms that can colonize the airways. An IgE response is triggered in some individuals. Patients with asthma and cystic fibrosis are most likely to be affected.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Proven disease is defined through tissue biopsy, which histopathologically demonstrates Aspergillus species or yields a positive culture result. Biopsy is the gold standard and should be performed whenever feasible, especially in patients in whom the differential diagnosis is complex.

Galactomannan serum antigen testing with an optical density greater than or equal to 0.5 is considered positive. This assay is best used in patients with a hematologic malignancy and in those who have neutropenia. The best galactomannan screening method is twice-weekly screening during periods of greatest risk of invasive aspergillosis. The assay has slightly decreased sensitivity in the setting of mold-active antifungal use and lower sensitivity in solid organ transplant recipients. Importantly, the assay has a very high false-negative rate in patients with primary immunodeficiency (e.g., in chronic granulomatous disease).

Bronchoalveolar lavage with culture and galactomannan assay should be used for the patient with suspected pulmonary aspergillosis. Blood culture is of no value (unless it yields A. terreus). A complete blood count and differential are not helpful in the diagnosis.

These diagnostic recommendations differ in a child with cystic fibrosis or asthma and presumed allergic bronchopulmonary aspergillosis. In these patients, a total IgE level and IGE-specific (A. fumigatus) assays will help define the extent of any allergic response.

ABPA should be suspected in a patient with symptoms of airway reactivity, blood eosinophilia, elevated serum IgE concentration, (including elevation in specific IgE antibody to A. fumigatus), precipitating antibody to A. fumigatus, and immediate cutaneous reactivity to A. fumitagus.

Would imaging studies be helpful? If so, which ones?

Radiologic imaging, such as a computed tomographic scan, is helpful if pulmonary or sinus disease is suspected, especially concentrating on the lung window view for pulmonary evaluation. Magnetic resonance imaging can be superior if cerebral aspergillosis is suspected.

Chest radiography in patients with ABPA may demonstrate infiltrates and evidence of bronchiectasis and fibrosis.

Confirming the diagnosis

In the high-risk patient, first obtain a galactomannan serum antigen assay; a value greater or equal to 0.5 is considered positive. Obtain a computed tomographic scan of the chest or sinuses, depending on the location of suspicion of disease. A plain chest radiograph is generally not helpful.

The next step it to perform bronchoalveolar lavage if results for galactomannan are negative but chest computed tomography (CT) is suggestive of disease. Obtain galactomannan testing as well as a culture on the bronchoalveolar lavage fluid, but recognize that a negative finding does not definitively exclude disease. If CT is suggestive of disease and galactomannan and bronchoalveolar lavage results are not revealing, obtain a tissue biopsy specimen. Histopathologic analysis is still useful even in the face of previous antifungal therapy, which may affect the culture results.

If you are able to confirm that the patient has aspergillosis, what treatment should be initiated?

Immunosuppressive agents should be immediately reduced if possible. Corticosteroids are an especially high-risk factor for the development and progression of invasive aspergillosis. Using corticosteroid-sparing regimens for treatment of graft-versus-host disease or general immunosuppression is greatly preferred.

Use colony-stimulating factors to increase neutrophil counts if neutropenia exists. The use of granulocyte transfusions from a donor is controversial; this is likely not harmful (except alloimmunization in a pretransplantation patient) but only questionably helpful because of the short-lived nature of the granulocytes.

Voriconazole is the preferred primary antifungal therapy (preferred over amphotericin B) after the results of a randomized clinical trial. Voriconazole dosing is very important in children because they metabolize the drug in a linear fashion, whereas adults metabolize it in a nonlinear fashion. Voriconazole dosing in children should begin at 9 mg/kg/dose given twice daily (load at 9 mg/kg/dose; maintenance dose is 8 mg/kg/dose). Voriconazole trough levels should be obtained to ensure adequate dosing.

Levels show a great deal of interpatient variability but reasonable intrapatient stability so that a single patient can be tracked with his/her voriconaozle levels. Target levels should exceed 1-2 µg/mL, and levels should be kept at less than 7 µg/mL. Toxicity is directly dependent on level, and it is not always clear that efficacy is in a linear relationship to voriconazole level. Oral voriconazole has a decreased bioavailability of only approximately 50% in children, compared with a much greater bioavailability (near 95%) in adults.

If primary therapy with voriconazole fails, as indicated by at least a week of no improvement in disease in the setting of adequate voriconazole levels, salvage therapy could include switching to a different antifungal class (lipsomal amphotericin B or an echinocandin) or adding another agent for combination therapy. If using combination therapy, agents from different antifungal classes are used. Primary combination antifungal therapy is not recommended at this time.

Posaconazole is another triazole with excellent anti-Aspergillus activity and great success in patients with chronic granulomatous disease, but the optimal dose is unknown in pediatric patients. A new intravenous and tablet formulation are now available, but also have unknown pediatric dosing.

The three available echinocandins appear to all have the same efficacy against invasive aspergillosis. Adjunctive immunotherapy is not recommended in every patient, but there has been some success with adjunctive interferon gamma. The duration of antifungal therapy is variable but is generally at least 3 months and throughout the period of highest immunocompromise. Surgery is helpful in central nervous system or sinus disease for debulking but is not felt to be beneficial in pulmonary disease unless there is an aspergillus mass impinging on a great vessel and there is an impending risk of rupture.

ABPA is treated with corticosteroids. Initial treatment with 1-2 mg/kg per day should be followed by gradual reduction in dose, titrating with clinical condition and reduction in pulmonary infiltrates. There is some evidence that the addition of an antifungal agent, particularly itroconazole, hastens the response to corticosteroid therapy. Response to therapy can be measured by the expected fall in IgE levels associated with clinical improvement.

What are the adverse effects associated with each treatment option?

Voriconazole side effects are all transient, dose-dependent, and resolve with discontinuation of the agent. They include elevated transaminase levels, photosensitive skin rash, loss of color perception (color blindness), and hallucinations. Amphotericin B side effects include acute effects (fever, hypotension) and chronic effects (renal impairment, potassium wasting, magnesium wasting). The echinocandins have few side effects and are very safe agents.

Corticosteroid therapy can be associated with a variety of adverse effects, including immunosuppression, elevated serum glucose, hypertension, gastritis, osteopenia, and growth retardation. These adverse effects are particularly problematic in patients with ABPA complicating cystic fibrosis.

What are the possible outcomes of aspergillosis?

Invasive apergillosis is fatal if the immune status does not recover. Antifungal agents are effective at reducing the burden of disease, but ultimately the host immune system is required for cure. Antifungal therapy is needed for this disease, and the doses must be increased or combination therapy used if primary therapy is not successful. Prognosis is generally best for invasive sinus disease because the patient is diagnosed earlier in the disease course. Patients with central nervous system disease often present later in the clinical course with onset of seizures or focal neurologic deficits.

ABPA can have a prolonged and waxing and waning course, and in some patients long-term corticosteroid therapy is required.

What causes this disease and how frequent is it?

The incidence of invasive aspergillosis is host dependent; patients with certain underlying conditions have a greater risk than others. Generally, patients with cellular-mediated immune deficits are at greatest risk; however, patients with HIV/AIDS generally do not acquire invasive aspergillosis.

Invasive aspergillosis has a bimodal incidence in hematopoietic stem cell transplant recipients, with the incidence being highest during initial periods of neutropenia/aplasia (mean of approximately 30 days after transplantation) and again during times of greatest risk of graft-versus-host disease (mean of approximately 100 days after transplantation). The incidence is higher in acute myelogenous leukemia (4%) compared with acute lymphoblastic leukemia (1%), likely because of the intensity of chemotherapy.

There is a high incidence of invasive aspergillosis in patients with aplastic anemia (2%) and chronic granulomatous disease (6%-10%). There is a greater risk of invasive aspergillosis after allogeneic stem cell transplantation (5%) than after autologous stem cell transplantation (1%). There is no known seasonal variation or age distribution and no definite genetic associations with invasive aspergillosis, except for patients with chronic granulomatous disease.

ABPA occurs most often in children with asthma or cystic fibrosis. The prevalence varies, but studies demonstrate a range of 7%-14% in patients with steroid-dependent asthma and 7%-14% in patients with cystic fibrosis.

How do these pathogens/genes/exposures cause the disease?

Aspergillus conidia (spores) are ubiqutious in nature, living in the soil in most countries. Spores are inhaled by everyone, but in those with competent immune systems the spores are phagocytosed by alveolar macrophages. If the macrophages are unable to contain the disease and the spores germinate into hyphae, the patient’s neutrophils are able to destroy the hyphae. Only when both the macrophages and neutrophils are inadequate, due to either exogenous suppression or primary deficiency, does invasive aspergillosis develop. After inhalation of spores, the spores deposit in the lungs to create pulmonary aspergillosis, to the sinuses, or to the brain as the three major locations of invasive aspergillosis.

ABPA is caused by an allergic reaction to allergens of A. fumigatus.

Other clinical manifestations that might help with diagnosis and management

Cutaneous aspergillosis is often a primary disease in children (e.g., in neonates, found under tape used for arm boards), whereas in adult patients cutaneous disease is often an indication of dissemination and therefore secondary. If cutaneous disease is proved by biopsy, full radiologic evaluation to determine the extent of disease (CT of chest, sinus, head) is warranted.

What complications might you expect from the disease or treatment of the disease?

When angioinvasion by the fungus occurs in pulmonary invasive aspergillosis, there is a risk of massive pulmonary bleeding through dissection of a great vessel. Surgery is not indicated in invasive pulmonary aspergillosis except in the context of impending great vessel disease.

Are additional laboratory studies available; even some that are not widely available?

An Aspergillus polymerase chain reaction test is under development currently and will hopefully be available soon. This will allow greater sensitivity and specificity and will likely be used in conjunction with the galactomannan antigen test.

How can aspergillosis be prevented?

Prophylactic antifungal agents are used in the highest risk patients, such as those undergoing chemotherapy for acute myelogenous leukemia or aplastic anemia and those undergoing allogeneic stem cell transplantation. Additionally, lung, heart, and liver transplantation recipients are at high risk and warrant prophylaxis. These patient populations are also the ones that should be screened twice weekly with the serum galactomannan assay.

Prophylaxis against invasive aspergillosis is likely not indicated in lower risk patients. Prophylaxis should include a mold-active antifungal agent (not fluconazole), such as voriconazole, posaconazole, amphotericin B, or an echinocandin. Each has been shown to prevent invasive aspergillosis; the ideal anti-Aspergillus prophylaxis is unknown. Patients at risk for invasive aspergillosis should be cautioned to avoid gardening, as spores live in the soil. There are also reports of acquisition of disease through aerosolized water supplies (e.g., showerheads in hospitals).

There is no known method for preventing ABPA.

What is the evidence?

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.

Walsh, TJ, Driscoll, T, Milligan, PA. “Pharmacokinetics, safety, and tolerability of voriconazole in immunocompromised children”. Antimicrob Agents Chemother. vol. 54. 2010. pp. 4116-23.

Zaoutis, TE, Heydon, K, Chu, JH. “Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the United States, 2000”. Pediatrics. vol. 117. 2006. pp. e711-6.

Burgos, A, Zaoutis, TE, Dvorak, CC. “Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases”. Pediatrics. vol. 121. 2008. pp. e1286-94.

Stevens, DA, Moss, RB, Kurup, VP. “Allergic bronchopulmonary aspergillosis in cystic fibrosis—state of the art: Cystic Fibrosis Foundation Consensus Conference”. Clin Infect Dis. vol. 37. 2003. pp. S225-64.

de Almeida, MB, Bussamra, MHF, Rodrigues, JC. “Allergic pulmonary aspergillosis in paediatric cystic fibrosis patients”. Paediatr Respir Rev. vol. 7. 2006. pp. 67-72. (This reference provides a summary of this condition, including diagnostic criteria and a helpful discussion of therapy.)

Ongoing controversies regarding etiology, diagnosis, treatment

The underlying pathogenesis of aspergillosis is unclear but is likely multifactorial and host dependent. Therefore, epidemiologic clues can stratify those patients at greatest risk for the development of disease based on underlying disease (e.g., form of cancer).