Aspergillus

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Chapter 229 Aspergillus

Luise E. Rogg, William J. Steinbach

The aspergilli are ubiquitous fungi whose normal ecological niche is that of a soil saprophyte that recycles carbon and nitrogen. The genus Aspergillus contains approximately 185 species, but most human disease is caused by A. fumigatus, A. flavus, A. niger, A. terreus, and A. nidulans. Invasive disease is most commonly caused by A. fumigatus. Aspergillus reproduces asexually via production of sporelike conidia. Most cases of Aspergillus disease (aspergillosis) are due to inhalation of airborne conidia that subsequently germinate into fungal hyphae and invade host tissue. People are likely exposed to conidia on a daily basis. When inhaled by an immunocompetent person, conidia are rarely deleterious, presumably because they are efficiently cleared by phagocytic cells. Macrophage- and neutrophil-mediated host defenses are required for resistance to invasive disease. Disease can develop in hosts with neutropenia or suppressed macrophage function or after exposure to unusually high doses of conidia.

Aspergillus is a relatively unusual pathogen in that it can create very different disease states depending on the host characteristics, including allergic (hypersensitivity), saprophytic (noninvasive), or invasive disease. Immunodeficient hosts are at risk for invasive disease, whereas immunocompetent hosts tend to develop allergic disease. Disease manifestations include primary allergic reactions; colonization of the lungs or sinuses; localized infection of the lung or skin; invasive pulmonary disease; or widely disseminated disease of the lungs, brain, skin, eye, bone, heart, and other organs. Clinically, these syndromes often manifest with mild, nonspecific, and late-onset symptoms, particularly in the immunosuppressed host, complicating accurate diagnosis and timely treatment.

229.1 Allergic Disease (Hypersensitivity Syndromes)

Luise E. Rogg, William J. Steinbach

Asthma

Attacks of atopic asthma can be triggered by inhalation of Aspergillus spores, producing allergic responses and subsequent bronchospasm. Exposure to fungi, especially Aspergillus, needs to be considered as a trigger in a patient with an asthma flare.

Extrinsic Alveolar Alveolitis

Extrinsic alveolar alveolitis is a hypersensitivity pneumonitis that occurs due to repetitive inhalational exposure to inciting materials, including Aspergillus conidia. Symptoms typically occur shortly after exposure and include fever, cough, and dyspnea. Neither blood nor sputum eosinophilia is present. Chronic exposure to the triggering material can lead to pulmonary fibrosis.

Allergic Bronchopulmonary Aspergillosis

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity disease resulting from immunologic sensitization to Aspergillus antigens. It is primarily seen in patients with asthma or cystic fibrosis. Inhalation of conidia produces noninvasive colonization of the bronchial airways, resulting in persistent inflammation and development of hypersensitivity inflammatory responses. Disease manifestations are due to abnormal immunologic responses to A. fumigatus antigens and include wheezing, pulmonary infiltrates, bronchiectasis, and even fibrosis.

There are 7 primary diagnostic criteria for ABPA: episodic bronchial obstruction, peripheral eosinophilia, immediate cutaneous reactivity to Aspergillus antigens, precipitating antibodies to Aspergillus antigen, elevated IgE, pulmonary infiltrates, and central bronchietasis. Secondary diagnostic criteria include repeated detection of Aspergillus from sputum by identification of morphologically consistent fungal elements or direct culture, coughing up brown plugs or specks, elevated Aspergillus antigen–specific immunoglobulin E (IgE) antibodies, and late skin reaction to Aspergillus antigen. Radiologically, bronchial wall thickening, pulmonary infiltrates, and central bronchiectasis can be seen.

Treatment depends on relieving inflammation via an extended course of systemic corticosteroids. Addition of the antifungal agent itraconazole is used to decrease the fungal burden and diminish the inciting stimulus for inflammation. Because disease activity is correlated with serum IgE levels, these levels are used as one marker to define duration of therapy. An area of research interest is the utility of anti-IgE antibody therapy in the management of ABPA.

Allergic Aspergillus Sinusitis

Allergic Aspergillus sinusitis is thought to be similar in etiology to ABPA. It has been primarily described in young adult patients with asthma and may or may not be seen in combination with ABPA. Patients often present with symptoms of chronic sinusitis or recurrent acute sinusitis, such as congestion, headaches, and rhinitis, and are found to have nasal polyps and opacification of multiple sinuses on imaging. Laboratory findings can include elevated IgE levels, precipitating antibodies to Aspergillus antigen, and immediate cutaneous reactivity to Aspergillus antigens. Sinus tissue specimens might contain eosinophils, Charcot-Leyden crystals, and fungal elements consistent with Aspergillus species. Surgical drainage is an important aspect of treatment, often accompanied by courses of either systemic or inhaled steroids. Use of an antifungal agent may also be considered.

Bibliography

Agarwal R. Allergic bronchopulmonary aspergillosis. Chest. 2009;135:805-826.

De Almeida MB, Bussamra MHF, Rodrigues JC. Allergic bronchopulmonary aspergillosis in paediatric cystic fibrosis patients. Paediatr Resp Rev. 2006;7:67-72.

229.2 Saprophytic (Noninvasive) Syndromes

Luise E. Rogg, William J. Steinbach

Pulmonary Aspergilloma

Aspergillomas are masses of fungal hyphae, cellular debris, and inflammatory cells that proliferate without vascular invasion, generally in the setting of pre-existing cavitary lesions or ectatic bronchi. These cavitary lesions can occur as a result of infections such as tuberculosis, histoplasmosis, or resolved abscesses or secondary to congenital or acquired defects such as pulmonary cysts or bullous emphysema. Patients may be asymptomatic, with diagnosis made through imaging for other reasons, or they might present with hemoptysis, cough, or fever. On imaging, there may be thickening of the walls of a cavity initially, or later, a solid round mass separated from the cavity wall, as the fungal ball develops. Detection of Aspergillus antibody in the serum suggests this diagnosis. Treatment is indicated for control of complications, such as hemoptysis. Surgical resection is the definitive treatment but has been associated with significant risks. Systemic antifungal treatment with azole-class agents may be indicated in certain patients.

Chronic Pulmonary Aspergillosis

Chronic aspergillosis can occur in patients with normal immune systems or mild degrees of immunosuppression. Three categories have been proposed to describe different manifestations of chronic aspergillosis. The first is chronic cavitary pulmonary aspergillosis (CCPA), which is similar to aspergilloma, except that multiple cavities form and expand with occupying fungal balls. The second is chronic fibrosing pulmonary aspergillosis, where the multiple individual lesions progress to significant pulmonary fibrosis. The final is chronic necrotizing pulmonary aspergillosis (CNPA), also known as subacute invasive or semi-invasive pulmonary aspergillosis, a slowly progressive subset found in patients with mild to moderate immune impairment.

Management of CCPA can sometimes be via surgical resection, though long-term antifungal therapy, as for invasive aspergillosis, is indicated. Management of CNPA is similar to that of invasive pulmonary aspergillosis; however, the disease is more indolent, and thus there is a greater emphasis on oral therapy. Direct instillation of antifungals into the lesion cavity has been employed with some success.

Sinusitis

Sinus aspergillosis typically manifests with chronic sinus symptoms that are refractory to antibacterial treatment. Imaging can demonstrate mucosal thickening in the case of Aspergillus sinusitis or a single mass within the maxillary or ethmoid sinus in the case of sinus aspergilloma. If untreated, sinusitis can progress and extend into the ethmoid sinuses and orbits. Therapy of sinusitis depends on surgical débridement and drainage, including surgical removal of the fungal mass in cases of sinus aspergilloma.

Otomycosis

Aspergillus can colonize the external auditory canal, with possible extension to the middle ear and mastoid air spaces if the tympanic membrane is disrupted by concurrent bacterial infection. Symptoms include pain, itching, decreased unilateral hearing, or otorrhea. Otomycosis is more often seen in patients with impaired mucosal immunity, such as patients with hypogammaglobulinemia, diabetes mellitus, chronic eczema, or HIV and those using chronic steroids. Treatments have not been well studied, but topical treatment with acetic or boric acid instillations or azole creams as well as oral azoles such as voriconazole, itraconazole, and posaconazole have been described.

Bibliography

Daudia A, Jones NS. Advances in management of paranasal sinus aspergillosis. J Laryngol Oto. 2008;122:331-335.

229.3 Invasive Disease

Luise E. Rogg, William J. Steinbach

Invasive aspergillosis (IA) occurs after conidia enter the body, escape immunologic control mechanisms, and germinate into fungal hyphae that subsequently invade tissue parenchyma and vasculature. The invasion of the vasculature can result in thrombosis and localized necrosis and facilitates hematogenous dissemination. The incidence of IA appears to be increasing, possibly due to better management of other infections found in the at-risk populations and more use of severely immunosuppressive therapies for a widening array of diseases. The most common site of primary infection is the lung, but primary infection is also seen in the sinuses and skin and rarely elsewhere. Secondary infection can be seen after hematogenous spread, often to the skin, CNS, eye, bone, and heart.

IA is primarily a disease of immunocompromised hosts, and risk factors include cancer or chemotherapy-induced neutropenia, particularly if severe and/or prolonged, stem cell transplantation, especially during the initial pre-engraftment phase or if complicated by graft vs host disease, neutrophil or macrophage dysfunction such as occur in severe combined immunodeficiency (SCID) or chronic granulomatous disease (CGD), prolonged high-dose steroid use, HIV, or solid organ transplantation. There have only been a few studies in the pediatric age group to identify risk factors for IA, but allogeneic bone marrow transplantation and acute myelogenous leukemia have been suggested. Well-defined incidence of IA among pediatric patients has not been determined to date.

Invasive Pulmonary Aspergillosis

Invasive pulmonary aspergillosis is the most common form of aspergillosis. It plays a significant role in morbidity and mortality in the patient populations at increased risk for IA, namely stem cell and solid organ transplant recipients, cancer patients, patients with primary immunodeficiencies, and patients receiving immunomodulatory therapy. Presenting symptoms can include fever despite initiation of empirical broad-spectrum antibacterial therapy, cough, chest pain, hemoptysis, and pulmonary infiltrates. Patients on high-dose steroids are less likely to present with fever. Symptoms in these immunocompromised patients can be very vague, and thus maintaining a high index of suspicion when confronted with a high-risk patient is essential.

Diagnosis

Imaging can be helpful, although no finding is pathognomonic for invasive pulmonary disease. Characteristically, multiple, ill-defined nodules can be seen, though lobar or diffuse consolidation is not uncommon and normal chest X-rays can be seen even late in the disease evolution. Classic radiologic signs on CT include the halo sign, when angioinvasion produces a hemorrhagic nodule surrounded by ischemia. Early on there is a rim of ground-glass opacification surrounding a nodule. Over time, these lesions evolve into cavitary lesions or lesions with an air crescent when the lung necroses around the fungal mass, often seen during recovery from neutropenia. Unfortunately, these findings are not specific to invasive pulmonary aspergillosis and can also be seen in other pulmonary fungal infections, as well as pulmonary hemorrhage and organizing pneumonia. In addition, several reviews of imaging results of pediatric aspergillosis cases suggest that cavitation and air crescent formation are less common among these patients than among adult patients. On MRI, the typical finding for pulmonary disease is the target sign, a nodule with lower central signal compared to the rim-enhancing periphery.

Diagnosis of IA can be complicated for a number of reasons. Conclusive diagnosis requires culture of Aspergillus from a normally sterile site and histologic identification of tissue invasion by fungal hyphae consistent with Aspergillus morphology. However, obtaining tissue specimens is often practically impossible in critically ill patients. In addition, depending on the specimen type, a positive result from culture can represent colonization rather than infection. Isolation of Aspergillus from blood cultures is uncommon, likely because fungemia is low-level and intermittent.

Serology can be useful in the diagnosis of allergic Aspergillus syndromes as well as aspergilloma but is low yield for invasive disease, likely because of deficient immune responses in the high-risk immunocompromised population. Bronchoalveolar lavage (BAL) can be useful, but negative results cannot be used to rule out disease, owing to inadequate sensitivity. Addition of molecular biologic assays such as antigen detection and polymerase chain reaction (PCR) can improve the diagnostic yield of BAL for aspergillosis. An enzyme-linked immunosorbent assay (ELISA)-based assay for galactomannan, one of the components of the Aspergillus cell wall, has been developed to aid the diagnosis of invasive aspergillosis. This newer molecular test is useful when used in serial monitoring for development of infection and has been shown to be the most sensitive in detecting disease in cancer patients or hematopoietic stem cell transplant recipients. Earlier reports of increased false-positive reactions in children versus adults have been refuted. This test appears to have high rates of false negativity in patients with congenital immunodeficiency (e.g., CGD) and invasive Aspergillus infections. An ongoing area of research involves the use of serial monitoring of galactomannan levels to provide guidance for duration of therapy. PCR-based assays are in development for the diagnosis of aspergillosis but are still being optimized and are not yet commercially available.

Treatment

Successful treatment of IA hinges on the ability to reconstitute normal immune function and use of effective antifungal agents until immune recovery can be achieved. Therefore, lowering overall immunosuppression via cessation of corticosteroid use is vital to improve the ultimate outcome. In 2008, new treatment guidelines for Aspergillus infections were published by the Infectious Diseases Society of America, marking a major shift in management recommendations. In the past, first-line therapy was amphotericin B, notable for low response rates and significant infusion reactions and drug toxicity. Liposomal formulations of amphotericin B have been developed, which are associated with decreased toxicity and may still have a role as first-line therapy for invasive infection in certain patients.

Primary therapy is now the azole-class antifungal voriconazole, based on multiple studies showing both improved response rates and survival in patients receiving voriconazole when compared to amphotericin B. In addition, voriconazole is better tolerated than amphotericin B and can be given orally as well as intravenously. Azoles are metabolized through the cytochrome P-450 system, and thus medication interactions can be a significant complication. Other triazole antifungals are also available, including posaconazole, which is approved for antifungal prophylaxis and may be an alternative agent for first-line treatment of IA. Although the dosing of itraconazole and voriconazole have been established for pediatric patients, the pharmacokinetic studies for posaconazole have not yet been done.

The echinocandin class of antifungals may also a play a role in treatment of IA, but to date, these agents are generally employed as second-line medications, particularly for salvage therapy. There have been insufficient studies to permit any recommendations for combination antifungal therapy. Unfortunately, even with the new classes of antifungals, complete or partial response rates for treatment of IA are only approximately 50%. To augment antifungal therapies, patients have been treated with growth factors to increase neutrophil counts, granulocyte transfusions, interferon-γ, and surgery.

Special Populations

Patients with CGD represent a pediatric population at particular risk for pulmonary aspergillosis. Invasive pulmonary aspergillosis can be the first serious infection identified in these patients, and the lifetime risk of development is estimated to be 33%. The onset of symptoms is often gradual, with slow development of fever, fatigue, pneumonia, and elevated sedimentation rate. The neutrophils of patients with CGD surround the collections of fungal elements but cannot kill them, thereby permitting local invasion with extension of disease to the pleura, ribs, and vertebrae, though angioinvasion is not seen. Imaging in these patients is much less likely to reveal the halo sign, infarcts, or cavitary lesions and instead generally shows areas of tissue destruction due to the ongoing inflammatory processes.

Cutaneous Aspergillosis

Cutaneous aspergillosis can occur as a primary disease or as a consequence of hematogenous dissemination or spread from underlying structures. Primary cutaneous disease classically occurs at sites of skin disruption, such as intravenous access device locations, adhesive dressings, or sites of injury or surgery. Premature infants are particularly at risk, given their immature skin and need for multiple access devices. Cutaneous disease in transplant recipients tends to reflect hematogenous distribution from a primary site of infection, often the lungs. Lesions are erythematous indurated papules that progress to painful, ulcerated, necrotic lesions. Treatment depends on the combination of surgical débridement and antifungal therapy, with systemic voriconazole recommended as primary therapy.

Invasive Sinonasal Disease

Invasive Aspergillus sinusitis represents a difficult diagnosis because the clinical presentation tends to be highly variable. Patients can present with congestion, rhinorrhea, epistaxis, headache, facial pain or swelling, orbital swelling, fever, or abnormal appearance of the nasal turbinates. Because noninvasive imaging can be normal, diagnosis rests on direct visualization via endoscopy and biopsy. Sinus mucosa may be pale, discolored, granulating, or necrotic depending on the stage and extent of disease. The infection can invade adjacent structures, including the eye and brain. This syndrome is difficult to distinguish clinically from other types of invasive fungal disease of the sinuses such as zygomycosis, rendering obtaining specimens for culture and histology extremely important. If the diagnosis is confirmed, treatment should be with voriconazole. Because voriconazole is not active against the Zygomycetes, amphotericin B formulations should be considered pending definitive diagnosis.

Central Nervous System

The primary site of Aspergillus infection tends to be the lungs, but as the hyphae invade into the vasculature, fungal elements can dislodge and travel through the bloodstream, permitting establishment of secondary infection sites. One of the sites commonly involved in disseminated disease is the central nervous system (CNS). Cerebral aspergillosis can also arise secondary to local extension of sinus disease. The presentation of cerebral aspergillosis is highly variable but can include changes in mental status, seizures, paralysis, coma, and ophthalmoplegia. As the hyphae invade the CNS vasculature, hemorrhagic infarcts develop that convert to abscesses. Biopsy is required for definitive diagnosis, but patients are often too ill to tolerate surgery. Imaging can be helpful for diagnosis, and MRI is preferred. Lesions tend to be multiple, located in the basal ganglia, have intermediate intensity with no enhancement, and have no mass effect. CT shows hypodense, well-demarcated lesions, sometimes with ring enhancement and edema. Diagnosis often depends on characteristic imaging findings in a patient with known aspergillosis at other sites. Galactomannan assay testing of CSF has been studied and may become a future methodology to confirm the diagnosis. In general, the prognosis for CNS aspergillosis is extremely poor, likely owing to the late onset at presentation. Reversal of immunosuppression is extremely important. Surgical resection of lesions may be useful. Voriconazole is thought to be the best therapy, and itraconazole, posaconazole, and liposomal formulations of amphotericin B are alternative options.

Eye

Fungal endophthalmitis and keratitis may be seen in patients with disseminated Aspergillus infection. Pain, photophobia, and decreased visual acuity may be present, though many patients are asymptomatic. Emergent ophthalmologic evaluation is important when these entities are suspected. Endophthalmitis is treated with intravitreal injection of either amphotericin B or voriconazole along with surgical intervention and systemic antifungal therapy with amphotericin B or voriconazole. Keratitis requires topical and systemic antifungal therapy.

Bone

Aspergillus osteomyelitis can occur, most commonly in the vertebrae. Rib involvement occurs owing to extension of disease in patients with CGD and is most often caused by A. nidulans. Treatment depends on the combination of surgical débridement and systemic antifungals. Arthritis can develop owing to hematogenous dissemination or local extension, and treatment depends on joint drainage combined with antifungal therapy. Amphotericin B has been the most commonly employed agent in the past, although voriconazole is the preferred first-line therapy now.

Heart

Cardiac infection can occur as a result of surgical contamination, secondary to disseminated infection, or as a result of direct extension from a contiguous focus of infection and includes endocarditis, myocarditis, and pericarditis. Treatment requires surgical intervention in the case of endocarditis and pericarditis, along with systemic antifungals, sometimes lifelong due to possibility of recurrent infection.

Empirical Antifungal Therapy

Because the diagnosis of invasive Aspergillus infections is often complicated and delayed, empirical initiation of antifungal therapy is often considered in high-risk patients. At present, antifungal coverage with amphotericin B (conventional or liposomal), voriconazole, itraconazole, or the echinocandin caspofungin should be considered in patients at risk for prolonged neutropenia or with findings suggesting invasive fungal infections. At this time, our ability to diagnose and treat infections due to Aspergillus remains suboptimal, particularly among pediatric patients. Additional study of antigen detection assays based on galactomannan and other Aspergillus cell wall components as well as standardization of PCR-based assays will facilitate diagnosis. The optimal treatment remains another challenging question, because current therapeutic regimens tend to produce complete or partial response only about half of the time. In the future, we may have additional information on multiagent regimens that combine different antifungal classes as well as novel antifungal agents in our armamentarium.

Bibliography

Barnes PD, Marr KA. Aspergillosis: spectrum of disease, diagnosis, and treatment. Infect Dis Clin North Am. 2006;20:545-561.

Blyth CC, Palasanthiran P, O’Brien TA. Antifungal therapy in children with invasive fungal infections: a systematic review. Pediatrics. 2007;119:772-784.

Bochud PY, Chien JW, Marr KA, et al. Toll-like receptor 4 polymorphisms and aspergillosis in stem-cell transplantation. N Engl J Med. 2008;359:1766-1776.

Burgos A, Zaoutis TE, Dvorak CC, et al. Pediatric invasive aspergillosis: a multicenter retrospective analysis of 139 contemporary cases. Pediatrics. 2008;121:e1286-e1294.

Dotis J, Iosifidis E, Roilides E. Central nervous system aspergillosis in children: a systematic review of reported cases. Int J Infect Dis. 2007;11:381-393.

Hayden R, Pounds S, Knapp K, et al. Galactomannan antigenemia in pediatric oncology patients with invasive aspergillosis. Pediatr Infect Dis J. 2008;27:815-818.

Koo S, Bryar JM, Page JH, et al. Diagnostic performance of the (1→3)-β-D-glucan assay for invasive fungal disease. CID. 2009;49:1650-1659.

Maertens J, Buvé K, Theunissen K, et al. Galactomannan serves as a surrogate endpoint for outcome of pulmonary invasive aspergillosis in neutropenic hematology patients. Cancer. 2009;115:355-362.

Segal BH. Aspergillosis, N Engl JMed. 2009;360:1870-1884.

Steinbach WJ. Pediatric invasive aspergillosis. Pediatr Infect Dis J. 2010;29(10):964-965.

Steinbach WJ. Pediatric aspergillosis: disease and treatment differences in children. Pediatr Infect Dis J. 2005;24:358-364.

Steinbach WJ, Addison RM, McLaughlin L, et al. Prospective Aspergillus galactomannan antigen testing in pediatric hematopoietic stem cell transplant recipients. Pediatr Infect Dis J. 2007;26:558-564.

Upton A, Kirby KA, Carpenter T, et al. Invasive aspergillosis following hematopoietic cell transplantation: outcomes and prognostic factors associated with mortality. Clin Infect Dis. 2007;44:531-540.

Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327-360.

Zaoutis TE, Heydon K, Chu JH, et al. Epidemiology, outcomes, and costs of invasive aspergillosis in immunocompromised children in the United States, 2000. Pediatrics. 2006;117:e711-e716.

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