A 44-year-old man was admitted for upper extremity weakness that began after lifting at work. His medical history was significant for a cervical arteriovenous malformation, which had bled 13 years previously and was partially treated with a therapeutic embolization of the malformation; chronic obstructive pulmonary disease; and cirrhosis. His upper extremity weakness rapidly progressed to complete quadriplegia, which affected his respiratory muscles and required intubation and mechanical ventilation. Magnetic resonance imaging confirmed recurrent hemorrhage of the arteriovenous malformation into the cervical spinal cord. Partial embolization was performed, and swelling of the cord was treated with highdose corticosteroids.
The patient's hospital course was marked by persistent fever and progressive left-sided pulmonary infiltrates (Figure 1). Sputum cultures were positive for multiple organisms, including Klebsiella pneumoniae, Streptococcus pneumoniae, Proteus mirabilis, Acinetobacter baumanni, Aspergillus fumigatus, Candida albicans, and unspecified mold. Blood cultures grew alpha-hemolytic streptococcus, enterococci, and Acinetobacter baumanni. The urine also grew Acinetobacter baumanni on multiple occasions. The patient was diagnosed with nosocomial, gram-negative bacterial pneumonia and sepsis and was treated with multiple courses of antibiotics. Aspergillus fumigatus had only been definitively isolated on one occasion; therefore, it was considered a colonizing organism rather than a pathogen. Specific antifungal therapy was not administered. One month after admission, progressive worsening neurological status with a right seventh nerve palsy and eyes deviating to the right were noted. Brain and cervical spine magnetic resonance imaging indicated a 2-cm acute lesion with a subtle mass effect in the left globus pallidus (Figure 2) (seen grossly at autopsy Figure 3) and a smaller nonspecific left parietal lesion. The differential diagnosis for the lesion included thrombotic or embolic causes. The patient developed septic shock, renal and liver failure, and a coagulopathy. At no time was significant neutropenia noted, although the patients absolute lymphocyte count was mildly reduced throughout the course of his illness. The patients family decided to withdraw aggressive support, and he died shortly thereafter. Postmortem testing for human immunodeficiency virus was negative, although a test for hepatitis C virus was positive. Histologic sections, such as the section of lung stained with Gomori's methenamine silver (Figure 4), were diagnostic.
What is your diagnosis?
Pathologic Diagnosis: Disseminated Aspergillosis in a Nonneutropenic Patient
Histologic examination revealed fungal hyphae in the brain (cortex, left basal ganglia, cerebellum, medulla, and pons), thyroid, heart, lungs (Figure 4), and kidneys. Hyphae were septated with 45-degree dichotomous branching. The left lung contained multiple areas of high-density hyphal balls with necrotizing pneumonia and infarcted parenchyma. An angioinvasive pattern was observed with septic necrosis and both hemorrhagic and anemic infarcts in multiple regions. Culture of lung tissue grew predominantly Aspergillus fumigatus. Rupture of the arteriovenous malformation resulted in acute hemorrhage in the spinal cord with multifocal axonal swellings. Emphysema, cirrhosis, and moderate calcific atherosclerosis of the coronary arteries also were noted.
Such widely disseminated fungal infection is an unusual presentation in a patient without neutropenia. Pulmonary aspergillosis takes a variety of forms, including saprophytic colonization, allergic aspergillosis, and invasive aspergillosis that includes bronchopneumonia and angioinvasive disease.' Invasive aspergillosis with subsequent dissemination is a well-known phenomenon in immunocompromised patients, particularly in those with prolonged neutropenia. According to a German autopsy study,2 the incidence of recognized invasive aspergillosis increased from 0.4% in 1978 to 3.1% in 1992.
Known risk factors for invasive disease that may disseminate involve various forms of immunosuppression. These include hematologic/lymphoreticular malignancy, bone marrow transplants, solid organ transplants, acquired immunodeficiency virus, chronic granulomatous disease, and therapy with high-dose corticosteroids, cytotoxic chemotherapy, and possibly treatment with broadspectrum antibiotics.3-7
Diabetes mellitus and ethanol abuse compromise immune status, in part by impairing alveolar macrophage and neutrophil function. Both may predispose to dissemination.3,6,11 Rarely, invasive aspergillosis has been reported in previously normal hosts. However, with careful review, evidence of an immunocompromised state can sometimes be found even in these cases. For instance, influenza A infection has known immunosuppressive effects involving destruction of ciliary lung defenses with replacement by metaplastic squamous epithelium, as well as cell-mediated immunosuppression.4 Several case reports have described development of invasive disease after infection with influenza A virus.4,8 Lymphopenia (noted in our patient) and lymphocyte dysfunction also have been implicated in the pathogenesis of fungal infection.3,4
The patient described here received high doses of corticosteroids for spinal cord edema. Corticosteroids are thought to impair macrophage destruction of fungal spores and neutrophil and mononuclear cell destruction of hyphae.9 Additionally, hydrocortisone resulted in a 30% to 40% increased growth rate in vitro for Aspergillus fumigatus at pharmacologic concentrations in one laboratory study.5 In this case, high-dose corticosteroids and broadspectrum antibiotics probably were instrumental in the development of fungal angioinvasion and dissemination.
The postmortem examination revealed pathologic evidence of chronic obstructive pulmonary disease, which increases the risk of invasive aspergillosis. Other authors have reported invasive aspergillosis in patients with underlying pulmonary pathology, such as chronic obstructive pulmonary disease, asthma, bronchospasm of undetermined etiology, sarcoidosis, and berylliosis.6 Interestingly, hematogenous spread occurs particularly to the brain, heart, kidneys, liver, and thyroid.7 These organs are susceptible to embolic infarction. Cerebral aspergillus infection typically occurs via hematogenous spread from the lung and has been reported in nonimmunocompromised patients.8 In this setting, computed tomography of the brain often shows ring-enhancing lesions and mass effect. With decreasing immune function, computed tomography tends to show well-differentiated hypodense regions without hemorrhage or mass effect.9 However, diagnosis of cerebral aspergillus infection remains problematic in that it requires invasive techniques.9 Most cases are diagnosed postmortem. Similarly, radiographic findings in pulmonary aspergillosis are nonspecific. Multiple radiographic presentations are possible, including rounded densities, cavitation, and pleural-based, wedge-shaped lesions.9
This case illustrates the difficulty of antemortem diagnosis of disseminated aspergillus infection in nonneutropenic patients. Diagnosis is still dependent on tissue histology in the absence of other definitive testing, because cultures are often unrevealing. During the course of our patient's treatment, multiple positive bacterial cultures and delayed growth of fungal organisms caused difficulty in making a timely diagnosis of aspergillosis. Aspergillus has been reported in sputum cultures in up to 16% of normal subjects; some of these individuals may have had minimal respiratory disease, such as chronic obstructive pulmonary disease or asthma.10 Lung biopsy and histopathologic evaluation and culture are recommended in suspected cases of pulmonary infection due to nonspecific clinical and radiographic features.8 Pathologic examination retains a key role in appropriate diagnosis in spite of other developing serologic and molecular techniques. A heightened awareness of the occurrence of disseminated aspergillus infection in patients receiving corticosteroid treatment and in those with respiratory disease may allow earlier treatment, although the prognosis remains poor. Mortality ranges between 60% and 100%, depending on the level of dissemination.7,8 Current treatment options include amphotericin B (and liposomal preparations) and combination therapies such as amphotericin plus flucytosine.8
1. Fraser RS. Pulmonary aspergillosis: pathologic and pathogenetic features. Pathol Annu. 1993;28:231-277.
2. Groll AH, Shah PM, Mentzel C, Schneider M, Just-Neubling G, Huebner K. Trends in postmortem epidemiology of invasive fungal infections at a university hospital. I Infect. 1996;33:23-32.
3. D'Silva H, Burke JF, Cho SY. Disseminated aspergillosis in a presumably immunocompetent host. ]AMA. 1982;248:1495-1497.
4. Lewis M, Kallenbach J, Ruff P, Zaltzman M, Abramowitz J, Zwi S. Invasive pulmonary aspergillosis complicating influenza A pneumonia in a previously healthy patient. Chest. 1985;87:691-693.
5. Ng TTC, Robson GD, Denning DW. Hydrocortisone-enhanced growth of Aspergillus spp.: implications for pathogenesis. Microbiology. 1994;140:24752479.
6. Palmer LB, Greenberg HE, Schiff Mj. Corticosteroid treatment as a risk factor for invasive aspergillosis in patients with lung disease. Thorax. 1991;46:15-20.
7. Rex JH, Walsh Tj, Anaissie Ej. Fungal infections in iatrogenically compromised hosts. Adv Intern Med 1998;43:321-371.
8. Clancy CJ, Nguyn HM. Acute community acquired pneumonia due to Aspergillus in presumably immunocompetent hosts: clues for recognition of a rare but fatal disease. Chest. 1998;114:629-634.
9. Denning DW. Invasive aspergillosis. Clin Infect Dis. 1998;26:781-805. 10. Comstock GW, Palmer CE, Stone RW, Goodman NL. Fungi in the sputum of normal men. Mycopathol Mycol Appl. 1974;54:55-62.
Accepted for publication June 17, 1999.
From the Departments of Pathology and Laboratory Medicine (Mr Riesenfeld and Dr Shan) and Pulmonary and Critical Care Medicine (Dr Pietropaoli), University of Rochester, Rochester, NY.
Reprints: Erik Riesenfeld, Department of Pathology and Laboratory Medicine, Neuropathology and Post Mortem Medicine, 601 Elmwood Ave, Box 626, Rochester, NY 14642.
Copyright College of American Pathologists Mar 2000
Provided by ProQuest Information and Learning Company. All rights Reserved