Aspergillus Species

Pulmonary Infection

Clinical manifestations in different patient populations have been reviewed, but disease in most immunocompromised patients often is characterized by bilateral diffuse pulmonary infection ( Fig. 244.1 ). The most common presentation is unremitting fever in a high-risk neutropenic patient, but high fever can be absent in patients receiving corticosteroid therapy. Other early symptoms of pulmonary disease include a dry cough and possibly chest pain. Dyspnea is more common is patients with diffuse disease, and the presentation in some patients is similar to that of pulmonary embolism. Hemoptysis can occur and can be fatal as the first presenting episode, whereas in neutropenic patients, pneumothorax also is an occasional presenting feature.

Invasive pulmonary aspergillosis is the leading cause of death in patients with chronic granulomatous disease (CGD), and it can be the first manifestation of CGD. Invasive aspergillosis in patients with CGD usually manifests within the first 20 years of life. Invasive aspergillosis in a child or adult without a known predisposing risk factor should prompt an evaluation for CGD. Patients with CGD can lack typical clinical symptoms (including being completely asymptomatic), or they can be afebrile and have only an elevated erythrocyte sedimentation rate. In a review of clinical findings at diagnosis of invasive aspergillosis in 23 patients with CGD, only one-third of these patients were symptomatic, and only one-fifth were febrile; one-half had a white blood count of <10,000 cells/μL, and almost one-half had an erythrocyte sedimentation rate of <40 mm/hr.

In early disease in a patient with CGD, an acute neutrophilic response occurs, and neutrophils surround hyphae. However, hyphae remain intact as a result of impaired neutrophil-mediated killing. In this setting, pulmonary aspergillosis is a chronic progressive infection that can spread locally to involve pleura, vertebrae, and the chest wall ( Fig. 244.2 ). In contrast to patients with neutropenia, in patients with CGD hyphal angioinvasion is not a feature of disease. The halo sign (angioinvasion with surrounding tissue ischemia), cavitated lesions, and pulmonary infarcts seen in neutropenic patients are not seen typically in CGD. Areas of tissue destruction are secondary to a reactive acute and granulomatous inflammatory process rather than directly related to growth of the hyphae. Infection with A. nidulans is more common in patients with CGD; pulmonary disease is more likely to involve adjacent bone, more likely to cause disseminated disease, generally refractory to intensive antifungal therapy, and more likely to require surgical intervention in patients with CGD than in patients who do not have CGD.

Invasive Sinusitis

Invasive Aspergillus sinusitis likely is underdiagnosed for lack of detailed examination, but patients can come to medical attention with ear pain or discharge, facial pain or swelling, localized pallor of the nasal septum or turbinate mucosa, epistaxis, orbital swelling, or headache. ^, The maxillary sinus is involved most commonly ( Fig. 244.3 ), followed by the ethmoid, sphenoid, and frontal sinuses. A careful rhinoscopic examination is needed to look for insensitive areas with decreased blood flow, frank crusting or ulceration, or blackened, necrotic foci. One study reviewed 11 patients with invasive fungal sinusitis after bone marrow transplantation, including 8 patients with Aspergillus infection. The mean interval from bone marrow transplantation to the diagnosis of fungal sinusitis was 22 days, and all patients had maxillary sinus involvement; one-half also had ethmoid sinusitis involvement, and most patients had extension of the infection into the orbits, bone, or brain. One major difficulty is the critically important diagnostic distinction between mucormycosis and aspergillosis, given the divergent therapeutic approaches. In a study evaluating pulmonary aspergillosis and pulmonary mucormycosis, concomitant sinusitis was significantly associated with mucormycosis and not aspergillosis in patients with radiographic evidence of pulmonary disease.

Cerebral Infection

Cerebral involvement occurs in up to 40% of patients with invasive aspergillosis. ^, The pathogenesis is thought to involve hematogenous dissemination from an extracranial focus, most commonly the lung, or direct extension through the sinuses. Aspergillus hyphae are angioinvasive and thrombose arteries to create hemorrhagic infarcts, which then become abscesses ( Fig. 244.4 ). Cerebral aspergillosis is the most common brain abscess type in hematopoietic stem cell transplant (HSCT) recipients; in 1 study, 58% of brain abscesses were caused by Aspergillus, and 87% of these patients had concomitant pulmonary infection. In another report of 18 patients with invasive aspergillosis, 10 patients had cerebral involvement, including 3 patients who presented with neurologic signs and no pulmonary symptoms. The classic features of abscesses such as headache, nausea, and vomiting can be present in <10% of cases, with more prevalent features including altered mental status, confusion, hemiparesis, and cranial nerve palsies. Multiple lesions in the corticomedullary junction are consistent with infarct secondary to Aspergillus vasculopathy; dilated cortical vessels located in the central portion of the lesions in the corticomedullary junction are often distinctive signs of cerebral aspergillosis. Definitive diagnosis requires a brain biopsy, but these patients often are too coagulopathic for the diagnostic operation.

Cutaneous Infection

Cutaneous aspergillosis can be either primary, usually from skin injury or traumatic inoculation, or secondary, from contiguous extension of hematogenous dissemination. In general, burn victims, neonates, and solid-organ transplant recipients develop cutaneous inoculation after prolonged local skin injury. HSCT recipients often develop secondary disease from contiguous extension of infected structures under the skin or from hematogenously disseminated embolic lesions. In a review of >4000 patients with malignant disease, 15 had documented Aspergillus cutaneous infection, whereas in another review, embolic skin lesions were present in approximately 11% of patients with disseminated aspergillosis.

Cutaneous aspergillosis often begins as an area of raised erythema that progresses to include pain; skin involvement can be the first presenting sign of invasive infection. The center of the lesion changes from red to purple, and then to black, and it can ulcerate. Infections arising at the site of an intravenous catheter puncture typically begin with erythema and induration and progress to necrosis that extends radially. Compared with wound mucormycosis, patients with primary cutaneous aspergillosis appear to present with significantly less local necrosis and systemic toxicity.

Chronic Pulmonary Aspergillosis

Acute invasive aspergillosis occurs almost exclusively in patients with profound immunosuppression and displays rapid progression with poor outcome. However, some patients clearly have a more chronic Aspergillus infection. Chronic aspergillosis previously was known by several different terms, most notably semi-invasive aspergillosis, chronic invasive pulmonary aspergillosis, and symptomatic pulmonary aspergilloma. The blurred entity of chronic aspergillosis has been reclassified to include the following: chronic cavitary pulmonary aspergillosis, in which imaging findings consist of the formation and expansion of multiple cavities, with some containing fungus balls; chronic fibrosing pulmonary aspergillosis, which denotes progress to marked and extensive pulmonary fibrosis; and chronic necrotizing pulmonary aspergillosis, or subacute invasive pulmonary aspergillosis. These patients have a mild or moderate defect in immune function, and their course is unlike that of patients with the other 2 chronic aspergillosis classifications in which a slow and progressive enlargement of an Aspergillus -containing cavity is noted. The diagnosis requires at least 3 months of pulmonary symptoms of chronic illness, radiologic abnormalities, and elevated Aspergillus immunoglobulin G (IgG) antibody or other microbiologic data. Surgery appears to play a smaller role in managing chronic aspergillosis, and the mainstay of treatment is long-term antifungal therapy to halt the progression of disease. Although no randomized clinical trial has been conducted to demonstrate the benefit of antifungal therapy in chronic aspergillosis, anecdotal evidence suggests slow improvement.

Pulmonary Aspergilloma

Aspergilloma is considered a saprophytic, or noninvasive, form of infection in which Aspergillus colonizes preexisting pulmonary cavities caused by tuberculosis, sarcoidosis, bullous emphysema, bronchiectasis, or other conditions. Aspergilloma develops in approximately 15%–25% of patients with cavitating lung disease resulting from tuberculosis. Disease can be divided into simple and complex aspergillomas based on radiographic criteria. The simple aspergilloma can be differentiated from the complex aspergilloma by the absence of constitutional symptoms, parasitic lung opacities, cyst expansion, or progressive pleural thickening. In a study of 62 cases of pulmonary aspergilloma, chest radiograph showed a “fungus ball” in the cavities of 42 (67%) and thickening of the cavity wall in 16 (26%) cases. Patients with aspergilloma can be asymptomatic, but many patients have persistent and productive cough, hemoptysis, and weight loss. Surgical management to extricate the aspergilloma completely is the preferred treatment. Although the postoperative morbidity rate is higher in complex aspergilloma, in a series of 88 patients, surgical management led to nearly equivalent (80%) survival rates in patients with either simple or complex aspergilloma. Medical management often is unsuccessful because penetrance of the antifungal agent into the cavity is poor. Percutaneous intracavitary instillation of antifungal therapy designed to fill the cavity and create an anaerobic environment for the Aspergillus has led to some success, but it should be reserved for patients with inoperable cases.