Annals of B Pod: Aspergilloma
/HISTORY OF PRESENT ILLNESS
The patient is a male in his late 40s with a past medical history of pulmonary sarcoidosis who presents reporting hemoptysis upon waking each morning for the past three days. He describes the hemoptysis as one to two small teaspoons of blood mixed into his sputum. Last night he coughed up a larger amount of blood, about 3-4 tablespoons, and developed pleuritic chest pain, which prompted him to come to the Emergency Department. He continues to expectorate blood-mixed sputum at bedside. His pulmonologist prescribed levofloxacin for a possible bacterial infection, which he has been taking for the past three days. He endorses his baseline dyspnea and chest tightness, but denies fever, fatigue, nausea, vomiting, melena, hematochezia, or other changes in bowel or urinary habits.
PAST MEDICAL HISTORY: Pulmonary sarcoidosis, seasonal allergies
PAST SURGICAL HISTORY: Right lung biopsy
MEDICATIONS: Albuterol, azathioprine, budesonide-formoterol, cetirizine, levofloxacin, prednisone
ALLERGIES: No known drug allergies
PHYSICAL EXAM
Vitals: T 99.1 F HR 121 BP 152/96 RR 16 SpO2 93% RA
The patient is a well-appearing male in no acute distress. His oropharyngeal exam is unremarkable with no evidence of blood, erythema, or swelling in the posterior oropharynx or in the nares bilaterally. He has unlabored breathing with diffuse expiratory wheezes appreciated bilaterally but otherwise without focality. Auscultation of the heart reveals no murmurs, rubs, or gallops, and abdominal exam is unremarkable. All four extremities are symmetric, warm, well-perfused, and without edema. His skin is dry with no rashes or peripheral edema noted.
NOTABLE DIAGNOSTICS
WBC: 7.8 Hgb: 13.2 Hct: 38.3 Plt: 281
Na: 138 K: 4.0 Cl: 102 Bicarb: 28 BUN: 18 Cr: 0.88 Glu: 115
Venous blood gas pH: 7.38 pCO2: 51 HCO3: 29 BE: 3.1
Representative image of CTPA series
Chest X-ray: Consolidation and architectural distortion most pronounced in left upper lung, similar to prior CXR, consistent with diagnosis of sarcoidosis.
CT Pulmonary Angiography: 1. No acute pulmonary embolism. 2. Posterior left upper lobe cavitation with central soft tissue mass surrounded by a crescent of air suggestive of an aspergilloma. Some linear high-density foci within the cavitary lesion may represent areas of active extravasation or abnormal irregular pulmonary arteries in the setting of hemoptysis. 3. Background of sarcoidosis. 4. Enlarged pulmonary artery can be seen in the setting of pulmonary hypertension.
HOSPITAL COURSE
Given the patient’s risk factors for pulmonary embolism, he underwent CT pulmonary angiography which showed no evidence of pulmonary embolism but did reveal a 5.5 x 3 cm cavitary lesion consistent with likely aspergilloma with active bleeding into the left upper lung. He continued to have hemoptysis in the ED and was admitted to the medicine stepdown unit for close monitoring. The infectious disease (ID) team was consulted and recommended empiric treatment with voriconazole. The interventional pulmonology (IP) team performed a bronchoscopy which showed a cavitary lesion in the left upper lobe with a fungal ball. Bronchoalveolar lavage (BAL) with lung biopsy showed fungal hyphae morphologically consistent with aspergillus species, without evidence of vascular or tissue invasion. Fungal cultures eventually grew Aspergillus fumigatus. The remainder of the patient’s infectious workup was negative, including evaluation for HIV, tuberculosis, histoplasma, and cryptococcus.
Following his bronchoscopy and biopsy, the patient developed an increased oxygen requirement but was eventually weaned down to nasal canula oxygen at 1 liter per minute. The patient was evaluated by thoracic surgery for possible surgical resection of his aspergilloma, but unfortunately was not a candidate for intervention due to his severe pulmonary disease. The patient was discharged on home oxygen therapy and voriconazole, with plan to continue voriconazole indefinitely. Two months after this hospitalization, he had another episode of hemoptysis and underwent repeat bronchoscopy with voriconazole instillation. This procedure was repeated about one month later and since then, he has had no further hemoptysis recorded in our electronic medical record.
DISCUSSION
Aspergillosis Pathophysiology & Risk Factors
Figure 1. Aspergillus fumigatus.
Aspergillosis refers to a spectrum of disease caused by the aspergillus species of fungus, most commonly Aspergillus fumigatus (figure 1). Aspergillus is ubiquitous in our environment, living in soil and decomposing vegetation, and we are constantly inhaling its spores. Our immune systems have evolved to control the growth of aspergillus and prevent inflammation and injury from its presence, so that systemic fungal disease is uncommon. Disorders of immunity, however, can place patients at risk for infections due to aspergillus. [1] The type of aspergillus infection that occurs depends on host risk factors and most commonly involves the respiratory tract, although disseminated forms of the disease can occur as well. [2, 3]
The most feared presentation of aspergillosis is invasive pulmonary aspergillosis (IPA) which is classically seen in severely immunocompromised patients. Risk factors for IPA include severe or prolonged neutropenia, defects in cell-mediated immunity (such as human immunodeficiency virus), immunosuppressive therapy, bone marrow transplant, and solid organ transplant. Patients with prolonged stays in intensive care units have also been recently identified as a population at risk for IPA, particularly those with chronic obstructive pulmonary disease with steroid use, structural lung disease, acute respiratory distress syndrome, and impaired mucociliary clearance following infection. Multiple respiratory viral infections have been associated with IPA including avian flu, influenza A and B, respiratory syncytial virus, and COVID-19. These viruses are thought to cause epithelial damage that then allows invasion by colonizing aspergillus species. [3]
There are multiple chronic forms of pulmonary aspergillosis that occur in patients with underlying pulmonary disease, in some cases leading to inflammation, tissue destruction, fibrosis, and worsening pulmonary function. The most common manifestation of chronic pulmonary aspergillosis is aspergilloma, also known as a mycetoma or fungus ball, in which the fungus is able to grow inside a pre-existing cavitary lesion (secondary to chronic obstructive pulmonary disease, prior tuberculosis, sarcoidosis, or other causes). [3,4] An association between sarcoidosis and aspergilloma has been demonstrated in the literature, with an estimated 0.7-5% of sarcoidosis patients being affected by aspergilloma. [5-7]
Another distinct presentation of aspergillosis is allergic bronchopulmonary aspergillosis (ABPA), which occurs almost exclusively in patients with asthma and cystic fibrosis due to a hypersensitivity reaction to Aspergillus species in the lungs. ABPA leads to chronic immune activation and presents with fleeting pulmonary infiltrates, worsening of reactive airway disease, and bronchiectasis. [8] There are multiple pulmonary aspergillus overlap syndromes, and patients may develop more than one manifestation of aspergillosis or may progress from one form to another. For example, patients with ABPA and chronic pulmonary aspergillosis have gone on to develop fungal balls and IPA. [9] A summary of the spectrum of pulmonary aspergillosis according to risk factor is provided in Table 1. The remainder of this review will focus on pulmonary aspergilloma, since that is the most common manifestation of pulmonary aspergillosis and the entity with which our patient presented.
Table 1: Spectrum of pulmonary aspergillosis by risk factor
Spectrum of pulmonary aspergillosis
Aspergilloma Clinical Presentation
Hemoptysis is the most common clinical manifestation of aspergillomas, and aspergillomas remain one of the leading causes of hemoptysis worldwide (along with tuberculosis and lung abscess). In case series describing aspergilloma, the incidence of hemoptysis has been reported to range from 54%-87.5%, with up to 30% of patients experiencing massive fatal hemorrhage. [10-12] The hemoptysis is thought to be secondary to direct invasion of the capillaries lining the cavity wall, endotoxin-mediated inflammation, or mechanical irritation of exposed vessels within the cavity. [9,10] Symptoms can also include malaise, weight loss, chest pain, dyspnea, chronic cough, and, rarely, fever.10 Aspergillomas may remain stable, or they may grow, causing pneumonia, pulmonary fibrosis, and disseminated disease (such as IPA). [10]
Aspergilloma Diagnosis
The diagnosis of aspergilloma should be considered in a patient with hemoptysis and other risk factors, and the first step for diagnosis in the emergency department is identifying radiographic evidence of a rounded fungal ball inside a cavity on chest X-ray or computed tomography. Two radiographic signs may aid in the diagnosis: the air crescent sign, which is a crescent-shaped air space separating the fungal ball from the cavity wall, and Monod sign, which is characterized by the change in position of the fungal ball depending on the patient’s position. If a fungal ball is seen on imaging, the diagnosis can be confirmed with serum tests, which may include Aspergillus-specific IgG or IgE antibodies. Aspergillus cell wall components (such as galactomannan) may also be found in BAL fluid. A fungal culture positive for aspergillus species may aid in the diagnosis, but is not sufficient for diagnosis on its own since airway colonization by aspergillus species is common. [13]
Aspergilloma Treatment
In the emergency department, treatment of an aspergilloma may involve initiation of an antifungal medication along with supportive care, especially if the patient has significant hemoptysis. Ultimately, surgical resection is the gold standard of treatment for symptomatic aspergilloma, but many patients are poor candidates for surgery due to underlying lung disease, and morbidity and mortality with surgery is considerable. [13] Bronchial artery embolization by interventional radiology is a potential treatment strategy for patients with moderate to severe hemoptysis who are poor surgical candidates. [14]
Systemic antifungal medications, including amphotericin B and azoles, have been used in patients with aspergilloma. Amphotericin B has been shown to have a cure rate of approximately 10%, which is similar to the rate of spontaneous resolution. A multicenter randomized clinical trial using itraconazole for 6 months demonstrated a cure rate of 63.4%. Voriconazole is an alternative therapy that has also shown efficacy in treatment of IPA and may have a higher threshold for fungal resistance. [13,15] Currently, guidelines recommend treatment of chronic pulmonary aspergillosis, including aspergilloma, with at least 6 months of azole therapy. [15,16] Echinocandins, such as micafungin, are also an option in patients who have previously not responded well to azoles. [17]
For patients who fail systemic therapy and are not surgical candidates, a few other treatment options remain. Endobronchial instillation of voriconazole has been effective, with 30.6% of patients reporting resolution of hemoptysis after one treatment and an additional 37.8% reporting resolution after the second treatment. [18] Percutaneous intracavitary instillation of antifungals has also been used with some improvement. In some cases, bronchoscopic removal of the aspergilloma may be possible. [13]
SUMMARY
Aspergillosis is disease primarily of the respiratory tract caused by Aspergillus species in patients with underlying risk factors such as immunosuppression and structural lung disease. Aspergilloma is one manifestation of aspergillosis, in which a fungal ball develops in a preexisting cavitary lung lesion. Aspergillomas can cause life-threatening hemoptysis. Treatment options include surgical resection, bronchial artery embolization, systemic antifungal therapy and direct antifungal instillation.
AUTHORED BY MATTHEW M MANNION, MD
At the time of authorship, Dr. Mannion was a MS4 rotating student at the University of Cincinnati, from Southern Illinois Medical School
EDITING BY THE ANNALS OF B POD EDITORS
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