Despite recent advances in the diagnosis and treatment of pulmonary disease, massive hemoptysis remains a life-threatening emergency, with an in-hospital mortality as high as 40%.^1-3 Prompt diagnosis and subsequent treatment are essential to reduce the mortality risk. The management of a patient with massive hemoptysis requires a team effort, with a focus on protecting or establishing an airway and maintaining adequate oxygenation, because the most common cause of death is asphyxiation rather than exsanguination. Primary care physicians are more likely to encounter moderate rather than massive hemoptysis; nonetheless, they should be familiar with and be able to respond to massive hemoptysis, because of the high mortality rate associated with this condition.

Case Presentation

A 46-year-old woman presented to the family medicine clinic complaining of progressive shortness of breath and a productive cough, with a long history of blood-tinged sputum. She also reported occasional night sweats with chills, and a 10-lb weight loss in the past 6 months. This episode of hemoptysis prompted hospitalization. Her medical history included hypertension, hypothyroidism, chronic obstructive pulmonary disease (COPD), asthma, alcoholism, and heavy smoking (1 pack/d for 20 years). Initial physical examination showed a thin woman who was mildly agitated. On auscultation, she had right basilar crackles. No evidence of lymphadenopathy, clubbing, or cyanosis was found. The rest of the examination was unremarkable. The patient was using metered-dose inhalers of triaminolone acetonide (Azmacort) and albuterol (ProAir HFA, Proventil, Ventolin) for COPD and asthma, respectively.

An initial chest radiograph demonstrated a well-defined right upper lobe mass measuring 2.0 x 2.5 cm (Figure 1). Computed tomography (CT) findings revealed a cavity with a density consistent with aspergilloma (Figure 2). Bronchoscopy, with particular attention to the upper, middle, and lower lobes of the right lung, showed no abnormalities. Bronchoalveolar washings were also negative for fungal hyphae or malignant cells. The patient was started on voriconazole (Vfend) 200 mg/day as initial management.

Figure 1—Chest radiograph showing a well-defined right upper lobe mass (arrow) typical of aspergilloma.

Figure 2—CT of the thorax demonstrating a fungus ball in the right upper lobe, with an "air crescent" sign (arrow) characteristic of pulmonary aspergilloma.

The hemoptysis progressed, and the patient was referred to thoracic surgery. A right upper lobectomy was performed, effectively removing the fungus ball (Figure 3). During surgery, the aspergilloma was found to be adherent to the parietal pleura. Pathologic evaluation confirmed the diagnosis of noninvasive pulmonary aspergilloma. The patient continued to take voriconazole 200 mg/day for the remainder of her hospital stay, which lasted 8 days. A follow-up with the surgery department and the family medicine clinic showed she was asymptomatic.

Figure 3—The fungus ball (arrows) and aspergilloma are seen within the transected right upper lobe.

Discussion

Although uncommon, pulmonary aspergilloma is a well-known cause of massive hemoptysis (Table 1). The mortality rate from hemoptysis caused by pulmonary aspergilloma ranges from 2% to 14%,⁴ and the rate is higher for patients with pulmonary function limitations. Many organ systems may be affected, but Aspergillus usually targets the upper respiratory tract. Approximately 75% to 90% of patients with aspergilloma present with hemoptysis, which is massive in approximately 25% of cases.⁵ The location of the disease provides an enhanced opportunity for bleeding, because of the dual blood supply to the lungs.

The treatment of aspergilloma with antifungal medication has had limited success. Surgical resection is the most effective treatment, especially in the case of intractable or massive hemoptysis.

Etiology

Pulmonary aspergilloma is the most common consequence of infection with the ubiquitous fungus Aspergillus. Aspergillus fumigatus and Aspergillus flavus are the most common species responsible for pulmonary aspergilloma. Aspergillus is readily found in soil and organic material; decaying vegetation and birds are the main source of infection. It is a hardy fungus but has a low pathogenicity in humans. Therefore, aspergilloma usually develops in the preformed pulmonary cavities caused by tuberculosis, sarcoidosis, or another chronic lung disease (Table 2). Overwhelming exposure to spores and, in most cases, preexisting pulmonary cavitary disease are needed for aspergilloma to progress, often in the upper lung fields.

Common Presentations

A patient can develop a single lesion or multiple lesions of varying sizes in one or in both lungs. Bilateral involvement is only seen in about 5% to 10% of the cases.⁶ Aspergilloma is a noninvasive form of aspergillosis. However, semi-invasive aspergillosis, in which Aspergillus develops its own cavity, without invading the surrounding tissues, may occur in a patient with a mildly depressed immune system,⁷ such as in the case of COPD.

It is impossible to clinically distinguish between semi-invasive and classical aspergilloma at the time of presentation, because both may have massive hemoptysis, as was seen in our patient. A host immune system can be compromised as a result of a plethora of diseases or from the use of systemic or inhaled steroids.

Other forms of pulmonary aspergillosis include acute inhalational Aspergillus pneumonia, invasive pulmonary aspergillosis, and allergic bronchopulmonary aspergillosis.

Although aspergilloma can be asymptomatic, many patients present with a combination of signs and symptoms that include:

• Cough
• Blood-tinged sputum
• Clubbing
• Malaise
• Weight loss
• Chest pain
• Indeterminate nodule.

In the case of an indolent infection, diagnosis may be incidental during radiologic examination for a non-related illness.

Diagnosis

The clinical diagnosis of pulmonary aspergilloma is made by the combination of a hemoptysis presentation and a radiographic demonstration of an intracavitary mass. A chest radiograph or a CT scan will reveal an upper lobe or apical opaque round mass, surrounded by a cavity resembling an "air crescent" or a "meniscus" sign, with adjacent pleural thickening.⁸

Laboratory studies using double immunodiffusion tests will show a high number of precipitins, which are present in 92% to 100% of patients with aspergilloma; and enzyme-linked immunosorbent assay will show high immunoglobulin G antibody titers.^8,9

Pathologically, microscopic examination reveals uniform hyphae ranging from 3 to 6 µm in width, regularly septate, with parallel contours and acute-angle branching from the parent hyphae. The branching is progressive and dichotomous. Viable hyphae are basophilic and are therefore best visualized with Grocott-Gomori methenamine–silver nitrate stain (Figure 4). In contrast, necrotic hyphae are hyaline or eosinophilic.^9,10 Conidiophores originate from the basal (also known as foot) cell located on the supporting hyphae and terminate in a vesicle at the apex.

Figure 4—Grocott-Gomori methenamine–silver nitrate stain, revealing microscopic findings of pulmonary aspergilloma. Note the uniform, regularly septate hyphae branching at acute angles.

A definitive microscopic diagnosis of aspergillosis can be made by the presence of conidial heads, which are produced by fungus balls that are exposed to ambient air. The distinctive morphology of the conidial heads makes it possible to identify the species of Aspergillus. The surrounding cavity wall is usually thickened and is composed of reactive fibrocollagenous tissue with mixed inflammatory cells, including plasma cells, lymphocytes, eosinophils, and neutrophils.

Treatment

The management of pulmonary aspergilloma varies, ranging from bed rest with little or no intervention to systemic or local antifungal therapy to surgical resection. The initial management of massive hemoptysis should focus on protecting the airway and maintaining hemodynamic stability. Soon thereafter, bronchoscopy should be performed to evacuate the blood clots and localize the site of bleeding. Preemptive endotracheal intubation with a double-lumen tube will maintain the airway and protect the contralateral lung from aspirating blood; the most common cause of death in massive hemoptysis is acute respiratory failure secondary to aspiration. Surgical intervention should be done on an elective basis, when possible. If conservative management does not achieve stabilization, arterial embolization should be attempted. Conservative management alone, including close observation, airway management, oxygen therapy, recording volume of expectorated blood, and blood transfusion only increases the mortality rate.

The patient's overall status and pulmonary function determines the type of treatment. Asymptomatic patients may be observed for progression of disease, with 7% to 10% of patients having spontaneous lysis of the fungus ball.¹¹

Systemic antifungal agents have proved ineffective in treating pulmonary aspergilloma. Itraconazole (Sporanox) and voriconazole may show some promise. Intravenous amphotericin B (Abelcet, Amphocet, AmBisome) is ineffective because of poor diffusion into the fungus ball.¹¹

Direct intracavitary instillation of antifungals is reserved for sicker patients with poor pulmonary function who are not surgical candidates. Determination of dose and duration of treatment can be difficult and plays a part in the success or failure of intracavitary instillation.¹²

In high-risk patients who are not candidates for surgical resection, management includes bed rest, arterial embolization, and antifungal and antitussive medications. Arterial embolization is less effective as a curative treatment because of the many collateral arteries that are formed in aspergilloma, but it does have a role in stabilizing the patient during massive hemorrhage and avoiding the high risk of emergency surgery.^12,13 Although surgical resection is the only definitive treatment that completely eradicates the disease, this procedure is plagued with high operative morbidity and mortality rates.^14,15 This is in part due to the nature of this disease; most patients already have a diminished pulmonary reserve as a consequence of the underlying pulmonary disease.

Conclusion

The most common consequence of infection with the ubiquitous fungus Aspergillus is pulmonary aspergilloma. Pulmonary aspergilloma is a common cause of massive hemoptosis, which remains a life-threatening condition associated with a high mortality rate. The use of antifungal medications for the treatment of aspergilloma has shown only limited success. Surgical resection is currently the most effective treatment.

References

1. Reechapichitkul W, Latong S. Etiology and treatment outcomes of massive hemoptysis. Southeast Asian J Trop Med Public Health. 2005;36:474-480.
2. White RI Jr. Bronchial artery embolotherapy for control of acute hemoptysis: analysis of outcome. Chest. 1999;115:912-915.
3. Knott-Craig CJ, Oostuizen JG, Rossouw G, et al. Management and prognosis of massive hemoptysis: recent experience with 120 patients. J Thorac Cardiovasc Surg. 1993;105:394-397.
4. Soubani AO, Chandrasekar PH. The clinical spectrum of pulmonary aspergillosis. Chest. 2002;121:1988-1999.
5. Sharma OP, Chwogule R. Many faces of pulmonary aspergillosis. Eur Respir J. 1998;12:705-715.
6. Chen JC, Chang YL, Luh SP, et al. Surgical treatment for pulmonary aspergilloma: 28-year experience. Thorax. 1997;52:810-813.
7. Kristan SS, Kern I, Music E. Invasive pulmonary aspergillosis. Respiration. 2002;69:521-525.
8. Franquet T, Müller NL, Giménez A, et al. Spectrum of pulmonary aspergillosis: histologic, clinical, and radiologic findings. Radiographics. 2001;21:825-837.
9. Sharma OP, Chwogule R. Many faces of pulmonary aspergillosis. Eur Respir J. 1998;12:705-715.
10. Duarte IG, Gal AA, Mansour KA, et al. Pathologic findings in lung volume reduction surgery. Chest. 1998;113:660-664.
11. Mori T, Ebe T, Isonuma H, et al. Aspergilloma: comparison of treatment methods and prognoses. J Infect Chemother. 2000;6:233-239.
12. Bhatia P, O'Reilly JF, Karthik S, et al. Massive haemoptysis: causes and management. Ir Med J. 2004;97:52-53.
13. Johnson JL. Manifestations of hemoptysis. How to manage minor, moderate, and massive bleeding. Postgrad Med. 2002;112:101-106, 108-109, 113.
14. Kim YT, Kang MCW, Sung S, et al. Good long-term outcomes after surgical treatment of simple and complex pulmonary aspergilloma. Ann Thorac Surg. 2005;79:294-298.
15. Okubo K, Kobayashi M, Morikawa H, et al. Favorable acute and long-term outcomes after the resection of pulmonary aspergillomas. Thorac Cardiovasc Surg. 2007;55:108-111.