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Combined systemic and intrapleural treatment of Aspergillus pulmonary empyema after invasive aspergillosis

Baquero-Artigao, Fernando M.D.; García-Miguel, Maria Jesús M.D.; Hernández, Francisco M.D.; Hernández, Natalio M.D.; del Castillo, Fernando M.D.

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The Pediatric Infectious Disease Journal: May 2003 - Volume 22 - Issue 5 - p 471-473
doi: 10.1097/01.inf.0000066194.97650.6d
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A 12-year-old immunocompromised boy was hospitalized because of invasive aspergillosis with lung and central nervous system involvement. He was treated with surgery and liposomal amphotericin B, but he developed a pulmonary empyema and a bronchopleural-cutaneous fistula. A catheter was placed through the fistula, and amphotericin B (up to 50 mg in 10 ml of 5% dextrose) was instilled daily into the pleural cavity for 45 days. Treatment was well-tolerated, and the empyema resolved completely, with no evidence of recurrence after 2 years of follow-up.

Pleural aspergillosis is an uncommon condition that predominantly affects patients with a bronchopleural fistula complicating thoracic surgery or tuberculosis. 1–4 It may also develop by rupture of an aspergilloma cavity into the pleural space or by direct spread from the lung in the course of invasive pulmonary aspergillosis. 5 Treatment usually combines medical and surgical strategies. However, systemic antifungal therapy is not always effective, and surgery has been associated with serious postoperative complications. 6 Intrapleural administration of antifungal agents may be an alternative, 2–4 but there is no experience in pediatric patients. We present a child with invasive aspergillosis and pleural involvement who was successfully treated with a combination of intravenous and intrapleural amphotericin B.

Case reports.

A 12-year-old immunosuppressed boy was referred to our hospital with the diagnosis of invasive aspergillosis with lung and central nervous system involvement. He had been diagnosed by a private practitioner as having alopecia areata at the age of 6 years and had received intermittent courses of local and systemic corticosteroids since then. The patient was admitted to his regional hospital 1 week after completing a 6-month course of steroid treatment (Deflazacort, 2 mg/kg/day), with a 10-day history of malaise, anorexia, low grade fever and nonproductive cough. The patient also complained of frequent frontal headaches and weakness in his legs. Dyspnea and right sided pleuritic chest pain developed on the day before admission.

Physical examination revealed a well-nourished, pale and acutely ill boy with persistent irritative cough and respiratory distress. The body temperature was 38.5°C, blood pressure 110/65 mm Hg, pulse rate 120/min and respiratory rate 35/min. Decrease in breath sounds was noted over the right lower lung field. The abdomen was soft and nontender without hepatosplenomegaly. The rest of the physical examination was normal.

Laboratory tests showed a white blood cell count of 35 600/mm3 with 82% neutrophils, 9% band forms, 5% lymphocytes, 4% monocytes and 1% eosinophils; hemoglobin of 9.9 g/dl; and platelet count of 205 000/mm3. The erythrocyte sedimentation rate was 133 mm/h. While the patient breathed room air, the arterial blood gas analysis revealed hypoxemia with a pO2 of 55 mm Hg and a pCO2 of 20 mm Hg. Chest radiograph revealed bilateral infiltrates and a right lower lobe consolidation. Bacterial and fungal blood cultures were sterile. Gram stain and acid-fast stain of purulent, induced sputum and gastric aspirate were negative. Bronchoalveolar lavage was performed, but cultures of the fluid remained negative. Serum antibody titers for respiratory viruses, Mycoplasma pneumoniae, Chlamydia pneumoniae, Legionella pneumophila and Coxiella burnetii were negative.

Empiric therapy was started with intravenous erythromycin, cefotaxime and vancomycin. Despite this on Day 4 of hospitalization respiratory status worsened. He became increasingly tachypneic and had blood oxygen desaturation, requiring mechanical ventilation. A repeated chest radiograph showed worsening pulmonary infiltrates and a right lower lobe cavity with pleural effusion. Surgical treatment with marsupialization of the cavity and chest tube insertion was performed. Examination of pulmonary biopsies revealed branching septate hyphae invading alveolar spaces, pulmonary parenchyma and blood vessels, associated with hemorrhagic infarction and necrosis. Cultures from pleural fluid and lung tissue yielded Aspergillus fumigatus.

Antifungal treatment with liposomal amphotericin B (AmBisome) 5 mgkg/day was initiated. The patient’s condition slowly improved. He was extubated 3 days after the operation, and the pleural drainage tube was removed on Day 10 of hospitalization. However, when sedation was suspended he complained of a severe frontal headache and diplopia. On examination he was afebrile, alert and well-oriented, with decreased tone and brisk reflexes in his left extremities and bilateral papilledema on eye examination. Cerebral computed tomographic (CT) scan and magnetic resonance imaging showed a cortical-subcortical lesion in the right frontal lobe with contrast enhancement and perilesional edema (Fig. 1).

Fig. 1
Fig. 1:
T2-weighted magnetic resonance imaging showing a right frontal lobe abscess surrounded by marked edema.

In our neurosurgery unit he underwent right frontal craniotomy and excision of a hard and irregular mass attached to the dura mater. Almost all of the mass could be removed. Pathologic examination showed granulomata, inflammatory giant cells and necrosis. Acutely branching septate hyphae consistent with the appearance of Aspergillus species were found in a few granulomata, but culture of the specimen was negative.

The postoperative course was uncomplicated, but the chest tube wound continually drained purulent fluid and air, indicative of a bronchopleural-cutaneous fistula. Cultures of the fluid grew A. fumigatus. A repeat chest radiograph showed an intrapleural cavity containing a solid rounded mass. Thoracic CT scan confirmed the presence of a bronchopleural-cutaneous fistula and revealed a capsulated hydropneumothorax containing a globular mass (Fig. 2). A 15-day course of intravenous liposomal amphotericin B failed to sterilize the fluid or to cause a change in the size of the mass on the CT scan, so we decided to attempt antifungal intrapleural treatment.

Fig. 2
Fig. 2:
Thoracic CT scan showing right capsulated hydropneumothorax containing a globular mass.

A No. 6 French polyethylene pigtail catheter was inserted into the cavity through the fistula, under local anesthesia and with CT scan guidance. A. fumigatus was isolated from washings from the cavity. A 20-ml solution of 5% dextrose containing 5 mg of amphotericin B was infused during 5 min as an initial dose, which was gradually increased to 50 mg/day. The solution remained in the pleural cavity with the catheter clamped and the patient lying on the right side. After 30 minutes the catheter was unclamped, and the residual solution, mixed with purulent fluid and clots, was permitted to drain out. Suction was not applied to the catheter. Initially the instillation caused coughing and expulsion of the solution which was relieved by the injection of a smaller volume (10 ml). Within the second week the pleural fluid began to diminish in volume, and fungal cultures became negative. A total of 2 g was given during 45 days with no adverse drug reaction. After completion of therapy fluid cultures remained persistently negative, and the catheter was removed without complications. Follow-up thoracic CT scan revealed marked pleural thickening and closure of the fistula. Intravenous liposomal amphotericin B was discontinued after 3 months, and therapy was switched to itraconazole 200 mg orally twice daily to complete 6 months of treatment. A control cerebral CT scan showed only residual surgical findings. Two years later the patient was asymptomatic with normal lung function and no evidence of recurrent infection.


Pulmonary invasive aspergillosis most commonly presents as necrotizing bronchopneumonia characterized by vascular fungal invasion, vessel thrombosis and tissue necrosis. Extension of the infection to other organs occurs in up to 25% of patients. 7 Cerebral involvement is associated with a high mortality rate, and survival is invariably dependent on the return of immune function. 1 Fortunately our patient presented a reversible iatrogenic immunosuppression and could be successfully treated with surgery and liposomal amphotericin B. However, systemic antifungal treatment failed to control pleural aspergillosis.

Pleural aspergillosis is a rare condition with most cases resulting from secondary infection of chronic empyemas and bronchopleural fistulas complicating thoracic surgery or tuberculosis. 1–4 Less frequently pleural aspergillosis appears to arise from rupture of an aspergilloma cavity into the pleural space or from direct infection of the pleura in the course of invasive pulmonary aspergillosis. 5 Reported radiographic findings have included nonspecific pleural thickening, pleural empyema and intrapleural aspergillomas. 8 However, histologic examination of apparent aspergillomas after invasive aspergillosis have confirmed that most of these lesions are masses of necrotic lung debris infiltrated with fungus that differ from the classical aspergilloma occurring in patients with pre-existing lung disease. 9 In our patient pulmonary aspergillosis extended to infect pleural space, and surgical drainage was required, leaving a bronchopleural-cutaneous fistula and a capsulated hydropneumothorax containing an apparent pleural aspergilloma. Therapy in this condition usually requires systemic antifungal therapy, prolonged drainage of the pleural space and a secondary thoracoplasty. Surgical decortication or pleuropneumonectomy are appropriate if disease is extensive but are associated with high postoperative complication rates. 6 Our report showed the successful clearance of the infection and closure of the fistula by instillation of amphotericin B directly into the pleural cavity. Local administration of antifungal agents may be an alternative to surgery in Aspergillus pleural empyema and in localized aspergillomas. The mechanism of action is not certain, but sclerosis of the cavity appears more likely than antifungal activity. 10 However, only a few cases are reported in the literature, most of them involving patients with pulmonary aspergillomas, severe hemoptysis and inadequate pulmonary function for tolerating a surgical resection. 10, 11 Treatment of Aspergillus empyema with intrapleural instillation of antifungal agents has also been used in adult patients and has led to eradication of the fungus in 9 of 10 cases reported. 2–4 We believe that this is the first report describing intrapleural antifungal treatment in a child with Aspergillus empyema. Treatment was effective and well-tolerated, and the only complication was a mild cough at initial antifungal instillation. This is the most frequent complication reported in large series and can be prevented by using a small volume of solution or with neuroleptanalgesia. 11 Other rare complications include transient bronchospasm, pneumothorax, percutaneous emphysema and hemoptysis. 10, 11 We conclude that intrapleural administration of antifungal agents might represent a viable therapeutic alternative for immunocompromised children with pleural aspergillosis, especially when systemic antifungal therapy has failed.

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Invasive aspergillosis; empyema; intrapleural treatment; amphotericin B

© 2003 Lippincott Williams & Wilkins, Inc.