Pleural empyema caused by Aspergillus is a rare, potentially fatal invasive fungal infection,1 resulting generally from a complication of aspergilloma, chronic necrotizing pulmonary aspergillosis, or surgical resection of these diseases.2 Its incidence among cancer patients has increased in recent years, probably due to the increasingly complex immunosuppressive treatments and surgical procedures used.3 Due to its low prevalence, there is uncertainty surrounding the diagnosis and management of invasive fungal infection, and the situation is particularly problematic in patients with underlying malignancy.

We report a case of Aspergillus fumigatus pleural empyema in a patient with T-cell acute lymphoblastic leukemia, treated in our hospital. This was a 19-year-old man who had been diagnosed 7 months previously with intermediate-risk cortical phenotype T-cell acute lymphoblastic leukemia. He received induction, consolidation and reinduction therapies, according to standard protocols, and achieved complete remission. Complications associated with the various treatments included vitamin K deficiency, hypofibrinogenemia, pancytopenia (with hemolytic anemia requiring transfusions), hyperglycemia, and hypertransaminasemia.

Thirty days after reinduction therapy, he was admitted to the hematology department for loss of vision in the right eye, odynophagia, and fever. Vital signs showed temperature 37.5°C, blood pressure 110/60mmHg and heart rate 100bpm. Breathing at rest was normal, and notable findings on physical examination included pallor of the skin and mucosa, Cushingoid facies, bronchial breath sounds in the base of the left hemithorax, with crackles reaching the middle field, edema of the lower limbs, and exudative ulceration of the foreskin. Abdominal examination was normal and no peripheral lymphadenopathies were palpated.

The most relevant additional examinations included blood tests: hemoglobin 8.2g/dl, hematocrit 24.9%, leukocytes 1×103/μ1 (62% neutrophils, 35% lymphocytes), platelets 24×103/μl, total proteins 4.5g/dl, GOT 117IU/l, GPT 524IU/l, GGT 268IU/l, alkaline phosphatase 424IU/l, LDH 999IU/l, triglycerides 371mg/dl and cholesterol 320mg/dl. Bone marrow aspirate confirmed remission. A chest computed tomography was performed, showing a pulmonary consolidation in the left base with lucent foci suggesting cavitation, bilateral multiple pulmonary micronodules measuring less than 1cm associated with cavitation, and left pleural effusion. Abdominal ultrasonography revealed 2 hypoechogenic hepatic lesions with echogenic centers consistent with abscesses. Brain magnetic resonance imaging showed multiple cerebral and cerebellar focal lesions, with fine peripheral enhancement, central necrosis, and a perilesional halo of edema, consistent with abscesses. The ophthalmologic examination revealed severe right endophthalmitis, requiring vitrectomy. Cerebrospinal fluid and blood were positive for galactomanan antigen. After vitrectomy, the vitreous humor showed abundant septate hyphae; A. fumigatus was cultured. The pleural effusion was not loculated, and had a purulent appearance with pH 7.34, leukocytes 3.6×103/μl (69% segments, 31% lymphocytes), glucose 87mg/dl, total proteins 3.6g/dl, C-reactive protein 3.08mg/dl, procalcitonin 0.3ng/ml, LDH 894IU/l, adenosine deaminase 8U/l, interleukin-6 70393pg/ml. Fungal hyphae were observed and A. fumigatus was obtained on culture. A thyroid abscess was aspirated, and hyphae were observed. Enterococcus faecalis was isolated from culture of the foreskin, and trimethoprim–sulfamethoxazole sensitive Stenotrophomonas maltophilia from 2 sputum cultures, obtained 2 months after admission.

The clinical situation was interpreted as T-cell acute lymphoblastic leukemia with late post-chemotherapy bone marrow aplasia and disseminated aspergillosis (A. fumigatus) during the reinduction phase, with ophthalmic, cerebral, pulmonary, pleural (empyema), hepatic, and thyroid involvement with bacterial co-infections.

During admission, the patient received various courses of antifungals (amphotericin, voriconazole [up to 9mg/kg/12h depending on blood levels, as well as 8 intravitreal doses], AmBisome® and caspofungin), antibacterials (meropenem, vancomycin, linezolid, cotrimoxazole, levofloxacin, amikacin, and clindamycin), and dexamethasone, and a chest tube was placed (16F, 3 days then resolution). The patient progressed slowly, except for the pleural involvement, until voriconazole was administered at doses much higher than recommended in the package insert, and plasma levels within the therapeutic range were achieved. The patient was discharged after 3 months, having remained afebrile for the last month.

A diagnosis of fungal pleural empyema poses a clinical dilemma that is especially worrying in the setting of severely immunocompromised cancer patients. Our patient met the criteria for diagnosis of proven invasive fungal disease,4A. fumigatus on this occasion, and is one of the few cases in which pleural fluid has been infected by Aspergillus in an immunocompromised patient.5

A recent study reported a high percentage (16%; 111/708) of cultures positive for fungi in pleural fluid from cancer patients. This appears to be due to a higher incidence of invasive fungal infection in cancer patients, and improved detection of fungi by microbiological techniques. Aspergillus spp. were, in terms of percentages, the predominant microorganism in leukemia patients (the disease presented by our patient), suggesting that the type of cancer may be one of the risk factors for developing Aspergillus empyema.

Voriconazole is the recommended antifungal for the treatment of invasive aspergillosis in most patients.7 Although this drug achieves high concentrations in pleural fluid,8,9 pleural empyemas caused by Aspergillosis are usually treated with a combination of various antifungals5 due to the high mortality rate (34%–75%, depending on when it is evaluated).1,6 Intrapleural administration has been described in isolated cases,1,10 and more studies are required to support this strategy. Treatment for all empyemas requires chest drainage, and if the patient presents life-threatening hemoptysis, lung resection surgery should be considered.11

In summary, in an immunocompromised cancer patient with pleural empyema, cultures in the appropriate media should be performed to rule out fungal infection. Treatment must consist of chest drainage and the long-term administration of a combination of various antifungals, including voriconazole, since mortality in these infections is high.