Clinical characteristics and outcomes of pleural aspergillosis: a review of 13 cases

ABSTRACT

Aspergillus pleurisy is a rare complication of invasive pulmonary aspergillosis (IPA), which mostly occurs in the immunocompromised host. The clinical condition is critical, especially to those who develop bronchopleural fistula. This study aimed to assess the characteristics and the prognosis of aspergillus pleurisy. Clinical data from 13 patients diagnosed with aspergillus pleurisy in our hospital from January 2000 to December 2022 were retrospectively studied. Thirteen patients with Aspergillus pleurisy were included. There were 10 males and 3 females, with a median age of 65 (range: 18–79) years. Bronchopleural fistula was present in eight patients. A proven diagnosis of Aspergillus pleurisy was based on positive pleural fluid culture in seven cases and histopathological examination of pleural biopsies in six cases. Four patients refused further treatment and were discharged from the hospital against medical advice. Nine cases recovered and were discharged after multiple antifungal treatments (systemic and topical antifungal therapies, pleural drainage and irrigation, and surgical repair). During follow-up, one patient, who suffered underlying bronchiectasis, died of massive hemoptysis 2 years after discharge. The remaining eight cases are still under close follow-up, with a median follow-up of 5.4 (range: 1.3–18.9) years. The prognosis of aspergillus pleurisy complicated with bronchopleural fistula is poor. Thoracic surgery, especially lung resection, is a risk factor associated with the incidence of Aspergillus pleurisy. Systemic antifungal therapy and adequate pleural irrigation could improve the prognosis.

IMPORTANCE

Aspergillus pleurisy is a rare complication of invasive pulmonary aspergillosis (IPA), associated with a poor prognosis. The morbidity and mortality of this condition have not been thoroughly studied, and recent research on this topic is limited. The current study included 13 patients diagnosed with Aspergillus pleurisy, with the majority presenting concomitantly with a bronchopleural fistula. Among these patients, nine had a history of thoracic surgery, including lung transplantation and lobectomy. Four patients refused further treatment and were discharged against medical advice, while one patient succumbed to massive hemoptysis 2 years after discharge. This case series provides essential insights into Aspergillus pleurisy and evaluates the therapeutic strategy based on a limited cohort.

INTRODUCTION

Aspergillus pleurisy is a rare clinical condition secondary to invasive pulmonary aspergillus (IPA), which is a common opportunistic infection in individuals with impaired immune systems or underlying lung disease (1). IPA is associated with increased mortality (20%–69%) among critically ill patients, especially when it involves pleurisy (2–6). A previous study found that nearly 12% of patients with IPA develop fungal empyema thoracis, with a mortality rate reaching 73% (7). Aspergillus pleurisy can also result from surgery or a bronchopleural fistula and may persist long term (8).

The clinical manifestations and imaging findings of aspergillus pleurisy remain nonspecific, and the culture of pleural fluid for aspergillus is often negative, making the diagnosis challenging. The criteria from European Organization for Research and Treatment of Cancel/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) are used to defined invasive pulmonary aspergillosis (9). However, the occurrence of aspergillus pleurisy often goes unnoticed, and the diagnosis criteria remain unclear. Recent studies focused on this topic have been limited, mostly comprising case reports, and lack comprehensive epidemiological data (7, 8, 10, 11).

This study aimed to retrospectively evaluate prognosis of aspergillus pleurisy by analyzing the clinical characteristics of 13 patients.

MATERIALS AND METHODS

From January 2000 to February 2023, 13 patients (10 males) were diagnosed with aspergillus pleurisy at our hospital. This retrospective study was approved by the Ethics Committee Board of Guangdong Provincial People’s Hospital (GPPH), and informed written consent was waived due to the retrospective nature of the study.

The including criteria were as follows: (i) age older than 18 years and (ii) proven pleural Aspergillus infection. Patients were classified as having proven Aspergillus disease based on the revised diagnostic criteria proposed by the EORTC/MSG (9). The criteria for diagnosis of fungal empyema thoracis were as follows: (i) pleural histopathologic, pleural effusion cytopathologic, or direct microscopic examination of a specimen obtained by needle aspiration or biopsy in which hyphae or melanized yeast-like forms are seen accompanied by evidence of associated tissue damage (ii) and/or isolation of Aspergillus species on more than one occasion from pleural effusion. Excluding criteria were as follows: (i) age younger than 18 years, (ii) pregnancy, and 3) insufficient available information.

Clinical characteristics, including clinical manifestations, imaging features, etiological examination, pathological biopsy, and the treatment strategy, were extracted and retrospectively analyzed. The diagnosis of aspergillus pleurisy was confirmed by pleural effusion or pleural biopsy. The criteria used to diagnose IPA were based on clinical manifestation, radiology, and mycological criteria according to the EORTC/MSG criteria (9, 12). The overall survival rate was evaluated from the diagnosis of aspergillus pleurisy to the day of death from any cause.

Descriptive statistics were used to summarize clinical and demographic data. Continuous variables were presented as average and standard deviations, when normally distributed and as median and range otherwise. Categorical data were summarized as frequencies and percentages. Data were analyzed using SPSS version 21.0.1. Figures were designed using Prism version 9.0.

RESULTS

Clinical characteristics

Thirteen patients with Aspergillus pleurisy were included. The characteristics of all patients were summarized in Table 1. Two patients were excluded from the study due to insufficient clinical data (n = 2). Among the 13 cases, there were 10 males, with a median age of 65 (range: 18–79) years. Six of the cases had a history of smoking. The main clinical manifestations included fever (8/13), cough (13/13, dry cough or coughing up small amounts of yellow-white sputum), hemoptysis (9/13, bloody sputum or blood in sputum, in small amount), dyspnea (7/13), chest pain (4/13), and weight loss (3/13). The underlying diseases in the current study included uremia (n = 1), rheumatic heart disease (n = 1), rheumatoid arthritis (n = 1), lung cancer (n = 9), and bronchiectasis (n = 1). One case was diagnosed as severe community-acquired pneumonia before the admission to our center, with one of them experiencing neutropenia (<0.5 × 10⁹ neutrophils/L for >10 days) temporally related to the onset of invasive fungal disease. One patient received corticosteroids (0.2 mg/kg/day) and methotrexate (15 mg/week) for rheumatoid arthritis 28 days before the hospitalization and one patient underwent mitral valve replacement because of rheumatic heart disease. Two patients underwent lung transplantation due to interstitial lung disease. Ten cases had bronchopleural fistula, with seven patients undergoing lobectomy for lung cancer and one patient undergoing lobectomy for pulmonary bulla. In the current study, lung surgery, including lung resection and transplantation (69.2%, 9/13), is a risk factor related to the incidence of bronchopleural fistula. Two cases without surgical history were diagnosed with IPA with direct invasion to the pleural cavity, forming a fistula.

TABLE 1.

Clinical characteristics of the suspected aspergillus pleurisy patients^a

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6	Case 7	Case 8	Case 9	Case 10	Case 11	Case 12	Case 13
Sex	Male	Female	Male	Male	Male	Male	Female	Male	Female	Male	Male	Male	Male
Age (years)	68	18	70	79	54	74	58	65	51	66	49	71	65
Underlying disease	Lung resection for cancer	Lung resection for giant bulla, IPA	Lung resection for cancer	Lung resection for cancer	IPA, CAP	Uremia	Rheumatic heart disease, MVR	Lung resection for cancer	Lung resection for cancer, rheumatoid arthritis	Interstitial pneumonia, lung resection for cancer, left lung transplantation	Lung resection for cancer	Postchemotherapy and checkpoint inhibitors treatment for SCLC	Interstitial pneumonia, lung transplantation
Bronchopleural fistula	Y	Y	Y	Y	Y	N	N	Y	Y	Y	Y	N	Y
Median duration of postoperative fistula formation (days)	NA	7	60	90	NA	NA	NA	NA	40	6	30	/	50
Treatment/outcome	Surgery/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole/hospital discharge against doctor’s will	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge/death	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge against medical advice	Surgery/hospital discharge against doctor’s will	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge	Intravenous voriconazole, drainage, and instillation of AmB/hospital discharge against medical advice
CRP (mg/L)	230	80	200	139	15.2	NA	182	79.4	122.9	200	13	382	93
PCT (ng/mL)	0.33	0.29	0.89	0.52	NA	NA	67.16	0.05	0.69	0.52	＜0.05	5.85	17.07
BDG (pg/mL)	254.6	NA	50	NA	NA	NA	1028.2	139.6	230.1	70.3	NA	456.5	364.8
GM	NA	NA	NA	1.5	2.0	3	NA	NA	NA	NA	NA	1.5	0.5
Protein (pleural effusion, g/L)	33.2	NA	39.8	NA	33.4	38.3	32.5	NA	22.9	NA	23.6	36.2	NA
LDH (pleural effusion, U/L)	8921	NA	45388	NA	3070	13355	4140	NA	13911	NA	7707	21300	NA
Neutrophils (pleural effusion, *106/L)	3057	NA	8259	NA	15101	62400	1677	NA	286165	NA	27214	1100	NA
Aspergillus culture in sputum	N	N	Y	N	Y	N	N	N	N	Y	N	N	N
Aspergillus culture in BAL fluid	NA	Y	NA	NA	NA	NA	NA	NA	Y	Y	NA	NA	Y
Aspergillus culture in pleural fluid	NA	Y	N	NA	N	N	Y	Y	Y	Y	Y	Y	Y
Biopsy of pleura	Y	Y	Y	Y	Y	Y	NA	NA	NA	NA	NA	NA	NA
Fungus infections	Aspergillus fumigatus	Aspergillus fumigatus	Aspergillus terreus	Aspergillus fumigatus	Aspergillus fumigatus	Aspergillus terreus	Aspergillus terreus	Aspergillus fumigatus	Aspergillus terreus	Aspergillus fumigatus	Aspergillus fumigatus	Aspergillus fumigatus	Aspergillus fumigatus
Concomitant bacterial infections	Pseudomonas Aeruginosa	Stenotrophomonas Maltophilia	Stenotrophomonas Maltophilia	Pseudomonas Aeruginosa	Stenotrophomonas Maltophilia	Pseudomonas Aeruginosa	Pseudomonas Aeruginosa	/b	Streptococcus	Pseudomonas Aeruginosa	Stenotrophomonas Maltophilia; Enterococcus Faecium	Streptococcus	Enterococcus Faecium

^a IPA, invasive pulmonary aspergillus; AmB, amphotericin B; CAP, community-acquired pneumonia; SCLC, small cell lung cancer; ECMO, extracorporeal membrane oxygenation; MVR, mitral valve replacement; CRP, C-reactive protein; PCT, procalcitonin; BDG, (1,3)-β-D-glucan; GM, galactomannan; LDH, lactate dehydrogenase; BAL fluid, bronchoalveolar lavage fluid.

^b "/" means NA.

Laboratory tests and auxiliary examinations

The clinical data are shown in Table 1. C-Reactive protein and procalcitonin levels were elevated to varying degrees in most cases. Two of the 13 cases underwent blood or pleural effusion (1,3)-β-D-glucan (BDG) and GM test. Nine of the 13 cases underwent routine examination of pleural effusion, with results showing elevated white blood cell counts to varying degrees, predominantly polymorphonuclear cells in seven cases and predominantly lymphocytes in one case. The median protein concentration was 33.4 g/L (range: 22.9–39.8 g/L), and the median lactate dehydrogenase concentration was 13,355 U/L (range: 3,070–45,388 U/L), with a predominance of neutrophils [median count 8,259*10⁶ /L (range: 1,100–286,165*10⁶/L)]. Chest computed tomography (CT) examination showed pleural effusion (small to moderate amount, n = 10), encapsulated empyema (n = 3), pneumothorax (n = 5), and varying degrees of pleural thickening (n = 13). The EORTC-defined radiological criteria, including halo sign or air-crescent sign, were found in three patients. Five of the 13 cases had pneumothorax (Fig. 1).

Fig 1.

Computed tomography of the chest for abnormalities in aspergillus pleurisy. (A) Postoperative pneumothorax: air-fluid level in the left side (case 1). (B) Left-sided air-fluid level after pulmonary lobectomy, concomitant with a left lower-lobe pneumonia (case 8). (C) Right-sided interstitial pneumonia and left-sided pneumothorax (case 13). (D) Encapsulated empyema, pneumatosis, and pleural thickening in the right side.

In 13 patients with Aspergillus pleurisy in the current study, one case was proven by diagnosis with both positive culture of pleural effusion and pleural biopsy, six patients were diagnosed by pleural biopsy (two of them also isolation of Aspergillus species from sputum), and seven cases were identified by isolation of the same Aspergillus species in pleural effusion (three of them also isolation of the same Aspergillus species from BALF). The fungi identified included Aspergillus terreus (n = 4) and Aspergillus fumigatus (n = 9), (see Fig. 2A). Concomitant lung bacterial infections included Stenotrophomonas Maltophilia (n = 4), Pseudomonas Aeruginosa (n = 5), Enterococcus Faecium (n = 2), and Streptococcus (n = 2). Aspergillus pleurisy was diagnosed at a median of 10 days (range: 6–20 days) after admission to the hospital. Bronchopleural fistula was present in 10 patients, confirmed by chest CT and/or bronchoscope (see Fig. 2B and C). The median duration between surgery and postoperative fistula formation was 40 days (range: 6–90 days).

Fig 2.

(A) Histopathological findings of the parietal pleura on Periodic Acid-Schiff staining. Septate hyphae with acute-angle branching are typical findings of Aspergillus spp. Magnification, ×200. (B–C) Fiberoptic bronchoscopy showed a large opening of the right middle lobar bronchus indicating a bronchopleural fistula.

Treatment and follow-up

All patients were initially treated with empirical antibiotics to cover common pathogens, with subsequent adjustments based on drug susceptibility results. Antifungal therapeutic strategies included systemic and topical antifungal drug therapies, closed thoracic drainage, and surgical repair. Antifungal drugs were categorized into two main types: systemic and topical. Systemic antifungal therapy in our center involved intravenous voriconazole (dosage: 6 mg/kg, every 12 hours, changed to 4 mg/kg, every 12 hours after 24 hours). Oral voriconazole (sequential treatment: 200 mg, every 12 hours) was recommended after 1–3 weeks of intravenous treatment, depending on the clinical condition. Topical antifungal drugs were applied directly to the mucous membranes (pleura) and targeted to the limited infections. After the diagnosis of Aspergillus pleurisy, topical antifungal lavage was recommended in our center. Amphotericin B pleural lavage treatment (amphotericin B 25 mg + 5% glucose 500 mL, intrapleural lavage daily) was applied to 10 cases who received closed chest drainage. Additionally, two patients underwent surgical repair for the bronchopleural fistula, including elective left upper lobe bronchus stump repair + latissimus dorsi muscle flap transfer surgery. These two patients showed clinical improvement after surgery and were discharged from the hospital with close follow-up.

Three patients developed organ dysfunction, including renal and respiratory dysfunction. Two patients had chronic kidney dysfunction and required renal replacement therapy. Case 10 required extracorporeal membrane oxygenation after the lung transplantation and was successfully weaned off after 3 days. Four patients refused further treatment and were discharged from the hospital against medical advice. Nine cases were cured and discharged after systemic antifungal therapy and pleural irrigation. During follow-up, one patient who suffered underlying bronchiectasis died of massive hemoptysis 2 years after discharge. The remaining eight cases are still under follow-up, with a median follow-up time of 5.4 years (range: 1.3–18.9 years).

DISCUSSION

Fungal pleurisy is a rare invasive fungal infection with a high mortality rate (10). However, the incidence of deep fungal infections has increased significantly in recent years (13). Aspergillus spp. are the second most common pathogens causing fungal pleurisy, following Candida spp. (14). Previous studies have reported cases of pleural effusion associated with aspergillus infection, but large-scale clinical studies have been rare (7, 10, 15). Patients with Aspergillus pleurisy have poor prognosis, especially those concomitants with bronchopleural fistula. The current study summarized 13 cases of Aspergillus pleurisy and evaluated the therapeutic strategy from the limited cohort.

The occurrence and development of Aspergillus pleurisy are related to the immune status of the host, the route of infection, and the amount of aspergillus (16). Aspergillus infection can occur at any age, typically in an immunocompromised host (5). Consistent with previous studies, the incidence was significantly higher in males than in females (5, 17). Most cases in our study suffered from immunodeficiency status, such as a history of chemotherapy for lung cancer and solid organ transplantation, which are considered a host factor for invasive pulmonary aspergillosis. Additionally, they had other underlying diseases, including uremia, rheumatic heart disease, and severe community-acquired pneumonia.

The main routes of aspergillus pleurisy are direct invasion from the lung, adjacent bronchi, and chest wall (such as cases 2, 5, and 7) or invasion of the pleural cavity from the surgical wound or trauma (such as cases 1, 3 ~ 4, and 8 ~ 13). Additionally, aspergillosis bloodstream infection can spread to the pleural cavity through hematogenous dissemination, causing pleural infection (18). The routes of infection for case 6 are unclear and may be associated with disseminated aspergillus colonization in the lung during hemodialysis or cardiac valve surgery. Few reports suggested that a bronchopleural fistula is a unique risk factor for Aspergillus pleurisy (17). Lung resection and transplantation were associated with the development of bronchopleural fistula. Among the 13 cases, 10 cases had bronchopleural fistula, with 8 cases occurring after lobectomy and 2 cases after lung transplantation. These patients had long-term bronchopleural fistula, which may represent another important route of aspergillus pleurisy. The possible mechanism is that long-term bronchopleural fistula following lobectomy disrupts the normal body defense barrier. Aspergillus spores are very small (diameter approximately 2.5 ~ 3.5 µm) and can be easily inhaled into the alveoli (16). In addition, long-term use of broad-spectrum antibacterial drugs in some patients increased the chances of fungal infection (6).

The clinical manifestations of aspergillus pleurisy are nonspecific, making diagnosis challenging (19). Diagnostic imaging, such as EORTC-defined radiological criteria, lacks specificity, and positive signs often occur late in the course of disease. Chest radiograph may demonstrate large bilateral pleural effusion, which can mask true imaging features such as halo sign or air-crescent sign. Tissue biopsy, blood and respiratory samples, and pleural fluid culture are the main methods for diagnosing aspergillus empyema. For patients with probable pulmonary aspergillosis and pleural effusion, repeated pleural fluid cultures are necessary to increase the culture’s positive rate for Aspergillus. In all forms of IPA, culture yield can be increased by culturing multiple samples (13). For patients with a bronchopleural fistula, thoracoscopy and pathological biopsy should be performed as soon as possible. The GM test has relatively high sensitivity and specificity for aspergillus infection, making it important for early diagnosis (19, 20). PCR detection is also crucial for the confirmed diagnosis of aspergillus empyema (21, 22). In our study, 11 cases were diagnosed based on pleural effusion etiological examination or thoracoscopic pathological biopsy.

This study is subjected to limitations of its retrospective nature and the small sample size. This was a single-center study, and the results may be biased. Radiologic features other than cavities and nodes were not collected.

Conclusions

Aspergillus pleurisy is rare, especially when concomitant with bronchopleural fistula in immunocompetent patients, but it has a poor prognosis. Multiple antifungal therapies, including systemic and topical antifungal therapies, could improve prognosis. Further studies are warranted to investigate the relationship between different therapeutic strategies and the outcome.

ETHICS APPROVAL

This retrospective study was approved by the Ethics Committee Board of Guangdong Provincial People’s Hospital (GPPH) [No. GDREC2019177H(R1), 20191030].