Treatment of Post-COVID-19 Pulmonary Aspergilloma: Insights from a Clinical Case

Introduction

Aspergillosis is an opportunistic fungal infection caused by Aspergillus species primarily affecting the respiratory system. In recent years, with the rise of the COVID-19 pandemic, there has been increasing recognition of secondary infections, including mycobacterial and fungal co-infections, especially in critically ill patients. Pulmonary aspergillosis has been recognized as a potential sequela of severe SARS-CoV-2 infection [1]. Pulmonary disease caused by Aspergillus fumigatus encompasses a spectrum of clinical syndromes, including allergic bronchopulmonary aspergillosis, invasive pulmonary aspergillosis, chronic cavitary pulmonary aspergillosis, and aspergilloma. The primary symptoms of aspergilloma in immunocompromised patients, particularly those with COVID-19-associated aspergilloma, include hemoptysis, shortness of breath, productive cough, weight loss, and fatigue. Major risk factors include neutropenia, solid organ transplantation, prolonged high-dose corticosteroid therapy, hematological malignancies, cytotoxic therapy, acquired immunodeficiency syndrome, and chronic granulomatous disease. Pulmonary aspergillosis has been associated with increased 30-day mortality in patients with severe COVID-19 who were admitted to the intensive care unit and subsequently intubated [2]. Aspergilloma formation is common, and antifungal medications, with a preference for azoles as the first-line therapy, are the mainstay of treatment for up to 1 year. Minimally invasive techniques for treating aspergilloma have rarely been used [3]. We describe the case of a 49-year-old man at Houston Methodist Hospital who developed pulmonary aspergilloma 6 months after a SARS-CoV-2 infection and was treated with a robotic-assisted lobectomy.

Case Report

A 49-year-old man with no significant occupational exposure, who worked in an office and had a medical history of hypertension, hyperlipidemia, nonsmoking status, mild obstructive sleep apnea, normal glycated hemoglobin, COVID-19 pneumonia, right lung pneumothorax, and pneumomediastinum, required veno-venous extracorporeal membrane oxygenation (VV ECMO), tracheostomy, and a prolonged 3-month hospitalization during the COVID-19 pandemic. Initial laboratory data at the time of COVID-19 diagnosis showed a white cell count of 7.6 k/UL, hemoglobin level of 10.1 g/dL, and a platelet count of 306 k/UL. Serum creatinine, serum sodium, and liver enzyme levels were within the reference range. Nasal swab was positive for quantitative real-time polymerase chain reaction (RT-PCR). Severe COVID-19 pneumonia and acute respiratory distress syndrome were diagnosed, and he required mechanical ventilation. A computed tomography (CT) scan showed extensive bilateral ground glass opacities and multifocal consolidations predominantly in a peripheral distribution (Figure 1). During his hospital stay, he was treated with dexamethasone, tocilizumab, and remdesivir. After completing rehabilitation, his tracheostomy was decannulated.

Six months later, he presented to a pulmonary clinic with mild hemoptysis, cough, and shortness of breath. His physical examination was unremarkable except for bilateral scattered crackles, and his oxygen saturation was 94%. A CT scan showed a right upper lobe (RUL) cavitary lesion measuring approximately 9.6×6.1 cm, along with bilateral ground-glass opacities (Figure 2). Outpatient bronchoscopy showed no active bleeding, but bronchoalveolar lavage revealed A. fumigatus. He was treated with voriconazole for 1 year for suspected invasive pulmonary aspergillosis, which resolved the hemoptysis and reduced the size of the cavity to 5.6 cm.

However, hemoptysis recurred within weeks after discontinuing voriconazole. A repeat bronchoscopy revealed old blood in the RUL without active bleeding, and the bronchoalveolar lavage fluid again tested positive for A. fumigatus. His antifungal therapy was switched to isavuconazonium sulfate. The case was discussed in a multidisciplinary team consisting of a radiologist, pulmonologist, infectious disease specialist, and thoracic surgeon.

Due to the patient’s complicated history of prior SARS-CoV-2 infection, pneumothorax, pneumomediastinum, and VV ECMO support, he was at high surgical risk, due to significant adhesions. Nonetheless, the decision was made to proceed with a RUL lobectomy, due to persistent hemoptysis, cough, and shortness of breath. A pulmonary function test showed moderate restrictive lung disease. Forced expired volume during the first second (FEV1) was 2.59 L (68), forced vital capacity (FVC) was 2.95 L (61.3%), total lung capacity (TLC) was 3.93 L (58%), and diffusing capacity of the lungs for carbon monoxide (DLCO) was 16.62 mL/min/mm Hg (52%).

The patient underwent a robotic-assisted RUL lobectomy and lysis of adhesions, with an uneventful intraoperative course. He was discharged on postoperative day 3, with complete resolution of hemoptysis at the 6-week follow-up. Pathology analysis confirmed the presence of an aspergilloma in gross sections (Figure 3), and histopathology analysis using hematoxylin and eosin staining confirmed aspergilloma (Figure 4A, 4B). Histopathology also showed septated, acute, and branching hyphae (Figure 4C). The wall of cavitation was also well demarcated (Figure 4D). Pathology results were negative for malignancy and mycobacterial species.

Six weeks after surgery, a pulmonary function test showed significant improvement in lung function, with better ventilation in the healthy lung and decreased restriction following adhesion lysis. Additionally, the degree of ventilation-perfusion mismatch improved after the removal of the large cavitary lesion. The 6-week postoperative pulmonary function test data showed an FEV1 of 2.88 L, FVC of 3.26 L, TLC of 4.04 L and DLCO of 20.11 mL/min/mm Hg. Isavuconazonium sulfate was continued for 1 month postoperatively due to the risk of fungal spillage and then discontinued.

Discussion

COVID-19-associated pulmonary aspergillosis has been increasingly documented in critically ill patients, particularly those requiring mechanical ventilation. The incidence varies widely across studies, with reported rates ranging from 1.9% to 33% among intensive care unit patients [4–8] Hemoptysis is frequently associated with aspergilloma, with life-threatening hemoptysis being the most severe complication of pulmonary aspergilloma. COVID-19-associated pulmonary aspergillosis is a recognized condition, and there are now several diagnostic and management guidelines [10]. Treatment options include antifungals, bronchial artery embolization, and surgery. Patients with pulmonary aspergillosis who undergo surgery have lower inpatient mortality rates than do patients treated with medical therapies. Additionally, mortality is lower in patients who undergo video-assisted thoracoscopic surgery than in those who undergo open surgery. The efficacy and safety of robotic lung surgeries, including lobectomy, segmentectomy, and wedge resection, have been well demonstrated [9]. However, robotic-assisted lobectomy for pulmonary aspergilloma in patients with severe post-COVID-19 complications has rarely been reported [11]. Furthermore, aspergilloma, a delayed sequela of COVID-19, is uncommon. In one reported case, a fungal ball that developed within 1 weeks of a COVID-19 infection was resistant to medical treatment, leading to the patient undergoing a thoracotomy with left upper lobectomy [12]. In another case, a fungal ball developed shortly after a SARS-CoV-2 infection and was successfully treated with antifungal medication [12]. Banke et al reported that patients with aspergilloma following COVID-19 were treated with antifungal medications and did not require surgical intervention. The patient responded to the medical treatment with resolution of hemoptysis and clearance of cultures at 10 months after discharge [13]. Surgical intervention is indicated for patients with localized disease that is accessible to resection, particularly in cases of recurrent hemoptysis or when medical therapy fails. Surgical options include lobectomy or video-assisted thoracoscopic surgery, depending on the patient’s condition and the extent of the disease. Surgery is generally reserved for patients who can tolerate the procedure and have adequate respiratory reserve. It is unclear why some patients fail medical treatment alone. Potential reasons could include an immunocompromised state, obesity, the size of the aspergilloma, and interruptions in medical treatment. In the case described by Blanke et al, the antifungal treatment was transitioned to itraconazole; however, we used voriconazole and isavuconazonium sulfate. Itraconazole can have some implications for treatment success, but the exact reason remains unknown. Our case is unique and novel because the patient developed aspergilloma as a delayed sequela of SARS-CoV-2 infection. He was at increased surgical risk due to adhesions, previous pneumothorax, pneumomediastinum, VV ECMO, and a history of tracheostomy, yet he was successfully treated with minimally invasive robotic RUL lobectomy.

Conclusions

In conclusion, clinicians should consider Aspergillus infection in COVID-19 survivors presenting with pulmonary symptoms. Additionally, minimally invasive robotic lobectomy is a feasible option for high-risk patients with post-COVID-19 aspergilloma and hemoptysis who do not respond to medical treatment.