[Expert consensus on the diagnosis and treatment of pulmonary aspergillosis in patients with chronic obstructive pulmonary disease].

The prevalence of pulmonary aspergillosis is increasing in patients with chronic obstructive pulmonary disease (COPD) and can manifest in different forms such as invasive pulmonary aspergillosis (IPA), chronic pulmonary aspergillosis (CPA) and allergic bronchopulmonary aspergillosis (ABPA). With the variations of individual conditions such as immune status, these forms of the disease may transform into each other or even overlap. Moreover, the atypical clinical manifestations and the limited use of invasive sampling techniques have posed a challenge to the diagnosis and treatment of invasive pulmonary aspergillosis in patients with COPD. To provide recommendations for the management of pulmonary aspergillosis in patients with COPD and to construct a clinical workflow, the consensus panel reviewed the evidence and critically appraised the existing studies. As the majority of the recommendations were supported by low levels of evidence, the evidence levels were not listed in the consensus and the strong and weak recommendations were expressed as "recommend" and "suggest", respectively.Recommendations for COPD with IPA: The Panel recommends that high-resolution chest computed tomography (HRCT) be performed in patients suspected with IPA. If IPA cannot be excluded by CT scanning, mycological examination of sputum and bronchoalveolar lavage fluid (BALF) is recommended. Bronchoscopy and BALF Aspergillus-related examination are recommended in COPD patients with respiratory symptoms such as dyspnea despite the use of broad-spectrum antibiotics and systemic glucocorticoids and pulmonary infiltrates observed on chest CT. If the diagnosis is in doubt in patients with probable IPA, histopathological examination is recommended. In COPD patients with an acute infection of more than 10 days' duration, the Panel recommended the detection of Aspergillus-specific IgG antibodies in peripheral blood to aid in the diagnosis of IPA, especially in those who cannot obtain BALF. It is not recommended to initiate antifungal therapy based on clinical symptoms such as cough, fever, and dyspnea empirically in COPD patients. In critically ill patients (such as those admitted to ICU and those with respiratory failure) who are unresponsive to broad-spectrum antibiotic treatment and have imaging findings consistent with IPA, patients with HRCT or bronchoscopy findings consistent with airway invasive aspergillosis, patients with a history of oral or intravenous glucocorticoid use in the past 3 months, or patients with a history of airway Aspergillus infection or colonization, empirical antifungal therapy may be initiated after a comprehensive evaluation of Aspergillus infection risk, and at the same time, pathogen examination should be started as early as possible. Voriconazole, isavuconazole, and posaconazole are recommended as the first-line treatments for COPD with IPA. Echinocandins and amphotericin B may be used as alternative options. Antifungal treatment for COPD with IPA should be continued for at least 6-12 weeks. The duration of antifungal therapy should be determined based on clinical symptoms, pulmonary imaging, and microbiological test results. Significant lesion absorption and stabilization, as well as the elimination of related risk factors, are important references for discontinuation of treatment.Recommendations on COPD with CPA: Chest CT scan and dynamic observation are recommended for COPD with suspected CPA. Peripheral blood Aspergillus-specific IgG antibody testing is recommended in COPD patients with suspected CPA. For those who are difficult to diagnose by routine methods or need further differential diagnosis, pulmonary tissue histopathological examination is recommended. Oral itraconazole solution or voriconazole tablets are recommended as the first-line treatment options for COPD with CPA. Oral isavuconazole capsules or enteric-coated posaconazole tablets can be used as an alternative. Intravenous administration of echinocandins or amphotericin B (deoxycholate or lipid formulations) are suggested as a second-line treatment options in cases of triazole treatment failure, resistance, or intolerance. Antifungal treatment for COPD with CPA should be continued for at least 6 months, and for patients with CCPA for at least 9 months. In those with cavities communicating with the bronchial lumen, if systemic antifungal therapy is ineffective or cannot be tolerated due to adverse reactions, and surgery is also not feasible, the Panel suggests considering nebulized inhalation of amphotericin B and intracavitary injection of amphotericin B or azoles (voriconazole, itraconazole) to control recurrent hemoptysis.Recommendations on COPD with Aspergillus sensitization: When COPD patients present with refractory wheezing and/or rapid decline in lung function, it is recommended that an assessment for Aspergillus sensitization be performed, including Aspergillus-specific IgE, skin Aspergillus antigen test, Aspergillus-specific IgG, total IgE, blood eosinophil count, and sputum examination. The Panel recommends that antifungal therapy should not be routinely initiated in COPD patients with Aspergillus sensitization. For those who meet the diagnostic criteria for ABPA, antifungal therapy is suggested. The most commonly used medication is oral itraconazole solution, but other azoles such as voriconazole, isavuconazole and posaconazole enteric-coated tablets can also be chosen. The general course of antifungal therapy is 3-6 months.Recommendations on the use of glucocorticoids in COPD with pulmonary aspergillosis: In exacerbating COPD patients with secondary IPA or subacute invasive aspergillosis, the Panel suggests that the use of glucocorticoids should be controlled. For COPD patients with concomitant CPA who experience exacerbations with predominantly wheezing, it is suggested that short-term, low-dose glucocorticoids be considered on the basis of antifungal treatment to control symptoms. Glucocorticoid use for COPD exacerbations is suggested to be guided by peripheral blood eosinophil count. It is recommended to avoid systemic glucocorticoids and long-term or high-dose inhaled glucocorticoids (ICS) in stable COPD patients with concomitant CPA. In patients with concomitant Aspergillus sensitization and persistent wheezing despite standardized COPD treatment or patients with ABPA, the Panel recommends systemic glucocorticoids in combination with antifungal therapy and consideration of the use of ICS to reduce the dose of systemic glucocorticoids. Close monitoring for progression to IPA or subacute invasive aspergillosis is essential during treatment.

A 65-Year-Old Man with Refractory Hemoptysis Associated with Chronic Progressive Pulmonary Aspergillosis Who Failed to Respond to Combined Endobronchial Occlusion and Bronchial Artery Embolization: A Case Report and Literature Review.

BACKGROUND Hemoptysis due to airway hemorrhage is treated with hemostatic agents, bronchial artery embolization (BAE), or surgical resection. We present the case of a 65-year-old man with refractory hemoptysis associated with chronic progressive pulmonary aspergillosis (CPPA) who failed to respond to combined endobronchial occlusion (EBO) with endobronchial Watanabe spigot (EWS) and BAE. CASE REPORT A 63-year-old man was diagnosed with CPPA in the right upper lung and presented to our hospital 2 years later for hemoptysis at age 65. He developed severe hemoptysis during an outpatient visit, and was urgently admitted, intubated, and ventilated to prevent choking on blood clots. Chest computed tomography showed a large mass in the apical portion of the right lung, constituting apical pleural thickening and an encapsulated pleural effusion, and dilatation in the bronchial artery supplying the right upper lung lobe. Bronchoscopy revealed the right upper lobe B1-B3 as the bleeding source. The patient had recurrent hemoptysis that was not controlled by BAE or 6 EBO+EWS procedures, and he ultimately died of hypoxemia.In the literature review, EBO+EWS can effectively control hemoptysis in appropriate cases, without the need for BAE or surgical lung resection. It is less invasive, is associated with fewer adverse events than BAE or surgery, and can achieve temporary hemostasis for severe hemoptysis. CONCLUSIONS BAE and EBO+EWS were ineffective in controlling recurrent hemoptysis caused by CPPA in this case. However, a multidisciplinary approach such as attempting hemostasis with combined EBO+EWS and BAE may be a viable treatment option in severe cases of hemoptysis.

Chronic pulmonary aspergillosis - a guide for the general physician.

This collaborative article presents a review of chronic pulmonary aspergillosis (CPA) from the perspective of a multidisciplinary team comprising of respiratory physicians, radiologists, mycologists, dietitians, pharmacists, physiotherapists and palliative care specialists. The review synthesises current knowledge on CPA, emphasising the intricate interplay between clinical, radiological, and microbiological aspects. We highlight the importance of assessing each patient as multidisciplinary team to ensure personalised treatment strategies and a holistic approach to patient care.

Chronic Pulmonary Aspergillosis as a Considerable Complication in Post-Tuberculosis Lung Disease.

Post-tuberculosis lung disease (PTLD) has only recently been put in the spotlight as a medical entity. Recent data suggest that up to 50% of tuberculosis (TB) patients are left with PTLD-related impairment after completion of TB treatment. The presence of residual cavities in the lung is the largest risk factor for the development of chronic pulmonary aspergillosis (CPA) globally. Diagnosis of CPA is based on four criteria including a typical radiological pattern, evidence of Aspergillus species, exclusion of alternative diagnosis, and a chronic course of disease. In this manuscript, we provide a narrative review on CPA as a serious complication for patients with PTLD.

[Non-surgical local treatment for pulmonary aspergilloma].

Pulmonary aspergilloma (PA) is usually secondary to pulmonary cavities. The main purpose of PA treatment is to prevent life-threatening hemoptysis. Many patients cannot tolerate surgical resection, which is considered the preferred treatment. Oral or intravenous antifungal therapy is less effective because PA usually does not invade the blood vessels of the pulmonary cavity. In this case, arterial embolization, local injection with drugs, and radiation therapy can be considered. This article will summarized various non-surgical local treatments for PA (hemoptysis) to refer clinical decision-making.

SARS-CoV-2 Associated Immune Dysregulation and COVID-Associated Pulmonary Aspergilliosis (CAPA): A Cautionary Tale.

As the global SARS-CoV-2 pandemic continues to plague healthcare systems, it has become clear that opportunistic pathogens cause a considerable proportion of SARS-CoV-2-associated mortality and morbidity cases. Of these, Covid-Associated Pulmonary Aspergilliosis (CAPA) is a major concern with evidence that it occurs in the absence of traditional risk factors such as neutropenia and is diagnostically challenging for the attending physician. In this review, we focus on the immunopathology of SARS-CoV-2 and how this potentiates CAPA through dysregulation of local and systemic immunity as well as the unintended consequences of approved COVID treatments including corticosteroids and IL-6 inhibitors. Finally, we will consider how knowledge of the above may aid in the diagnosis of CAPA using current diagnostics and what treatment should be instituted in probable and confirmed cases.

Clinical manifestations, associated risk factors and treatment outcomes of Chronic Pulmonary Aspergillosis (CPA): Experiences from a tertiary care hospital in Lahore, Pakistan.

BACKGROUND: Chronic pulmonary aspergillosis (CPA) has a wide spectrum of illnesses depending on the progression of the disease and comorbid conditions. However, there is an inadequacy of investigations regarding clinical, laboratory, risk factor and prognostic data on CPA. The current study is aimed to consider the clinical manifestations, risk factors and outcomes of CPA. METHODOLOGY: Retrospective records of all patients with a confirmed diagnosis of CPA who sought treatment at Gulab Devi Chest Hospital Lahore, Pakistan from January 2017 to December 2019 were evaluated. Data regarding demographics, clinical manifestations, comorbidities, radiographic and microbiological findings, length of hospital stay (LOS) and intensive care unit (ICU) admission was collected and analyzed to identify the factors associated with mortality. The independent factors associated with mortality were also identified by appropriate analyses. RESULTS: A total of 218 CPA patients were included in this study. The mean age was 45.75 ± 6.26 years. Of these, 160 (73.4%) were male, and 65 (29.8%) had diabetes. The mean LOS was 18.5 ± 10.9 days. The most common type of CPA was simple aspergilloma (56%) followed by chronic cavitary pulmonary aspergillosis (CCPA) (31.2%). About one half of the patients had a history of pulmonary tuberculosis (TB) and treatment response rates were low in patients with active TB. The overall mortality rate was 27.1%. ICU admission was required for 78 (35.8%) patients. Diabetes mellitus (DM), hematological malignancies and chronic kidney disease (CKD) were the common underlying conditions predicting a poor outcome. Mean LOS, hematological malignancies, consolidation and ICU admission were identified as the independent factors leading to mortality. CONCLUSIONS: CPA had a significant association with TB in the majority of cases. Treatment response rates in cases with active TB were comparatively low. Cases with high mean LOS, hematological malignancies, consolidation, ICU admission, CKD and DM experienced poor outcomes. High mean LOS, hematological malignancies, consolidation and ICU stay were identified as independent risk factors for mortality. Future large prospective studies, involving aspergillus specific immunoglobulin G (IgG) antibody testing, are required for a better understanding of CPA in Pakistan.

The therapeutic dilemma in pre-transplant asymptomatic aspergilloma: A case report and review of literature.

Aspergillus species are ubiquitous, and inhalation of infectious conidia is not so uncommon. With immunosuppression, it can invade adjacent structures and lead to widespread invasive disease. There is no randomized, prospective trial for optimized treatment including the antifungal and surgical approach for aspergilloma. The available literature related to the management of asymptomatic aspergilloma in pre-renal transplant setting is scarce and debatable. Opinion favoring surgery is that it is necessary to eliminate the fungus reservoir before transplantation because of the inadequacy of pharmacological fungus control measures in immunocompromised patients. We present a case of end-stage renal disease that was planned for renal transplantation and during the workup, was detected to have asymptomatic right upper lobe aspergilloma. He underwent surgical resection of the aspergilloma before undergoing successful renal transplantation. In this case report, we will discuss this case and controversies related to its management before undergoing successful renal transplantation.

Pulmonary Aspergillosis: What the Generalist Needs to Know.

Aspergillus spp. is a ubiquitous mold found commonly in our environment that can cause a spectrum of pulmonary disorders, ranging from a hypersensitivity reaction to an acutely invasive disease with significant mortality. Allergic bronchopulmonary aspergillosis results from airway hypersensitivity from aspergillus colonization almost exclusively in patients with asthma and cystic fibrosis. Chronic pulmonary aspergillosis typically presents in immunocompetent patients with underlying lung pathology. Treatment is primarily with antifungal agents; however, other measures such as surgical resection may be necessary. Invasive pulmonary aspergillosis is a severe infection in immunocompromised patients and is characterized by invasion of pulmonary vasculature by the Aspergillus hyphae. Recent advances in the diagnosis and management of invasive pulmonary aspergillosis include emerging risk factors such as critically ill patients, and those with chronic obstructive pulmonary disease and liver disease. In addition, noninvasive biomarkers have made it easier to suspect and diagnose invasive pulmonary aspergillosis. There are more effective and better-tolerated antifungal agents that have improved patient outcomes. This review introduces the spectrum of pulmonary aspergillosis geared toward generalists, including disease manifestations, most recent diagnostic criteria, and first-line treatment options. Involving a multidisciplinary team is vital to the early diagnosis and management of these diseases.

Non-surgical treatment options for pulmonary aspergilloma.

Aspergilloma, also known as mycetoma or fungus ball, is the most common manifestation of pulmonary involvement by Aspergillus species. The fungal ball typically forms within preexisting cavities of the lungs. Diagnosis requires both radiographic evidence along with serologic or microbiologic evidence of Aspergillus species involvement. While clinical features such as hemoptysis, chest pain, shortness of breath, cough, and fever are helpful in diagnosis, they are non-specific symptoms. Surgery is currently the mainstay of treatment for aspergilloma but is associated with considerable mortality and morbidity. Alternative options exist for patients who are poor surgical candidates and for those who prefer a less invasive treatment modality. Systemic treatment with amphotericin B is ineffective and is not recommended as a monotherapy, but systemic azoles is effective in approximately 50-80% of patients. Potential alternatives to surgery include intracavitary instillation or endobronchial administration of antifungal medication, as well as direct transbronchial aspergilloma removal. Bronchial artery embolization and radiotherapy are options to manage hemoptysis until definite eradication of the aspergilloma. More rigorous studies are needed to better establish non-surgical treatment paradigm for inoperable patients.

Pulmonary aspergillosis as a late complication after surgery for locally advanced non-small cell lung cancer treated with induction chemoradiotherapy.

PURPOSE: Some long-term survivors after surgery for locally advanced non-small cell lung cancer (NSCLC) treated with induction chemoradiotherapy (trimodality treatment) develop chronic pulmonary aspergillosis (CPA). The aim of our study was to assess the characteristics and outcomes of CPA that develops after trimodality treatment. METHODS: We retrospectively reviewed the data of 187 NSCLC patients who underwent trimodality treatment between 1999 and 2018. RESULTS: Six male ever-smoker patients developed CPA. All 6 patients had undergone extended resection for NSCLC and had a history of either adjuvant chemotherapy (n = 3) or radiation pneumonitis (n = 4). Among the 4 patients with CPA localized in a single lung, 3 patients were treated surgically (completion pneumonectomy or cavernostomy) and 1 patient was treated with antifungal therapy alone. Both treatments led to the improved control of CPA. In contrast, patients with CPA in both lungs were not candidates for surgery, and died of CPA. The survival rates after trimodality treatment in the CPA group and the group without CPA were comparable (10-year survival rate, 50.0% vs. 57.6%, P = 0.59). CONCLUSION: The early diagnosis of CPA localized in a single lung after NSCLC surgery is critical to improving control and survival in patients with CPA.

Sixty-four-year-old man with non-productive cough and lung mass.

A 64-year-old manpresented with non-productive cough and dyspnoea and was evaluated and diagnosed to have a left lung mass on CT of the chest. A transthoracic needle biopsy under CT guidance revealed necrotic tissue on histopathology and was inconclusive. Positron emission tomography scan revealed a fluoro-deoxyglucose-avid left lung mass with a left upper lobe luminal cut-off. A flexible video bronchoscopy was performed and revealed left upper lobe complete obstruction with an endoluminal plug which was removed in piecemeal fashion, and deeper biopsies were taken from the lingula. Histopathology revealed underlying adenocarcinoma colonised by aspergillosis. This case serves to remind us of the possibility of missing underlying malignancy when taking superficial biopsies of clearly visualised endobronchial necrotic tissue and the need for debulking it to a reasonable extent and to take deeper biopsies in order to not miss a possible underlying malignancy.

Intensive care management of influenza-associated pulmonary aspergillosis.

BACKGROUND: Severe pulmonary infections are among the most common reasons for admission to intensive care units (ICU). Within the last decade, increasing reports of severe influenza pneumonia resulting in acute respiratory distress syndrome (ARDS) complicated by Aspergillus infection were published. OBJECTIVES: To provide a comprehensive review of management of influenza-associated pulmonary aspergillosis in patients with ARDS. SOURCES: Review of the literature pertaining to severe influenza-associated pulmonary aspergillosis. PubMed database was searched for publications from the database inception to January 2019. CONTENT: In patients with lower respiratory symptoms, development of respiratory insufficiency should trigger rapid and thorough clinical evaluation, in particular in cases of suspected ARDS, including electrocardiography and echocardiography to exclude cardiac dysfunction, arrhythmias and ischaemia. Bronchoalveolar lavage should obtain lower respiratory tract samples for galactomannan assay, direct microscopy, culture, and bacterial, fungal and viral PCR. In case of positive Aspergillus testing, chest CT is the imaging modality of choice. If influenza pneumonia is diagnosed, neuraminidase inhibitors are the preferred approved drugs. When invasive aspergillosis is confirmed, first-line therapy consists of isavuconazole or voriconazole. Isavuconazole is an alternative in case of intolerance to voriconazole, drug-drug interactions, renal impairment, or if a spectrum of activity including the majority of Mucorales is desired. Primary anti-mould prophylaxis with posaconazole is recommended in haematology patients at high-risk. It may be considered in newly diagnosed influenza and ARDS, but ideally in clinical trials. IMPLICATIONS: The rising reports of influenza-associated pulmonary aspergillosis in patients with ARDS, who are otherwise not considered at risk for fungal pneumonia demands heightened clinical awareness. Tracheobronchitis and Aspergillus in respiratory tract samples should prompt suspicion of invasive fungal infection and further work-up. The management algorithm should comprise bronchoalveolar lavage, CT imaging, sophisticated ventilator-management, rescue extracorporeal membrane oxygenation, and antifungal and antiviral therapy. To decrease the burden of influenza-related illness, vaccination is of utmost importance, specifically in patients with co-morbidities.

Exacerbation of chronic pulmonary aspergillosis was associated with a high rebleeding rate after bronchial artery embolization.

BACKGROUND: Hemoptysis is a common symptom associated with chronic pulmonary aspergillosis (CPA). While surgery is the primary choice to manage hemoptysis, it is often avoided because patients with CPA are more likely to have complications such as respiratory insufficiency and low pulmonary function. Bronchial artery embolization (BAE) may be considered one of the treatments of massive and persistent hemoptysis for such patients. METHODS: We retrospectively reviewed medical records of 41 patients, admitted to National Hospital Organization Tokyo National Hospital, Tokyo, Japan with hemoptysis arising from CPA between January 2011 to December 2016, who were considered inoperable and had undergone BAE. RESULTS: Out of the 41 cases analyzed in this study, 21 (51.2%) developed rebleeding after BAE within the mean follow-up duration of 24 months. The non-rebleeding rate of patients after BAE was 92.7% within a month and 65.8% within a year. Patients who developed rebleeding had significantly more non-bronchial systemic arteries responsible for the bleeding compared with patients who did not develop rebleeding (mean of 2.55 vs. 4.86, respectively, P = 0.011). Patients with stable or improved radiological findings demonstrated significantly lower rebleeding rates than those with radiological deterioration (P < 0.001). The non-rebleeding patients had significantly better survival than those with rebleeding (79.7% vs. 39.9% over 5 years, P = 0.046). CONCLUSIONS: Bronchial artery embolization was effective in controlling hemoptysis in patients with CPA, especially those who could not undergo surgical resection. However, disease control of CPA was important to prevent rebleeding over the long term and to improve survival after BAE.

Massive haemoptysis secondary to mycotic pulmonary artery aneurysm in subacute invasive aspergillosis.

A 68-year-old man, presented with 3 week history of infective symptoms and mild haemoptysis. Past medical history included severe emphysema and a chronic right upper lobe (RUL) cavity. He was discharged from follow-up a year ago in view of clinical and radiological stability; previous bronchoscopic examinations yielded no specific diagnosis. CT scan on admission confirmed complex cavitary consolidation of RUL. He developed massive haemoptysis requiring intubation and ventilation. CT pulmonary angiogram (CTPA) revealed 16 mm RUL pulmonary artery (PA) aneurysm which was successfully embolized. Sputum cultures, aspergillus antigen and rapidity of clinical progression suggested a diagnosis of subacute invasive aspergillosis (SAIA), prompting treatment with Voriconazole. Bronchoscopy showed blood ooze from RUL even after embolization. Unfortunately, patient continued to deteriorate and succumbed to profound septicaemia.