ECCMID 2023: What's New in the Diagnosis and Treatment of Chronic Pulmonary Aspergillosis?
The session highlighted discusses diagnosis antifungal therapy in chronic pulmonary aspergillosis through a case-based approach.
The first case is a forklift driver with a history of stage III sarcoidosis in 2014 (managed with prednisolone) and Aspergilloma in 2015. For aspergilloma, the patient was given voriconazole 200 mg for 4 months; however, he developed toxicity and was switched to itraconazole. The patient was referred to the hospital a few months later due to increased dyspnea, cough and fatigue and weight loss (4kg). His medications included 4mg methylprednisolone and 100 mg itraconazole OD. Itraconazole was discontinued; CT scan revealed bilateral lesions and bilaterally positive galactomannan. The fungal culture study came back negative. The patient was initiated on voriconazole at 450 mg BID; he suffered from severe visual disturbances because of high peak levels. It was found that the patient's hobby was being a falconeer. He developed phototoxicity and was switched to posaconazole with which he achieved adequate plasma levels. A few years later, the patient suffered from recurrent haemoptysis; CT angiography revealed a tortuous left bronchial artery managed with embolization. One year later he reported coughing on pieces of fungal balls and chest CT revealed fibrosis.
Based on clinical experience, the oral triazole therapies for chronic pulmonary aspergillosis (CPA) include itraconazole, voriconazole and posaconazole orally. Lower doses are advised in those > 70 years, low weight, with significant liver disease and in those belonging to NE Asian descent. It is important to have therapeutic dose monitoring (TDM). There are no drugs formally registered for CPA. The guidelines published in 2016 recommend a minimum 6 months of therapy (marginal evidence) as short courses are ineffective and result in relapses. In immunocompromised patients who develop chronic necrotizing PA are usually treated for 6 months with curative intent. In treatment of 6 months versus 12 months in patients with chronic aspergillosis using itraconazole, a 72% response rate is seen with the 6-month group and an 88% response rate in the 12 month group with a low relapse rate. Fungal culture results are often negative as the organisms adapt well to live in CPA patients and they grow slowly. Performing PCR with high volume culture can yield up to 76% higher as compared to 20% in the conventional method. establishing that HVC is an effective method to obtain maximum fungal culture. CPA can be diagnosed by combining imaging data (chest CT scan) with Aspergillus specific IgG and culture findings. The European and the IDSA guidelines concur that the characteristic imaging should be present for at least 3 months There should also be either direct or indirect serological evidence of the presence of Aspergillus. In the case above, where the patient was inadequately treated with 3 individual azole treatment regimens, surgical resection is not an option due to his lung function due to sarcoidosis. In a case series of CPA complicating sarcoidosis (n=3137), most patients had positive aspergillus IgG serology. In sarcoidosis the relapse after surgery is very high because it is not possble to completely resect all the underlying lesions. The case presented was suspected to have a mutation of the CYP51A gene which corresponded to itraconazole and posaconazole resistance. Susceptibility testing is required as 75-80% strains from such patients are pan-azole resistant. In this patient, Voriconazole was the treatment option available and was given 500 mg BID to obtain therapeutic drug levels (in 2017). Isavuconazole was started in this patient on compassionate use (2018) and was continued till reimbursement (2019). Isavuconazole demonstrated a favorable clinical, microbiological and radiological evolution. During follow-up, the patients aspergillus IgG levels had dropped, the wall thickening and the pleural thickening was reduced. At present, the patient is followed-up every 2-3 months and sputum culture is done. Imaging is done upon indication is done every 2-3 years. In conclusion, CPA management should follow guidelines of acute invasive pulmonary aspergillosis; oral triazoles are the gold standard therapies to stabilize the condition. Quantification of infection can be done by ELISA or CAP ELISA, sputum culture should be done regularly to understand resistance and radiological findings of the cavity must be analyzed for indication of response along with the quality of life score.
The second case was a 68-year old dock-worker with chronic obstructive pulmonary disease (COPD) and cardiovascular morbidity of myocardial infarction. He suffered pneumonia in 2018 and he suffered from recurrent COPD exacerbations. He had severe underlying emphysema and also bronchiectasis in his right lower lung. He had frequent exposure to a moist environment. The patient had progressive dyspnea, unintended weight loss (20kg) and night sweats (2021) Chest X-ray showed consolidation in the left upper lobe. Lung function tests showed a FVC of 3.8L, FEV1 of 1.34L. Chest CT revealed pronounced emphysema.
A diagnosis of Non-tuberculous mycobacterial pulmonary disease (NTM-PD) was established. The patient was started on hypertonic saline nebulization and chest physiotherapy. He was initiated with Azithromycin 250mg OD, Moxifloxacin 400 mg OD, Ethambutol 1000 mg OD, Rifampicin 600 mg OD, Amikacin 1000 mg IV daily.
On presentation to the ER, he had significant haemoptysis, general malaise, continuous weight loss, nausea, abdominal discomfort, progressive dyspnea and painful productive cough. A diagnosis of subacute/chronic cavitary pulmonary aspergillosis was made. The patient was on active NTM treatment and had hemoptysis. Bronchoscopy showed inflamed mucosa of the left upper lobe. The sputum culture was positive for Aspergillus fumigatus. The IgG values for A. fumigatus were 179 mg/L.
A study from France on Mycobacterium xenopi infections showed that the outcome for this infection is much worse than NTM and if left untreated the mortality is 85% within 1.5 years and 50% mortality over 3 years. A database on antifungal drug interactions, it was found that itraconazole or voriconazole is associated with life threatening or hospitalization level drug interactions. Thus, while prescribing azoles, it is important to check for drug interactions. Since the case here presented with hemoptysis, bronchial artery embolisation was conducted. The patient was initiated with Posaconazole at a standard dose. After 1 week, the patient had suboptimal levels, the dose was titrated to 400 mg to achieve therapeutic drug levels. There was good evolution of aspergillosis and improvement in his clinical status. The case highlights that con-infections with NTM and Aspergillus are not infrequent in fibrocavitary disease. The central dogma is treat first what kills first and avoid treating different pathogens at the same time. Monitoring of galactomannan is not validated in serum and bronchoscopy is advised in such patients.
The third case is of a woman with rheumatoid arthritis treated with various immunosuppressants and has bilateral Aspergillus empyema with bilateral pneumothorax, intermittently treated with voriconazole without TDM. She underwent anterolateral thoracotomy with empyema drainage and decortication of the left lung, which was the most severely affected. Direct examination of the pleural fluids revealed several hyphae. The culture testing was positive for A. fumigatus. The patient was prescribed voriconazole therapy guided by strict TDM. There was a local instillation of amphotericin B via a chest tube and the surgeons placed a Heimlich valve.
In cases such as presented above, it is important to offer a good quality of life in the period after the procedure and treatment should be chosen wisely. Data of the penetration of the antifungals into the different tissues demonstrate that voriconazole is the only antifungal that penetrates into the pleural fluids. The pleural infection at the right side resolved spontaneously and a very favorable evolution on the left side was observed. The standard indications for surgery include single aspergilloma in patients with adequate pulmonary function. Complete resection can be done but spillage of fungal spores in the pleural cavity must be avoided. Other indications include hemoptysis and CCPA refractory to fungal treatment if it is clinically feasible. It is important to perform the surgery under optimal antifungal coverage. In empyema due to Aspergillosis, if there is a spillage of spores in the pleural cavity during the surgery, it can be washed off with amphotericin B. The overall risk of survival after surgery with compromised lung function is very low. The risks of survival are much higher if the patient is well-nourished. A retrospective study done on giving antifungals prior to surgery and during surgery, compared to giving antifungal after surgery, has shown that the relapse rate (50-60%) is moderately high when given with surgery. This rate increases to 90% when antifungals are not administered making pre-treatment with antifungals important.
In conclusion, high volume cultures are important, aspergillus IgG is a critical part of the diagnosis, if bronchoscopy can be arranged then performing Aspergillus galactomannan is usefuland fungal ball is present in only 40% patients in CT with CPA. CPA is a subtle infection without high CRP values and high fever. Long- term treatment is the norm in those patients where you cannot take away the underlying disease and risk factors. The unmet needs include update of the guidelines and newer evidence. There is need for improvement of guideline adherence and there is a need for multicenter, randomized controlled trials on existing antifungals.
European Congress of Clinical Microbiology and Infectious Disease 2023, 15th April - 18th April 2023, Copenhagen, Denmark
