Expert consensus on diagnosis and treatment of severe COVID-19 associated pulmonary aspergillosis and mucormycosis

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The incidence and mortality of COVID-19 associated pulmonary aspergillosis (CAPA) are high in critically ill patients. Although COVID-19 associated mucormycosis (CAPM) is relatively rare, its severity and often a delayed diagnosis or misdiagnosis lead to its high mortality. The diagnosis and treatment of CAPA and CAPM in critically ill patients are challenging. Early diagnosis and a standardized therapy are the two most important factors for a good outcome. Therefore, a working group of experts from Chinese Thoracic Society and Chinese Association of Chest Physicians Critical Care Group was organized to develop this consensus based on the current medical evidence and clinical practice, in order to improve the ability of clinical treatment for critically ill patients with CAPA and CAPM. The working group drafted a preliminary text based on the literature and clinical practice experience. Following two rounds of discussion, 16 final recommendations were made, with the recommendation strength divided into recommend, suggest and not recommend.-Utilization of chest images and bronchoscopy1. Chest CT, rather than chest X-ray, is recommended for possible CAPA or CAPM patients to provide diagnostic evidence and localization for bronchoscopy to obtain microbiological specimens. A diagnosis of CAPA could not be made on the basis of positive signs on chest CT alone. Chest contrast CT or pulmonary artery CT (CTPA) is recommended in patients with probable CAPM.2. In the case of possible CAPA or CAPM, it is recommended that bronchoscopy and BALF collection for microbiological examinations be pereformed as soon as possible.-The selection strategies of microbiological examinations3. Microscopic examination, culture, GM testing and PCR for aspergillus Spp. of BALF are recommended in patients with probable CAPA. Fungal staining and culture of BALF are suggested for possible CAPM. Selected appropriate specimens for molecular biological detection are suggested in critically ill patients and possible CAPM.-Diagnostic critieria4. The revised ECMM/ISHAM consensus statement is recommended as the diagnostic criteria for CAPA and the Delphi consensus statement is recommended as the diagnostic criteria for CAPM.-Appropriate time for antifungal therapy5. Prophylactic therapy of CAPA with amphotericin B or its liposomes is suggested for patients with severe COVID-19, especially those with risk factors for CAPA.6. It is recommended to start the empirical anti-Aspergillus therapy as soon as possible for possible CAPA, and obtain the microbiological evidence for aspergillosis at the same time.7. Prophylactic therapy for CAPM is not recommended for severe COVID-19 patients.8. Early initiation of empirical therapy for possible CAPM is recommended, and microbiological evidence should be obtained at the same time.-Clinical applications for antifungal agents9.Voriconazole or isavuconazole are recommended as initial treatment for CAPA. Amphotericin B liposomes are suggested as the initial treatment for CAPM. Isavuconazole or posaconazole may be an option in patients with renal insufficiency or amphotericin B liposome intolerance/unavailability.10. In CAPA patients with tracheobronchitis, antifungal drug inhalation is recommended in addition to systemic antifungal medication.11. Combination therapy is not recommended as initial therapy for CAPA, but may be used as a salvage therapy strategy. Triazole or amphotericin B in combination with caspofungin or micafungin is recommended; whereas amphotericin B in combination with triazole is not recommended. For CAPM patients with extensive lesions, rapid progression or poor general condition, a combination of amphotericin B liposome with isavuconazole or posaconazole is suggested.-Response assessment and treatment duration12. It is recommended that treatment response be assessed comprehensively according to the clinical symptoms/signs, imaging and microbiological examination of patients. CAPA can be evaluated in combination with the dynamic change in serum GM.13. The recommended treatment duration of CAPA is at least 6-12 weeks. A total course of at least 3-6 months is suggested for CAPM, and the sequential treatment should be considered according to the response to 4-6 weeks of intravenous therapy.-How to adjust the anti-inflammatory therapy14. In patients with severe COVID-19 combined with possible or probable filamentous fungal infection, it is suggested that of anti-inflammatory therapy be stopped or reduced appropriately, taking into account of the severity of the infection and inflammation of the disease course. The combination of baritinib and/or tozzizumab based on glucocorticoids is not suggested in these patients.-How to treat the underlying diseases15. In patients with diabetes, strict glycaemic control is suggested. In patients with long-term use of glucocorticoids and/or immunosuppressants, it is suggested to reduce the intensity of immunosuppression. Granulocyte colony-stimulating factor is suggested to use to improve the circulating granulocyte levels in patients with granulocyte deficiency due to various causes.-When an operation should be considered16. In patients with CAPA, surgery is not recommended unless large blood vessels, pericardium, or chest wall are involved, or the patient has recurrent or massive hemoptysis. For CAPM patients, early surgical removal of lesions after diagnosis is recommended. Surgery is a high-risk procedure in patients with severe COVID-19, and a multidisciplinary team discuss is suggested.