3 DISCUSSION
Although Scedosporium infection is more common in immunocompromised patients, it can also cause infection in immunocompetent hosts8,17,18. And the lung is one of the most common sites of Scedosporium infections. Patients with underlying lung diseases are more likely to develop infections. According to present knowledge of Scedosporium lung infection in immunocompetent adult patients3,19, the infection rate of males and females is similar, and their age ranges from 26 to 84-year-old (mean 56.4 years). The most common underlying lung disease is the cavitary lesion caused by pulmonary tuberculosis, followed by bronchiectasis. Asthma, pleural tuberculosis, and chronic restrictive or obstructive pulmonary disease have also been reported. Here we reported a case series including a 43-year-old female, a 36-year-old female and a 45-year-old male, all of them were non-Transplant, non-HIV-infected hosts, and without a history of long-term high-dose glucocorticoid use, so they were considered the immunocompetent adult hosts. Among them, 2 female patients had a history of bronchiectasis. The left pulmonary bullectomy was also performed for the first female. And another was infected with pulmonary nontuberculous mycobacteria for many years. Both of them were mixed infection cases. Until now, only three mixed pulmonary infection cases of Scedosporium and nontuberculous mycobacteria was reported15,20,21. Two patients had a history of pulmonary tuberculosis and one had a 15-year history of nontuberculous mycobacteria (NTM) pneumonia. Although the reason for the rareness of coinfection with NTM and Scedosporium is unclear, some investigators considered it might be related to the lower frequency of cavitations in individuals with NTM than in those with tuberculosis15. Another male patient in our case had a history of emphysema. He was in good health before this thick and had no habit of smoking. However, he had been working on a construction site for a long time and had a history of exposure to second-hand smoke, which may be the important incentive caused him to developSedosporium infection.
There are many similarities between the clinical and imaging features ofSedosporium and Aspergillus infection. But their antifungal drug resistance is much different. The susceptibility to antifungal drugs among different species for Sedosporium is also quite different. Therefore, the differential diagnosis of microorganisms timely and accurately is crucial for conducting precise treatment13. In the reported cases3,22, etiological culture of sputum, bronchoalveolar lavage fluid and lung biopsy specimens, NGS and polymerase chain reaction are the main methods to diagnoseSedosporium infection. Among them, the positive rate of biopsy tissue samples are higher than that of bronchoalveolar lavage fluid and sputum samples, and even multiple tests may be required to obtain positive results for bronchoalveolar lavage fluid and sputum samples. In our case, the first patient used NGS of bronchoalveolar lavage fluid to assist in the diagnosis of Sedosporium . The second patient was diagnosed the Sedosporium infection by continuous sputum cultures. The NGS and cultures of sputum and bronchoalveolar lavage fluid were all performed in the third patient to diagnose theSedosporium . And NGS combined with traditional microbial culture could make diagnosis more accurate and efficient.
Sedosporium species are highly resistant to many available antifungals, including amphotericin B, echinocandins, flucytosine and the first-generation azoles. Currently, voriconazole is still preferred for the first-line drug therapy, and the recommend adult dosage was 6 mg·kg-1, q12h on the first day, followed by 4 mg·kg-1, bid with intravenous administration, or 200 mg bid with oral administration13, but its duration of therapy is uncertain. In 10 cases of Sedosporium pulmonary infections in immunocompetent hosts treated with voriconazole3,19, the treatment dosage was adjusted according to a combination of recommended dosage and TDM results, and the therapy duration ranged from 1 to 10 months. Among them, one was recovered, eight was improved in clinical symptoms or images, and one was died. The maximum follow-up time of them was 18 months. And there was no recurrence case reported. The cured case was a 51-year-old female with no underlying lung diseases, but with surgery history. And she was continuously treated with voriconazole for 3 months. All three patients in this case received no operation but voriconazole alone with a recommended dose or above. The TDM results of their voriconazole were all reached the standard between 0.5-5mg·L-1. There was no Sedosporiumdetected in the first patient with 2-month treatment. The third patient was treated for 3-month with complete improvement in symptoms and imaging. The second patient responded poorly to the recommended dose of voriconazole and failed to achieve pathogenic clearance even after 12-month of continuous treatment, but her symptoms improved slightly. Research23 found voriconazole therapy may have a better effect when MIC was below 2 g·mL-1, but a limited effect to treatment at MIC of 4 g·mL-1 and may lead to treatment failure. No guideline recommendation could be given because no antifungal susceptibility testing results were available for the second patient. In the cases of pulmonary nontuberculous mycobacterial and Sedosporiumcoinfection15,20,21, only one patient who had no indication for surgery was treated with voriconazole alone for 6-month with initial dose of 400 mg daily, then increased to 500 mg daily based on TDM results. The symptoms and imaging improved after 6 months, but no follow-up records were reported. Another patient was followed up for 2 years after discontinuation of methylprednisolone and no deterioration was found with pulmonary imaging. Therefore, patients without indications for surgery could be treated with voriconazole alone with the recommended dose or above and treatment outcomes such as pathogens clearance or clinical and imaging improvement in most patients could be received. TDM would be required for dose adjustment and continuous treatment for at least 2 months also would be required. To patients with long duration of pulmonary nontuberculous mycobacterial infection and mixed infection with Sedosporium with no indication for surgery, voriconazole monotherapy could be less effective in clearing the pathogenic, and real-time drug sensitivity may be an important option to guide treatment. Current treatment experience needs to be confirmed with more clinical practices. Besides, posaconazole has been shown effective against Sedosporium in animal models, but was less active than voriconazole24-26. In this case, patient 2 failed to achieve clearance of pathogenic even after switching to posaconazole treatment for more than 1 month. It suggests that posaconazole only have limited effect to those patients Sedosporium is not cleared with voriconazole.
Considering the experience of Sedosporium clearance from patients with cystic fibrosis, combination therapy may be a good option, such as voriconazole or posaconazole was synergistic with echinocandins in a double combination27, and a combination of voriconazole, caspofungin and amphotericin B aerosol was recommended in a triple combination28. Besides, novel drug studies found that Manogepix (APX001A), Olorofim (F901318), and fosmanogepix (APX001) showed good antifungal activity, and vitro activity of the first two kinds were higher than voriconazole againstSedosporium 29-31. The antirheumatic drug Auranofin32 was also found effective against a variety of fungus, including Sedosporium . And the Sedosporiumevading host immunity is associated with thioredoxin reductase33. The appearance of the above new drugs, new applications and new targets will provide new basis and options for the treatment of Sedosporium infections.