Mucormycosis is a rare, emerging and opportunistic fungal infection with high morbidity and mortality caused by filamentous fungi of the Mucoraceae family, order Mucorales. Mucorales fungi are ubiquitous in nature. Humans are infected mainly by inhaling sporangiospores, occasionally through the ingestion of contaminated food or traumatic inoculation (Prakash and Chakrabarti, 2019; Shariati et al., 2020). The prevalence of mucormycosis varies between developing and developed countries, ranging from 0.01 to 14 per 100 000 population in Europe and India (Bitar et al., 2009; Chakrabarti and Singh, 2014; Ruhnke et al., 2015). With the growth of the number of immunocompromised patients, increased awareness and development of diagnostic techniques, the incidence of mucormycosis is rising (Prakash et al., 2019). According to clinical presentations, mucormycosis is mainly classified as rhino-orbito-cerebral, pulmonary, cutaneous, gastrointestinal and disseminated types (Skiada et al., 2020). The common risk factors of mucormycosis are diabetes, hematological malignancy, use of corticosteroids or immunosuppressants, and trauma (Petrikkos et al., 2014; Jeong et al., 2019). However, the main cause of mucormycosis also varies in different countries. Hematological malignancies are the main cause in countries with high income, while diabetes mellitus (DM) or trauma are the main cause in developing countries (Chakrabarti and Singh, 2014). Diagnosis of mucormycosis is challenging because of the low sensitivity and specificity of clinical diagnostic methods (Skiada et al., 2018).

The mortality of mucormycosis remains high, it may be related to delayed diagnosis, high cost of managing mucormycosis and limited treatment options (Skiada et al., 2018). Previous studies on the characteristics of mucormycosis have been conducted mainly in America, Europe and India (Prakash and Chakrabarti, 2019). Data about mucormycosis from China is sparse. The causative agents of mucormycosis vary with different geographical locations (Prakash and Chakrabarti, 2019), and the epidemiology, the clinical disease pattern of mucormycosis vary from country to country.

To better understand the clinical characteristics of patients with mucormycosis in China, in this retrospective study, we compared the demographic features, clinical presentations, laboratory data, radiographic findings and therapeutic strategies in mucormycosis patients with different clinical outcomes who were admitted to a university hospital from Jan 2010 to Dec 2019 in western China.

Mucormycosis is rare, neglected, and associated with high mortality rates. The study found that 52.5% of patients with mucormycosis had poor clinical outcomes. Which is similar to previous research results (Jeong et al., 2019). PM was the most common form of mucormycosis, accounting for 78.0% of all the patients with mucormycosis. Although previous studies have reported that rhino-orbital mucormycosis was the most common clinical type (Patel et al., 2020), PM maybe more common in China (Peng et al., 2019). This study also found the most common underlying disease was diabetes mellitus. Previous studies have shown that PM mainly occurred in patients with hematological malignancies, while rhino-orbital mucormycosis mostly occurred in patients with diabetes mellitus (Skiada et al., 2011; Chakrabarti and Singh, 2014). However, our results were consistent with those from China (Peng et al., 2019). Perhaps because the number of diabetes patients in China is much larger than that of hematological malignancies (Liu et al., 2019; Khan et al., 2020), the underlying disease of more mucormycosis patients is diabetes. The high prevalence of diabetes in China and endemic mucor species different from other countries may also be the reasons for the high incidence of PM in diabetic patients in China. More detailed etiological studies of mucormycosis need to be done. We found the incidence of mucormycosis was tended to rise, which may be owing to the improvement of fungal diagnostic technology, health awareness and the visiting rate. In addition, diabetes incidence is on the rise worldwide, especially in China and India (Khan et al., 2020), which may be the reason for the increase in the incidence of mucormycosis in China.

For PM, the most common clinical symptoms were cough, fever, and hemoptysis/bloody phlegm. This result was similar to some previous studies (Skiada et al., 2011; Peng et al., 2019). Molecular-based assays can help to identify different fungal species and it can be used as a supplement to conventional diagnostic methods (Machouart et al., 2006; Springer et al., 2016). The study also found that laboratory results were not associated with patient outcomes. Most previous studies have not found a correlation between laboratory results and clinical outcomes in patients with mucormycosis (Patel et al., 2020; Son et al., 2020), and only a few studies have found that neutropenia may be associated with increased mortality (Spellberg et al., 2012). Neutropenia was not found in our patients with PM, it might not be an important risk factor for mortality in these patients.

The most frequent imaging findings of PM were patchy shadows, cavitation and pulmonary nodules in this study. According to the imaging findings, PM might be misdiagnosed as tumor or pulmonary aspergillosis. Nodule was more common in good outcome group. Lymph node enlargement were more common in patients with worse outcome. Many previous studies have found multiple nodules, reversed halo sign, and cavities associated with PM (McAdams et al., 1997; Marom and Kontoyiannis, 2011). Pulmonary nodules, halo sign and cavitation was also found in patients pulmonary invasive aspergillosis (Althoff Souza et al., 2006; Muldoon et al., 2016). The reversed halo sign has been considered an important clue to the diagnosis of PM, however, it has also been described in other pulmonary diseases, including invasive pulmonary aspergillosis, tuberculosis, organising pneumonia and malignancy (Sullivan and Rana, 2019). Therefore, early biopsy to establish the underlying cause is very important in patients with suspected pulmonary fungal infections.

Diagnosis of mucormycosis is challenging. In clinical practice, laboratory diagnosis of mucormycosis includes histopathology, direct examination and cultures (Skiada et al., 2020). Most patients in this study were diagnosed by histopathology. Many previous studies have also reported that histopathology was the main diagnostic method of mucormycosis (Prakash and Chakrabarti, 2019). In this study, Mucorales culture positive was found only in 13 patients. It was previously reported that the positive rate of Mucorales culture could reach 79% (Prakash and Chakrabarti, 2019). Which may be related to the low vigilance of doctors to invasive pulmonary mycosis and the absence of fungal culture for puncture specimens. More needs to be done to raise awareness of pulmonary mycosis among doctors.

In this study, twelve patients did not receive treatment and left the hospital against medical advice after diagnosis because of their critical condition and financial constraints. PM patients were treated with amphotericin B or posaconazole had better clinical outcomes, while untreated patients had poor outcomes. For rhino-orbito-cerebral and disseminated mucormycosis patients, there was no statistically significant difference in clinical outcome between different treatment strategies, which maybe related to the small number of cases. In addition, patients with rhino-orbito-cerebral mucormycosis who underwent surgery and antifungal therapy had better clinical outcomes. At present, treatment options for mucormycosis remain very limited. LAmB combined with surgery are strongly recommend as first-line therapy. Isavuconazole and posaconazole are also options as second-line agents (Cornely et al., 2019). For patients with PM, only 3 patients in this study were received pulmonary lobectomy, so no benefit of antifungal combined surgical treatment over antifungal therapy alone was observed. Bilateral lobe involvement occurred in 84.8% of patients in this study, which was similar to previous studies (Peng et al., 2019). Multifocal involvement limited the surgical options, early and effective antifungal therapy may be more important for patients with PM. The recommended combination of antifungal agents and surgical treatment as a treatment option for mucormycosis may be based on the presence of more rhino-orbito-cerebral mucormycosis in other countries. More researches may be needed to optimize treatment options for different types of mucormycosis. New treatment drugs or methods, such as combination of lipid amphotericin B and caspofungin or posaconazole, VT-1161, deferasirox in combination with a polyene, hyperbaric oxygen and so on, still deserve to be expected to improve clinical outcome (Skiada et al., 2018).

This study has some limitations. First, it was a retrospective observational study. Only some patients have complete follow-up data in our hospital, especially imaging data, and the follow-up of some patients could only be completed by telephone. Second, the detection rate of tissue culture was low, the pathological diagnosis was determined mainly by morphology and special staining. It is important to raise the awareness of doctors about fungal disease and the importance of tissue culture. Third, because mucormycosis is a relatively rare fungal disease in China (Liao et al., 2013), the number of cases in this study was limited. More larger-scale, multicenter studies of mucormycosis in the real world should be done.

The most common clinical type of mucormycosis in China was PM. The most common risk factor was diabetes mellitus. Diabetic patients with clinical manifestations of febrile and hemoptysis, CT findings of nodules, cavities and bilateral lung involvement should be vigilant against PM. Early diagnosis and effective anti-mucor treatment are very important to improve the prognosis of patients with mucormycosis.

The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Ethics Committee of West China Hospital, Sichuan University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

XL and JQ conceived of and designed the study. JQ and XL collected, analysed or interpreted data. JQ wrote the draft. All authors read, revised and approved the final manuscript.

This study was supported by Sichuan Province Science and Technology Support Program of China (grant number: 2021YFS0170), 1•3•5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (grant number: 2021HXFH032).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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