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. 2025 May 16;20(5):e0323624. doi: 10.1371/journal.pone.0323624

Diagnosis, clinical features, and mortality risk factors in a Chinese cohort with pulmonary mucormycosis

Junjun Wan 1, Teng Liu 2, Fang Li 3, Shaohua Xu 1,*
Editor: Felix Bongomin,4
PMCID: PMC12083791  PMID: 40378175

Abstract

Background

Pulmonary mucormycosis is a rare and often fatal fungal infection. Identifying high-risk factors for pulmonary mucormycosis holds the potential to improve patient outcomes. This study aimed to identify the clinical characteristics and risk factors associated with pulmonary mucormycosis outcomes in a Chinese cohort.

Materials and methods

A retrospective analysis was conducted on 37 patients diagnosed with pulmonary mucormycosis, focusing on clinical records, laboratory findings, and computed tomography (CT) imaging. Diagnosis was primarily based on histopathology or next-generation sequencing.

Results

The median age of the patients was 55 years, and the most common underlying conditions were hematological malignancies, diabetes, and organ transplantation. Imaging frequently revealed bilateral lung involvement with ground-glass opacities and nodular lesions. The overall mortality rate was 29.7%, with significant risk factors for 90-day mortality including hypertension (Hazard Ratio [HR] = 3.36, 95% Confidence Interval [CI] = 1.01–11.12, P = 0.048), organ transplantation (HR = 4.93, 95% CI = 1.48–16.4, P = 0.009), and immunosuppression (HR = 8.83, 95% CI = 1.13–69.14, P = 0.038).

Conclusions

Early suspicion and timely diagnostic measures, such as biopsy or metagenomic sequencing, are crucial for improving patient outcomes. These findings underscore the importance of recognizing and managing pulmonary mucormycosis in high-risk populations.

1 Introduction

Mucormycosis, often referred to as zygomycosis, is an acute or subacute invasive fungal infection caused by members of the Mucorales order [1,2]. These fungi are ubiquitous in soil, decaying organic matter, and animal excrement environments. While generally non-pathogenic to healthy individuals, Mucorales can become opportunistic pathogens, particularly in immunocompromised individuals, such as those with diabetes mellitus, organ transplantation, or neutropenia [3]. The primary route of infection is through the inhalation of sporangiospores, leading to pulmonary infection.

The incidence of the deadly mucormycosis has surged during the Coronavirus Disease 2019 (COVID-19) pandemic, elevating public health concerns and increasing clinical awareness. However, diagnosing mucormycosis remains challenging due to its rarity and the overlap of its symptoms with other conditions, often leading to delays in diagnosis and treatment. Mucormycosis can manifest in various forms, including rhino-orbit-cerebral, pulmonary, cutaneous, gastrointestinal, and disseminated types [4]. This diagnostic complexity contributes to the high mortality rate [5] with the 90-day mortality rate for patients with pulmonary mucormycosis ranging from 45% to 57% [6–9].

Most patients present with prolonged fever, though some may remain asymptomatic [10]. On chest CT, pulmonary mucormycosis may appear as ground-glass opacity, halo sign, crescent sign, thick-walled cavities, or fungal balls [11]. Early diagnosis is crucial for improving outcomes, however, current diagnostic methods’ low sensitivity and specificity complicate early detection [12].

In this retrospective single-center study, we review the experience of the Second Hospital of Shandong University in treating patients with pulmonary mucormycosis. The primary objective of the study was to investigate the clinical manifestations, radiological features, treatment strategies, and outcomes of patients with pulmonary mucormycosis, with a particular focus on identifying factors that influence clinical outcomes. These cases highlight the critical importance of prompt diagnosis and the implementation of combined therapy in managing this life-threatening infection.

Materials and methods

Ethical considerations

This study was conducted following the ethical principles outlined in the Helsinki Declaration and was approved by the Research Ethics Committee of the Second Hospital of Shandong University (No. KYLL2024LW035). Due to the study’s retrospective nature and the absence of identifying information, written informed consent was waived.

Patients

This study included all cases of pulmonary mucormycosis diagnosed at our institution between 2018 and 2023. Data were retrospectively extracted from electronic medical records, covering demographic characteristics, infection sites, host factors, underlying diseases, diagnosis, clinical course, management, and outcomes. Clinical outcomes were defined as either survival or death within 90 days after diagnosis.

Data were accessed for research purposes between July 1, 2024, and July 15, 2024, and all information was handled in accordance with institutional guidelines for data privacy and security.

Criteria for pulmonary mucormycosis

We applied the criteria set forth by the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) to classify cases of invasive fungal disease as proven, probable, or possible [3]. The study included all consecutive subjects aged 18 years or older with proven or probable pulmonary mucormycosis. Proven pulmonary mucormycosis was identified in cases where there was both clinical and radiological suspicion of invasive mold infection, supported by the observation of aseptate hyphae or the confirmed growth of Mucorales from typically sterile sites, such as lung tissue or pleural fluid. Probable pulmonary mucormycosis was diagnosed in patients who exhibited consistent clinical and imaging findings, along with the detection of aseptate hyphae or positive Mucorales cultures from sputum or bronchoalveolar lavage fluid [13]. Patients who presented with host factors and clinical characteristics indicative of mucormycosis but lacked fungal evidence were classified as having “possible” fungal infections; these patients were excluded from the analysis due to the lower diagnostic certainty associated with this classification.

Laboratory studies

Laboratory evaluations included complete blood count (CBC), C-reactive protein (CRP), procalcitonin (PCT), albumin (ALB), and the galactomannan (GM) test. All 37 patients were diagnosed through a combination of microbial culture, metagenomic sequencing, and/or histopathological analysis. Most patients underwent bronchoscopy with bronchoalveolar lavage (BAL), and clinical samples (including sputum and BAL fluid) were cultured under both aerobic and anaerobic conditions. Fungal cultures were performed on Sabouraud dextrose agar (SDA) medium, incubated at 30°C. Once colonies formed, macroscopic identification of colony morphology was performed, followed by microscopic examination using lactophenol cotton blue staining for species identification.

NGS testing (Next-Generation Sequencing) is a high-throughput and highly efficient DNA or RNA sequencing technology capable of parallel sequencing multiple DNA fragments in a short period of time. The DNA from the alveolar lavage fluid was extracted and processed for amplification and sequencing. The sequencing data were then assembled, annotated, and classified to determine the microbial species present in the samples.

Histological sections obtained from bronchoscopic or surgical biopsies were stained with periodic acid-Schiff (PAS) or hexamine silver, which enhanced the visualization of fungal elements. In cases of mucorales infection, characteristic hyphae were observed in the tissue samples.

Radiological assessment

Chest CT scans were performed for all patients, however, cranial MR examinations were conducted only for patients presenting with head-related symptoms. The images were independently reviewed by two experienced radiologists. For patients diagnosed with pulmonary mucormycosis, the following CT findings were recorded: nodules, masses, cavities, consolidations, ground-glass opacities, reverse halo signs, lymphadenopathy, pleural effusions, and the distribution of lesions within the lungs.

Treatment strategies and clinical outcomes

The treatment of mucormycosis includes surgical intervention, antifungal therapy, and management of underlying diseases. Whenever feasible, we perform surgical interventions on the lesions, including local debridement or resection of infected tissues or organs. Systemic antifungal therapy is essential, with treatment regimens including liposomal amphotericin B (LAmB, 3–6 mg/kg daily), amphotericin B deoxycholate (AmB, 0.5–1 mg/kg daily), isavuconazonium (200 mg three times daily on days 1–2, followed by 200 mg once daily from day 3 onwards), and posaconazole oral suspension (400 mg twice daily).

Simultaneous management of underlying conditions is critical for improving treatment outcomes. In patients with underlying diseases, we implemented corresponding management measures. This involves optimizing blood glucose control, boosting granulocyte counts, and reducing or discontinuing glucocorticoids or immunosuppressive drugs where possible. The duration of antifungal therapy is individualized, based on the patient’s clinical response and lesion size.

Clinical outcomes were evaluated 90 days after the diagnosis of mucormycosis and categorized as survival or death.

Statistical analysis

All statistical analyses were performed using R Statistical Software (Version 4.2.2, http://www.R-project.org, The R Foundation) and the Free Statistics Analysis Platform (Version 1.8, Beijing, China). Categorical variables were compared using Fisher’s exact test, and continuous variables were analyzed using the Wilcoxon rank-sum test. The univariable Cox regression model was utilized to compare the characteristics between surviving and deceased patients. Survival curves for patients with different immune statuses were generated using the Kaplan-Meier method. A two-tailed P-value of < 0.05 was considered statistically significant.

Results

Demographic characteristics and clinical manifestations

A total of 37 patients were included in the analysis, with 9 patients (24.3%) classified as having proven pulmonary mucormycosis and 28 patients (75.7%) classified as having probable pulmonary mucormycosis, according to the EORTC/MSG definitions for invasive fungal diseases (Table 1). The demographic characteristics, underlying conditions, predisposing factors, treatment regimens, and outcomes of these patients are summarized in Table 2.

Table 1. Demographics, clinical diagnosis, treatment, and outcome for patients with pulmonary mucormycosis.

Case Age (y)/Sex T1 (d) T2 (d) Immune status Site of infection Identification method Treatment Surgery Outcome
1 61/M 1 18 Suppression Lung Pathology Posaconazole No Deceased
2 35/F 15 41 Suppression Disseminated Pathology Amphotericin B Yes Survivor
3 31/F 1 15 Normal Lung NGS Amphotericin B No Survivor
4 44/M 14 2 Suppression Lung NGS Amphotericin B No Survivor
5 49/M 20 3 Normal Lung NGS Isavuconazole No Survivor
6 56/M 3 28 Suppression Lung NGS Posaconazole No Deceased
7 72/M 20 6 Normal Lung Culture Amphotericin B No Survivor
8 62/F 15 21 Normal Lung Pathology Isavuconazole No Survivor
9 22/F 14 5 Suppression Lung Pathology Amphotericin B No Deceased
10 74/M 15 10 Suppression Lung NGS Amphotericin B No Deceased
11 68/F 30 6 Suppression Lung Pathology Amphotericin B, Posaconazole No Survivor
12 38/F 2 11 Suppression Lung Pathology Posaconazole, Amphotericin B No Survivor
13 57/F 20 3 Suppression Lung NGS Isavuconazole No Deceased
14 73/M 15 15 Suppression Lung NGS Amphotericin B No Deceased
15 50/M 8 9 Normal Lung Pathology Amphotericin B, Isavuconazole No Survivor
16 26/M 20 12 Normal Lung Pathology Amphotericin B,
Isavuconazole		 Yes Survivor
17 73/M 90 20 Normal Lung NGS Isavuconazole No Survivor
18 59/M 20 4 Suppression Lung NGS Isavuconazole No Survivor
19 59/M 60 15 Suppression Lung NGS Isavuconazole No Survivor
20 55/M 20 7 Normal Lung NGS Isavuconazole No Survivor
21 44/M 4 7 Suppression Lung Pathology Isavuconazole No Survivor
22 26/M 2 19 Normal Lung Pathology Amphotericin B Yes Survivor
23 80/F 15 8 Suppression Lung Culture Isavuconazole No Deceased
24 64/M 7 12 Normal Lung Culture Isavuconazole No Survivor
25 63/F 7 15 Suppression Lung Culture Amphotericin B No Survivor
26 56/M 20 4 Suppression Lung NGS Isavuconazole No Survivor
27 68/M 21 9 Suppression Lung Pathology Amphotericin B, Isavuconazole No Survivor
28 49/M 2 27 Suppression Lung NGS Amphotericin B No Deceased
29 56/M 40 10 Normal Lung NGS Amphotericin B, Isavuconazole No Survivor
30 70/F 5 8 Suppression Lung NGS Amphotericin B No Survivor
31 84/M 10 13 Normal Lung Culture Amphotericin B No Survivor
32 61/F 10 14 Normal Lung NGS Isavuconazole, Amphotericin B No Deceased
33 43/M 3 25 Suppression Disseminated NGS Amphotericin B No Deceased
34 65/M 50 6 Suppression Lung NGS Isavuconazole No Survivor
35 29/F 21 12 Normal Lung Culture Isavuconazole No Survivor
36 45/M 2 15 Normal Lung Pathology Isavuconazole, Amphotericin B Yes Survivor
37 75/M 7 35 Suppression Lung NGS Amphotericin B, Posaconazole No Deceased
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Abbreviations: T1, time from symptom onset to hospital admission; T2, time from admission to diagnosis; F, female; M, male; NGS, next-generation sequencing

Table 2. Clinical characteristics of patients with pulmonary mucormycosis and differences between 90-day survivors and non-survivors.

Patient demographics Total (n = 37) Patient survived (n = 26) Patient deceased (n = 11) P value
Male, n (%) 25 (67.6) 18 (69.2) 7 (63.6) 1
Age, mean ± SD 55.2 ± 16.2 53.5 ± 15.9 59.2 ± 16.9 0.336
duration of hospitalization, mean ± SD 30.3 ± 20.1 29.0 ± 19.0 33.5 ± 23.2 0.534
clinical manifestations, n (%)
Fever 26 (70.3) 18 (69.2) 8 (72.7) 1
Cough 17 (45.9) 14 (53.8) 3 (27.3) 0.138
Hemoptysis 11 (29.7) 8 (30.8) 3 (27.3) 1
Chest tightness 13 (35.1) 10 (38.5) 3 (27.3) 0.711
Others 9 (24.3) 5 (19.2) 4 (36.4) 0.404
Time from symptom onset to hospital admission, mean ± SD 17.00 ± 18.03 20.15 ± 20.38 9.55 ± 6.64 0.102
Time from admission to diagnosis, mean ± SD 13.24 ± 8.97 11.62 ± 7.94 17.09 ± 10.45 0.090
Underlying disease, n (%)
Diabetes 14 (37.8) 10 (38.5) 4 (36.4) 1
Hypertension 9 (24.3) 4 (15.4) 5 (45.5) 0.091
Hematological disorders 11 (29.7) 6 (23.1) 5 (45.5) 0.244
Organ transplant 7 (18.9) 2 (7.7) 5 (45.5) 0.016
Pulmonary diseases 6 (16.2) 6 (23.1) 0 (0) 0.151
Tumor 3 (8.1) 2 (7.7) 1 (9.1) 1
Others 6 (16.2) 4 (15.4) 2 (18.2) 1
Identification method, n (%) 0.316
NGS 19 (51.4) 11 (42.3) 8 (72.7)
Pathology 12 (32.4) 10 (38.5) 2 (18.2)
Culture 6 (16.2) 5 (19.2) 1 (9.1)
Laboratory test
WBC, mean ± SD 8.49 ± 5.82 8.86 ± 5.56 7.63 ± 6.58 0.564
NE, mean ± SD 6.90 ± 5.46 7.17 ± 5.08 6.27 ± 6.50 0.653
LY, mean ± SD 0.93 ± 0.57 1.00 ± 0.52 0.75 ± 0.68 0.215
EOS, mean ± SD 0.04 ± 0.09 0.03 ± 0.06 0.07 ± 0.14 0.208
HB, mean ± SD 109.03 ± 28.43 114.54 ± 29.43 96.00 ± 21.86 0.069
GM, mean ± SD 2.00 ± 2.28 2.42 ± 2.57 1.02 ± 0.83 0.088
CRP, mean ± SD 66.92 ± 52.39 67.84 ± 54.41 64.74 ± 49.71 0.872
PCT, mean ± SD 0.42 ± 0.71 0.50 ± 0.84 0.24 ± 0.20 0.322
ALB, mean ± SD 32.35 ± 5.42 32.51 ± 4.84 31.97 ± 6.87 0.788
Concurrent infections, n (%) 30 (81.1) 20 (76.9) 10 (90.9) 0.649
Site of infection, n (%) 0.512
Disseminated 2 (5.4) 1 (3.8) 1 (9.1)
Lung 35 (94.6) 25 (96.2) 10 (90.9)
Imaging findings, n (%)
Patchy opacities 16 (43.2) 10 (38.5) 6 (54.5) 0.475
Ground-glass opacity (GGO) 17 (45.9) 13 (50) 4 (36.4) 0.447
Cavity 13 (35.1) 8 (30.8) 5 (45.5) 0.465
Reverse halo sign 15 (40.5) 10 (38.5) 5 (45.5) 0.728
Flocculated opacities 11 (29.7) 8 (30.8) 3 (27.3) 1
Nodule 18 (48.6) 14 (53.8) 4 (36.4) 0.331
Crescent sign 5 (13.5) 3 (11.5) 2 (18.2) 0.623
Vacuole 8 (21.6) 5 (19.2) 3 (27.3) 0.672
Consolidation 15 (40.5) 10 (38.5) 5 (45.5) 0.728
Pleural effusion 12 (32.4) 8 (30.8) 4 (36.4) 1
Lymphadenopathy 12 (32.4) 8 (30.8) 4 (36.4) 1
CT affected area, n (%) 0.688
Single 10 (27.0) 8 (30.8) 2 (18.2)
Double 27 (73.0) 18 (69.2) 9 (81.8)
Treatment, n (%)
Amphotericin B 22 (59.5) 15 (57.7) 7 (63.6) 1
Posaconazole 5 (13.5) 2 (7.7) 3 (27.3) 0.144
Isavuconazole 19 (51.4) 16 (61.5) 3 (27.3) 0.057
Suigery 4 (10.8) 4 (15.4) 0 (0) 0.296
Immune status, n (%) 0.014
Normal 15 (40.5) 14 (53.8) 1 (9.1)
Suppression 22 (59.5) 12 (46.2) 10 (90.9)
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Abbreviations: NGS: next-generation sequencing; WBC: white blood cells; NE: neutrophils; LY: lymphocyte; EOS: eosinophil; HB: hemoglobin; GM: galactomannan; CRP: C-reactive protein; PCT: procalcitonin; ALB: albumin.

The median age of the patients was 55.2 ± 16.2 years (22–84 years), and 67.6% of the cohort were male. Among the 37 patients with pulmonary mucormycosis, two also had concomitant rhino-orbital mucormycosis. The most common underlying condition was diabetes (n = 14, 37.8%), followed by hematological disorders (n = 11, 29.7%) and solid organ transplantation (n = 7, 18.9%). Of the seven patients who had undergone organ transplantation, five had received a renal transplant, and two had received a bone marrow transplant. Additionally, four patients (10.8%) had neutropenia. Up to 81% of patients with pulmonary mucormycosis had concurrent infections, including 3 with COVID-19, 1 with influenza A, 2 with rhinovirus, and 1 with Mycobacterium tuberculosis. Additionally, 9 patients had bacterial infections, 6 had aspergillosis, 3 had both viral and bacterial infections, and 5 had co-infections of bacteria and Aspergillus.

Clinical outcomes were assessed at 90 days post-diagnosis, with a 90-day mortality rate of 33.6% (11/37). No cases were lost to follow-up at the 90-day mark. Patients who had undergone organ transplantation appeared to have a significantly shorter survival time compared to those who had not received a transplant(P < 0.05). The clinical characteristics of pulmonary mucormycosis patients with different outcomes are detailed in Table 2.

The clinical manifestations of pulmonary mucormycosis were nonspecific. The most common symptoms included fever (70.3%) and cough (45.9%), followed by chest tightness (35.1%) and hemoptysis (29.7%). The median time from hospital admission to diagnosis was 13 days. Of the 37 patients, 31 (83.8%) had an acute course of disease (≤1 month), four (10.8%) had a subacute course (1–3 months), and two (5.4%) had a chronic course (>3 months). There were no significant differences in clinical symptoms or diagnostic levels between survivors and non-survivors (P > 0.05).

Computed tomographic presentation

The CT findings in patients with pulmonary mucormycosis are varied, including nodules, masses, cavities, consolidations, ground-glass opacities, reverse halo signs, and lymphadenopathy, as demonstrated in Fig 1A–1C. All patients underwent chest CT scans, as detailed in Table 2. Multiple lobar lesions were observed in 73.0% of the infections. The most common imaging findings included ground-glass infiltration (45.9%), nodules (48.6%), and patchy opacities (43.2%). Other notable imaging features were consolidation (40.5%), cavitary lesions (35.1%), reverse halo sign (40.5%), pleural effusion (32.4%), and lymphadenopathy (32.4%).

Fig 1. CT Imaging and histopathology in patients with pulmonary mucormycosis.

Fig 1

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(A) The red arrow indicates ground-glass opacity and a cavitary lesion centered on a mass in the upper lobe of the right lung, with surrounding consolidation and a reverse halo sign. (B) The blue arrow highlights the formation of a cavity within the lesion in the upper lobe of the right lung. (C) The green arrow points to a nodule exhibiting a halo sign. Bronchoscopic Images: (D) The orange arrow marks a nodular bulge. (E) The yellow arrow identifies the site of pathological sampling. Pathological Results: (F) Under PAS staining (400 × magnification), thick hyphae with minimal or no septa and right-angled branching between the hyphae are observed.

Histopathology and microbiology

The majority of patients underwent bronchoscopy. Fig 1D shows the bronchoscopic appearance of the airway mucosa in mucormycosis patients. Fig 1E depicts a nodular, neoplasm-like lesion along with necrotic material obstructing the right upper lobe bronchus. Bronchoscopy with bronchoalveolar lavage was performed in all cases, and the lavage fluid was sent for microbiological analysis. Nineteen of the 37 subjects were diagnosed using NGS. Among the nine patients confirmed with pulmonary mucormycosis, seven were diagnosed through bronchoscopic biopsy, and two were diagnosed via surgical biopsy of living tissue. Six patients were diagnosed via culture methods. The median time from admission to confirmed diagnosis was 13 days, ranging from 2 to 41 days. Depending on the sample type and laboratory conditions, we employed traditional culture methods, NGS, and histopathological examination for species identification of fungal genera. At the genus level, the identified species included Rhizopus (51.4%), Mucor (10.8%), and Rhizomucor (5.4%), along with other genera such as Rhizophthora (2.7%) and HDC fungi (2.7%). Additionally, eight isolates (21.6%) were classified as “unclassified Mucorales.”

Treatment and outcome

All patients received treatment, which included antifungal drugs, surgery, or a combination of both. Of the 37 patients, 13 were treated with amphotericin B lipid complex alone, 13 with isavuconazonium alone, 2 with posaconazole alone, 6 with a combination of amphotericin B lipid complex and isavuconazonium, 3 with a combination of amphotericin B lipid complex and posaconazole, and 4 underwent surgical treatment. In total, 11 patients (29.7%) died within 90 days of diagnosis. Among these, 9 patients succumbed to uncontrolled pulmonary mucormycosis, and 2 patients died due to massive hemoptysis. Fig 2 illustrates the progression of chest CT scans in a young male patient with diabetes who was diagnosed with pulmonary mucormycosis. The images show significant improvement following surgical intervention after initial antifungal therapy proved unsuccessful.

Fig 2. Imaging of a 26-year-old male patient with diabetes and pulmonary mucormycosis.

Fig 2

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(A) At admission, chest CT revealed a cavitary lesion in the upper lobe of the right lung, containing liquefied necrosis. (B) One week after admission, CT imaging showed an increase in the range of inflammatory lesions, with multiple small nodular lesions in the right lung. (C) One month after surgical treatment, the lesion was significantly reduced.

Predictive risk factors for outcome

In our study, 26 patients were discharged in stable condition, while 11 patients died. We compared the clinical data of survivors and non-survivors (Table 3). Univariate analysis of 90-day mortality identified several predictors of death: hypertension (HR = 3.36, 95% CI = 1.01–11.12, P = 0.048), organ transplantation (HR = 4.93, 95% CI = 1.48–16.4, P = 0.009), and immunosuppression (HR = 8.83, 95% CI = 1.13–69.14, P = 0.038). Immunosuppression significantly worsened the survival of pulmonary mucormycosis patients compared to those under immunocompetent conditions (Fig 3).

Table 3. Univariate Cox Regression analysis of 90-day mortality risk factors in patients with pulmonary mucormycosis.

Parameter HR (95%CI) P (Wald’s test)
Sex, female 1.31 (0.38,4.49) 0.663
Age 1.02 (0.98,1.06) 0.314
Hemoptysis 0.81 (0.22,3.06) 0.757
Diagnosis, confirmed diagnosis 0.27 (0.03,2.13) 0.215
Time from hospital admission to diagnosis 1.04 (0.98,1.09) 0.195
Diabetes 0.94 (0.27,3.21) 0.92
Hypertension 3.36 (1.01,11.12) 0.048
Hematological disorders 2.07 (0.63,6.8) 0.229
Organ transplant 4.93 (1.48,16.4) 0.009
WBC 0.97 (0.86,1.09) 0.601
NE 0.98 (0.86,1.11) 0.724
LY 0.4 (0.12,1.35) 0.139
HB 0.98 (0.96,1) 0.087
Concurrent infections 2.63 (0.34,20.55) 0.357
Immune status, suppression 8.83 (1.13,69.14) 0.038
CT affected area: double 1.59 (0.34,7.38) 0.552
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Fig 3. Kaplan-Meier Survival Analysis Based on Immune Status.

Fig 3

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The two groups represent patients stratified by their immune status at the time of admission. The survival curves illustrate differences in survival outcomes between these groups.

Discussion

Mucormycosis is an invasive fungal disease often overlooked due to its rarity, yet its rapid progression is associated with high mortality rates [13]. Its incidence has been rising in recent years [14], particularly in 2020 following the COVID-19 pandemic, which saw an abnormal spike in cases [15,16]. The all-cause mortality rate of mucormycosis ranges between 40% and 80%, depending on underlying conditions and the site of infection [3]. Historically, pulmonary mucormycosis had a mortality rate of 56–76% [17,18], but recent trends indicate a decrease to 29–38% [19–21]. In this study, 29.7% (11/37) of pulmonary mucormycosis patients died within 90 days after diagnosis, consistent with recent reports.

This decline in mortality may be attributed to improved recognition and diagnostic techniques, facilitating early identification and treatment. Advances in antifungal therapy, enhanced patient support, better management of immunosuppression in organ transplant patients, and multidisciplinary collaboration have also contributed to better outcomes. However, mucormycosis remains a significant health concern, requiring continuous surveillance and research.

In our study, the median age of the patients was 55.2 years, aligning with previous reports [22]. The majority of patients were male (67.6%), consistent with other regional studies [6]. A recent murine study suggested female mice had a stronger anti-infective capacity and a longer median survival time than male mice in the context of diabetic ketoacidosis mucormycosis [23]. Whether estrogen has a protective effect on mucormycosis infection requires further exploration.

The most common clinical symptoms of pulmonary mucormycosis are cough, fever, and hemoptysis, which are similar to those of other molds, as noted in previous studies [6,24]. Diabetes was the most common underlying condition in our cohort (37.8%), followed by hematologic malignancies (29.7%), reflecting national trends [17,25]. Previous literature has identified diabetes mellitus as a potential adverse prognostic factor for pulmonary mucormycosis. However, our study did not demonstrate a significant correlation between diabetes and pulmonary mucormycosis outcomes. This discrepancy may be attributed to the lack of investigation into glycemic control status in our current research. Future studies are warranted to elucidate the relationship between glycemic control and pulmonary mucormycosis prognosis, with particular attention to the potential impact of long-term blood glucose management on patient outcomes.

Although risk factors for pulmonary mucormycosis patients are well established, different studies have reported varying mortality risk factors. One study found that poor outcomes were prevalent among patients with prolonged neutropenia and those receiving empirical voriconazole [26]. In a Pakistani cohort, mortality was associated with immunosuppression, thrombocytopenia, or the need for mechanical ventilation [27]. In our study, we identified hypertension, organ transplantation, and immunosuppression as predictors of 90-day mortality in pulmonary mucormycosis patients, with immunosuppression emerging as a significant risk factor for death. This finding aligns with previous research emphasizing the host’s immune status as a key determinant of prognosis. However, in a study by Elzein et al., trauma was the primary risk factor, likely reflecting the specialized nature of the trauma center and the population studied, where most patients had normal immune function [28].

In the context of organ transplantation, the use of immunosuppressant drugs can weaken the body’s natural defenses, making patients more susceptible to infections like mucormycosis. While these drugs are essential for preventing organ rejection, they also contribute to increased mortality in pulmonary mucormycosis patients. Although diabetes is commonly recognized as a risk factor for pulmonary mucormycosis [29], it was not identified as a mortality risk factor in our cohort. Interestingly, despite the increased incidence of hypertension in diabetic populations, our study highlights hypertension as an independent and significant risk factor for mortality in pulmonary mucormycosis patients. Hypertension is often associated with a chronic inflammatory state, which may impair the activity and function of immune cells, leading to immune dysregulation and reduced capacity to clear pathogens, thereby weakening the body’s immune response. Additionally, patients with hypertension typically require long-term use of antihypertensive medications, some of which (e.g., beta-blockers or calcium channel blockers) may indirectly affect the immune system. However, the specific mechanisms underlying these effects require further investigation to validate and elucidate. Our study underscores the critical role of immune status in the prognosis of patients with pulmonary mucormycosis, emphasizing the importance of early intervention in high-risk patients.

In our cohort, only 16.2% of patients had positive microbial cultures, which is lower than the 78.78% reported by Abanamy et al. [30]. The low positive rate in our study may be due to the lack of molecular pathogen testing, as 51.4% of patients were diagnosed with pulmonary mucormycosis via NGS. NGS is more sensitive than traditional methods and significantly improves the diagnosis rate, though clinical settings must strengthen the interpretation of sequencing reports.

Mucormycosis imaging typically shows nodules, masses, consolidation, halo sign, reversed halo sign, and air crescent sign, all related to angioinvasion and tissue necrosis. These imaging changes are not specific to mucormycosis and overlay with those of invasive pulmonary aspergillosis, complicating the differentiation between the two. This is also a challenge in the imaging diagnosis of mucormycosis. Our study found that 81.1% of patients had coinfections with other pathogens, indicating the necessity for early identification and management of mixed infections.

Treatment options for mucormycosis remain very limited. Liposomal amphotericin B (LamB) combined with surgery is the recommended first-line treatment [31]. Only four patients underwent lobectomy in our study, so the benefits of combined antifungal and surgical could not be assessed. Multifocal lung involvement, present in 84.8% of our patients, limited surgical options, making early and effective antifungal treatment more crucial. Although combined antifungal and surgical debridement is common in other regions, such as in Saudi Arabia [30], the difference may be due to the higher prevalence of rhino-orbital-cerebral mucormycosis in those areas. Further research is needed to optimize the treatment strategies for different types of mucormycosis.

The study has limitations. It is retrospective, so not all information can be obtained from the medical records. We included patients who met the strict pulmonary mucormycosis definition and had detailed case information. Additionally, morphologically, mucormycosis cannot be completely distinguished from aspergillosis, and not all cases can be subjected to molecular testing. Additionally, This study carries a potential risk of misclassification within the genus Mucor. Indeed 8 cases were “unclassified” Mucorales but may also not be Mucorales at all, given the difficulties of anatomopathological identification. The limited sample size also reduces the statistical power of this analysis. Despite these limitations, future multicenter studies with more cases and advanced molecular testing will help identify host-related factors associated with poor outcomes.

Early diagnosis of mucormycosis is crucial, especially for immunosuppressed patients who are prone to secondary fungal infections with poor prognosis. When mucormycosis is suspected and tissue is available, NGS can be employed for accurate species identification, providing critical insights into the infection source. Early diagnosis, reversal of host factors, surgical resection of infected lesions, and timely antifungal treatment are key to improving outcomes. These four elements are essential throughout the diagnosis and treatment process, and more efforts must be made to promote management to improve patient outcomes.

Conclusion

Mucormycosis is a rare and often overlooked infection with a high mortality rate. Clinicians must enhance their recognition and management of mucormycosis, particularly in immunocompromised patients who are at higher risk for pulmonary mucormycosis. Definitive diagnosis relies on invasive histopathology and culture methods, while the use of molecular biology techniques in serum or tissue samples is emerging as an effective diagnostic tool. We recommend that when mucormycosis is suspected, appropriate samples should be collected promptly, and tests such as biopsy, culture, or NGS should be performed to confirm the diagnosis. Early diagnosis and timely administration of effective antimucormycotic therapy are vital for improving the prognosis of pulmonary mucormycosis patients.

Acknowledgments

None.

Data Availability

The data supporting this study cannot be made publicly available due to legal and ethical restrictions. However, researchers may request access to the data by contacting the Ethics Committee of the Second Hospital of Shandong University (Approval No. KYLL2024LW035) for approval. Data access requests should be sent to: 18366117163@163.com.

Funding Statement

The author(s) received no specific funding for this work.

References

  • 1.Hibbett DS, Binder M, Bischoff JF, Blackwell M, Cannon PF, Eriksson OE, et al. A higher-level phylogenetic classification of the Fungi. Mycol Res. 2007;111(Pt 5):509–47. doi: 10.1016/j.mycres.2007.03.004 [DOI] [PubMed] [Google Scholar]
  • 2.Denning DW. Global incidence and mortality of severe fungal disease. Lancet Infect Dis. 2024;24(7):e428–38. doi: 10.1016/S1473-3099(23)00692-8 [DOI] [PubMed] [Google Scholar]
  • 3.Cornely OA, Alastruey-Izquierdo A, Arenz D, Chen SCA, Dannaoui E, Hochhegger B, et al. Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium. Lancet Infect Dis. 2019;19(12):e405–21. doi: 10.1016/S1473-3099(19)30312-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Skiada A, Pavleas I, Drogari-Apiranthitou M. Epidemiology and diagnosis of mucormycosis: an update. J Fungi. 2020;6. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Chamilos G, Lewis RE, Kontoyiannis DP. Delaying amphotericin B-based frontline therapy significantly increases mortality among patients with hematologic malignancy who have zygomycosis. Clin Infect Dis. 2008;47(4):503–9. doi: 10.1086/590004 [DOI] [PubMed] [Google Scholar]
  • 6.Skiada A, Pagano L, Groll A, Zimmerli S, Dupont B, Lagrou K, et al. Zygomycosis in Europe: analysis of 230 cases accrued by the registry of the European Confederation of Medical Mycology (ECMM) Working Group on Zygomycosis between 2005 and 2007. Clin Microbiol Infect. 2011;17(12):1859–67. doi: 10.1111/j.1469-0691.2010.03456.x [DOI] [PubMed] [Google Scholar]
  • 7.Lanternier F, Dannaoui E, Morizot G, Elie C, Garcia-Hermoso D. A global analysis of mucormycosis in France: the retrozygo study (2005-2007). Clin Infect Dis. 2012;54(Suppl 1):S35-43. [DOI] [PubMed] [Google Scholar]
  • 8.Sun H-Y, Aguado JM, Bonatti H, Forrest G, Gupta KL, Safdar N, et al. Pulmonary zygomycosis in solid organ transplant recipients in the current era. Am J Transplant. 2009;9(9):2166–71. doi: 10.1111/j.1600-6143.2009.02754.x [DOI] [PubMed] [Google Scholar]
  • 9.Muthu V, Agarwal R, Dhooria S, Sehgal I, Prasad K. Has the mortality from pulmonary mucormycosis changed over time? A systematic review and meta-analysis. Clin Microbiol Infect. 2021;27:538–49. [DOI] [PubMed] [Google Scholar]
  • 10.Pagano L, Ricci P, Tonso A, Nosari A, Cudillo L, Montillo M, et al. Mucormycosis in patients with haematological malignancies: a retrospective clinical study of 37 cases. GIMEMA Infection Program (Gruppo Italiano Malattie Ematologiche Maligne dell’Adulto). Br J Haematol. 1997;99(2):331–6. doi: 10.1046/j.1365-2141.1997.3983214.x [DOI] [PubMed] [Google Scholar]
  • 11.Casutt A, Lamoth F, Lortholary O, Prior JO, Tonglet A. Atypical imaging patterns during lung invasive mould diseases: lessons for clinicians. Eur Respir Rev. 2023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Skiada A, Lass-Floerl C, Klimko N, Ibrahim A, Roilides E, Petrikkos G. Challenges in the diagnosis and treatment of mucormycosis. Med Mycol. 2018;56(suppl_1):93–101. doi: 10.1093/mmy/myx101 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Cornely O, Arikan-Akdagli S, Dannaoui E, Groll A, Lagrou K. Escmid and ecmm joint clinical guidelines for the diagnosis and management of mucormycosis 2013. Clin Microbiol Infect. 2014;20(Suppl 3):5–26. [DOI] [PubMed] [Google Scholar]
  • 14.Petrikkos G, Skiada A, Drogari-Apiranthitou M. Epidemiology of mucormycosis in Europe. Clin Microbiol Infect. 2014;20 Suppl 6:67–73. doi: 10.1111/1469-0691.12563 [DOI] [PubMed] [Google Scholar]
  • 15. Garg D, Muthu V, Sehgal IS, Ramachandran R, Kaur H, et al. Coronavirus Disease (Covid-19) Associated Mucormycosis (CAM): case report and systematic review of literature. Mycopathologia. 2021;186:289–98. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.Patel A, Agarwal R, Rudramurthy S, Shevkani M, Xess I. Multicenter epidemiologic study of coronavirus disease-associated mucormycosis, India. Emerg Infect Dis. 2021;27:2349–59. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Roden M, Zaoutis T, Buchanan W, Knudsen T, Sarkisova T. Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis. 2005;41:634–53. [DOI] [PubMed] [Google Scholar]
  • 18.Lee FY, Mossad SB, Adal KA. Pulmonary mucormycosis: the last 30 years. Arch Intern Med. 1999;159(12):1301–9. doi: 10.1001/archinte.159.12.1301 [DOI] [PubMed] [Google Scholar]
  • 19.Feng J, Sun X. Characteristics of pulmonary mucormycosis and predictive risk factors for the outcome. Infection. 2018;46(4):503–12. doi: 10.1007/s15010-018-1149-x [DOI] [PubMed] [Google Scholar]
  • 20.Legouge C, Caillot D, Chrétien ML, Lafon I, Ferrant E, Audia S, et al. The reversed halo sign: pathognomonic pattern of pulmonary mucormycosis in leukemic patients with neutropenia?. Clin Infect Dis. 2014;58(5):672–8. doi: 10.1093/cid/cit929 [DOI] [PubMed] [Google Scholar]
  • 21.Lin E, Moua T, Limper AH. Pulmonary mucormycosis: clinical features and outcomes. Infection. 2017;45(4):443–8. doi: 10.1007/s15010-017-0991-6 [DOI] [PubMed] [Google Scholar]
  • 22.Hoenigl M, Seidel D, Carvalho A, Rudramurthy SM, Arastehfar A, Gangneux J-P, et al. The emergence of COVID-19 associated mucormycosis: a review of cases from 18 countries. Lancet Microbe. 2022;3(7):e543–52. doi: 10.1016/S2666-5247(21)00237-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Gebremariam T, Alkhazraji S, Alqarihi A, Wiederhold N, Najvar L. Evaluation of sex differences in murine diabetic ketoacidosis and neutropenic models of invasive mucormycosis. J Fungi. 2021;7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Qu J, Liu X, Lv X. Pulmonary mucormycosis as the leading clinical type of mucormycosis in Western China. Front Cell Infect Microbiol. 2021;11:770551. doi: 10.3389/fcimb.2021.770551 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Liu W, Liu J, Song Y, Zeng X, Wang X. Burden of lymphoma in China, 2006-2016: an analysis of the global burden of disease study 2016. J Hematol Oncol. 2019;12:115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Son H-J, Song JS, Choi S, Jung J, Kim MJ, Chong YP, et al. Risk factors for mortality in patients with pulmonary mucormycosis. Mycoses. 2020;63(7):729–36. doi: 10.1111/myc.13092 [DOI] [PubMed] [Google Scholar]
  • 27.Khalid R, Khanum I, Habib K, Ali A, Farooqi J. Clinical characteristics, outcome, and factors associated with mortality of pulmonary mucormycosis: a retrospective single-center study from Pakistan. Ther Adv Infect Dis. 2024;11:20499361241251744. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Elzein F, Albarrag A, Kalam K, Arafah M, Al-Baadani A, Eltayeb N, et al. Mucormycosis: an 8-year experience of a tertiary care centre in Saudi Arabia. J Infect Public Health. 2020;13(11):1774–9. doi: 10.1016/j.jiph.2020.08.002 [DOI] [PubMed] [Google Scholar]
  • 29.Khanna M, Challa S, Kabeil AS, Inyang B, Gondal FJ, Abah GA, et al. Risk of mucormycosis in diabetes mellitus: a systematic review. Cureus. 2021;13(10):e18827. doi: 10.7759/cureus.18827 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Abanamy R, Alsaud A, Alabdulali R, Alsobaie M, Alalwan B, Aljohani S, et al. Clinical characteristics and outcome of mucormycosis: a multi-center retrospective analysis in Saudi Arabia over 11 years. IJID Reg. 2022;4:152–6. doi: 10.1016/j.ijregi.2022.07.004 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Meena DS, Kumar D, Bohra GK. Combination therapy in Mucormycosis: Current evidence from the world literature, a mini review. J Mycol Med. 2023;33(1):101332. doi: 10.1016/j.mycmed.2022.101332 [DOI] [PMC free article] [PubMed] [Google Scholar]

Decision Letter 0

Felix Bongomin

18 Mar 2025

PONE-D-24-59709Diagnosis, Clinical Features, and Mortality Risk Factors in a Chinese Cohort with Pulmonary MucormycosisPLOS ONE

Dear Dr. Xu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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Felix Bongomin, MB ChB, MSc, MMed, FECMM

Academic Editor

PLOS ONE

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PLoS One. 2025 May 16;20(5):e0323624. doi: 10.1371/journal.pone.0323624.r003

Author response to Decision Letter 0

26 Mar 2025

Esteemed Editors and Reviewers,

We extend our heartfelt gratitude for your thorough review and invaluable feedback on our manuscript titled "Diagnosis, Clinical Features, and Mortality Risk Factors in a Chinese Cohort with Pulmonary Mucormycosis" (Manuscript Number: PONE-D-24-59709). In accordance with the suggestions provided by the reviewers and editors, we have meticulously revised our manuscript. Herein, we address each of the reviewers' comments point by point. It is our sincere hope that these revisions meet the journal's standards and contribute to the enhancement of the manuscript's overall quality.

1.Reviewer's Responses to Questions and Comments to the Author

Questions 1: Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

Author's reply: Thank you to the reviewers for their positive feedback on our research. We have ensured that all experimental designs and data analyses adhere to the rigorous standards of scientific research, and all conclusions are data-driven. In the revised manuscript, we have further clarified the details of the experimental methods and data analysis to ensure the reliability of our conclusions.

Questions 2: Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Author's reply: We have re-examined all statistical analysis procedures and ensured their appropriateness and rigor. All statistical methods have been described in detail.

Questions 3: Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: No

Author's reply: Since the data involves patient privacy, we are unable to disclose the original data. However, we have updated the data availability statement in the revised manuscript, detailing the reasons for the data restrictions and providing avenues for data access. Specifically, the data can be made available upon reasonable request and with approval from the ethics committee. We have provided the contact information for the ethics committee as required by the journal.

Questions 4: Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Author's reply: We have conducted a comprehensive language polish on the manuscript to ensure it adheres to standard English writing conventions. All grammatical and spelling errors have been corrected, and the manuscript has been proofread by a professional English editor.

Questions 5: Review Comments to the Author

Reviewer #1: The manuscript is well organized and contributes valuable findings on pulmonary mucormycosis. It provides valuable insights into pulmonary mucormycosis. The manuscript is is systematically presented and well-written overall.

Author's reply: We extend our gratitude to the reviewers for their overall positive assessment of our manuscript. In accordance with the reviewers' suggestions, we have further refined the manuscript, particularly in the areas of data analysis and interpretation of results. We are confident that the revised manuscript is now more lucid and rigorous.

2. Additional Editor Comments

Comments 1: Please write pulmonary mucormycois in full, all through the manuscript.

Author's reply: We have ensured that "pulmonary mucormycosis" is written out in full throughout the manuscript, accompanied by its abbreviation in parentheses, to maintain terminological consistency.

Comments 2: Structure your abstract ... and describe variables in both frequency and %, also include all effect sizes , 95%CI and p-value.

Author's reply: We have structured the abstract according to the editor's suggestions and supplemented the frequencies, percentages, effect sizes, 95% confidence intervals, and p-values for all variables. The revised abstract is more comprehensive and clearer.

Comments 3: Cite major papers eg Denning et al Lancet ID for burden of IFI including mucormycosis and the systematic review that inform WHO priority fungal pathogen list.

Author's reply: We have supplemented our references with the work of Denning et al. on the burden of fungal infections and have cited the systematic review that informed the WHO's priority list of fungal pathogens. These citations further bolster the context and significance of our research.

3.Other revisions

We have adjusted the manuscript according to the journal's formatting requirements to ensure it aligns with the PLOS ONE format template. We have updated the data availability statement, detailing the reasons for data restrictions and providing access pathways to the data. We have reviewed and updated the reference list to ensure its completeness and accuracy. All cited references are up-to-date and have not been retracted.

We believe that these revisions have adequately addressed the comments from the reviewers and editors, significantly enhancing the quality of the manuscript. We look forward to your further feedback.

Attachment

Submitted filename: Response to Reviewers.docx

pone.0323624.s002.docx (14KB, docx)

Decision Letter 1

Felix Bongomin

31 Mar 2025

PONE-D-24-59709R1Diagnosis, Clinical Features, and Mortality Risk Factors in a Chinese Cohort with Pulmonary MucormycosisPLOS ONE

Dear Dr. Xu,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by May 15 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Felix Bongomin, MB ChB, MSc, MMed, FECMM

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Additional Editor Comments:

DEAR AUTHORS

CHECK THE SPELLING OF MUCORMYCOSIS --THROUGH OUT THE MANUSCRIPT

DEFINE COVID-19 IN FULL IN FIRST USE

DEFINE HR AND CI IN THE ABSTRACT IN THE FIRST

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

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PLoS One. 2025 May 16;20(5):e0323624. doi: 10.1371/journal.pone.0323624.r005

Author response to Decision Letter 1

1 Apr 2025

Esteemed Editors and Reviewers,

We extend our heartfelt gratitude for your thorough review and invaluable feedback on our manuscript titled "Diagnosis, Clinical Features, and Mortality Risk Factors in a Chinese Cohort with Pulmonary Mucormycosis" (Manuscript Number: PONE-D-24-59709). In accordance with the suggestions provided by the reviewers and editors, we have meticulously revised our manuscript. Herein, we address each of the reviewers' comments point by point. It is our sincere hope that these revisions meet the journal's standards and contribute to the enhancement of the manuscript's overall quality.

1.Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

Re: We have reviewed the reference list to ensure its completeness and accuracy. All cited references are up-to-date and have not been retracted.

2.CHECK THE SPELLING OF MUCORMYCOSIS --THROUGH OUT THE MANUSCRIPT

Re: We have thoroughly checked the manuscript and corrected the spelling of "mucormycosis" throughout. It is now consistent and accurate.

3.DEFINE COVID-19 IN FULL IN FIRST USE

Re: We have defined "COVID-19" in full as "Coronavirus Disease 2019" at its first mention in the manuscript, as per your request.

4.DEFINE HR AND CI IN THE ABSTRACT IN THE FIRST

Re: We have defined "HR" (Hazard Ratio) and "CI" (Confidence Interval) in full at their first occurrence in the abstract.

We believe that these revisions have adequately addressed the comments from the reviewers and editors, significantly enhancing the quality of the manuscript. We look forward to your further feedback.

Attachment

Submitted filename: Response_to_Reviewers_auresp_2.docx

pone.0323624.s003.docx (12.3KB, docx)

Decision Letter 2

Felix Bongomin

11 Apr 2025

Diagnosis, Clinical Features, and Mortality Risk Factors in a Chinese Cohort with Pulmonary Mucormycosis

PONE-D-24-59709R2

Dear Dr. Xu,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Felix Bongomin, MB ChB, MSc, MMed, FECMM

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Felix Bongomin

PONE-D-24-59709R2

PLOS ONE

Dear Dr. Xu,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

You will receive further instructions from the production team, including instructions on how to review your proof when it is ready. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few days to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Felix Bongomin

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    Attachment

    Submitted filename: Response to Reviewers.docx

    pone.0323624.s002.docx (14KB, docx)
    Attachment

    Submitted filename: Response_to_Reviewers_auresp_2.docx

    pone.0323624.s003.docx (12.3KB, docx)

    Data Availability Statement

    The data supporting this study cannot be made publicly available due to legal and ethical restrictions. However, researchers may request access to the data by contacting the Ethics Committee of the Second Hospital of Shandong University (Approval No. KYLL2024LW035) for approval. Data access requests should be sent to: 18366117163@163.com.

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