Clinical Characteristics and Risk Factors for Nontuberculous Mycobacterial Pulmonary Disease with Chronic Pulmonary Aspergillosis in Patients

1. Introduction

Nontuberculous mycobacterial pulmonary disease (NTM-PD) is a chronic respiratory infection whose prevalence has sharply increased worldwide, affecting both high- and low-income settings.[1] In China, the Mycobacterium avium complex (MAC) and Mycobacterium abscessus complex (MABC) dominate the epidemiological landscape, col lectively accounting for approximately 84% of all culture-positive cases (MAC≈61% vs MABC≈23%).[2] NTM-PD caused by MABC and MAC is notoriously challenging to treat, with cure rates of only 36.1%-56.1% and 68.1%, respectively.[3,4,5] Therefore, identifying risk factors associated with treatment outcomes is essential to enhance the success rates of NTM-PD.

Chronic pulmonary aspergillosis (CPA) is a slowly progressive infection caused by As- pergillus species. Previous studies have explored CPA as a complication of NTM-PD. [6] It is also one of the most common complications following the treatment of pulmonary tuberculosis.[7] Recent years have seen an increase in the incidence of NTM-PD accompanied by CPA. CPA is associated with disease progression, elevated mortality rates, and increased therapeutic complexity. [8,9,10,11]

However, the majority of published data originate from Japan,[12] where MAC ac- counts for the overwhelming majority of NTM-PD isolates. Data from other regions, which exhibit different distributions of NTM species, are limited. Thus, we performed a retrospective analysis of NTM-PD patients in China, a setting in which MAC remains common but MABC comprises a substantially larger proportion of cases.

2. Materials and Methods

2.1. Ethical Approval

This study was approved by the ethics committee of Beijing Chest Hospital, Capital Medical University (YJS-2025-16).

2.2. Patients

This study reviewed the medical records of adult patients (≥18 years) diagnosed with NTM-PD at Beijing Chest Hospital from January 2022 to December 2024. All the patients met the diagnostic criteria for NTM-PD, based on the guidelines by the ATS/ERS/ESCMID/IDSA.[13] We excluded patients who: (1) did not receive antibiotic treatment; (2) underwent no testing for fungal pathogens; (3) were diagnosed with CPA prior to NTM-PD; or (4) received subsequent treatment at another facility. [Figure 1].

2.3. Study Design

This was a retrospective cohort study. Clinical data including age, sex, smoking history, drinking history, body mass index (BMI), complications, symptoms, use of steroid, laboratory data, isolated mycobacterial species, radiographic features, and treatment history were collected from the patients’ medical records. Patient follow-up was conducted until September 30, 2025. We defined overall survival as the duration from the diagnosis of NTM-PD until death or censoring. Use of steroids was defined as a daily dose of more than 10 mg or a cumulative dose of more than 700 mg of oral prednisolone or a long-term inhaled steroid [14,15].

2.4. Diagnosis of Chronic Pulmonary Aspergillosis (CPA)

The diagnostic criteria for Chronic Pulmonary Aspergillosis encompass the following components:

1) Clinical Symptoms: The presence of respiratory symptoms, including unexplained cough, sputum production, or hemoptysis, persisting for three months or longer.

2) Radiological Features (Chest imaging revealing one or more of the following): (I)Progressive enlargement of a cavity (II)An intracavitary fungal ball (aspergilloma) (III)Pleural thickening, fibrosis, or infiltrates surrounding the cavity

3) Microbiological or Serological Evidence (Laboratory confirmation of Aspergillus infection, demonstrated by at least one of the following):

(I) A positive test for Aspergillus-specific IgG antibodies (II) Direct microscopy of a respiratory tract specimen showing hyphae consistent with Aspergillus (III) A positive culture for Aspergillus from respiratory specimens on at least two separate occasions (IV) Histopathological examination of lung tissue indicating Aspergillus infection. [16,17]

2.5. Statistical Analysis

All data are presented as median [interquartile range (IQR)] for continuous variables and as number (percentage) for categorical variables. The data were compared using the Mann-Whitney U test for continuous variables, and the Fisher’s exact test for categorical variables. Multiple logistic regression was performed to identify independent risk factors, which were pre-specified based on clinical relevance as well as findings from prior studies. Results are presented as adjusted odds ratios with 95% confidence intervals (CIs). A p-value < 0.05 was considered statistically significant. Survival analysis was performed using the Kaplan-Meier method, with groups compared by the log-rank test. The Cox proportional hazards model was also utilized for further analysis. Statistical analyses were conducted using R (version 4.4.2; The R Foundation for Statistical Computing, Vienna, Austria).

3. Results

3.1. Patient Characteristics

A total of 248 patients with NTM-PD were included in the study (Figure 1). The me dian observation period was 30 months (interquartile range [IQR]: 20.75-42 months). Among these patients, 66 were diagnosed with CPA during the observation period. This group included 12 cases diagnosed concurrently with NTM-PD and 54 cases diagnosed subsequently. The median time from NTM-PD to CPA diagnosis was 14 months (IQR: 4-26.75) (Figure 2). During the observation period, 59 out of the 66 patients diagnosed with CPA underwent antifungal therapy.

Regarding the distribution of NTM species, MAC accounted for 64.5% of the cases, while MABC represented 27.8%. One patient with CPA was co-infected with both MAC and MABC, and one patient without CPA was co-infected with M. xenopi and M. chelonae. These two cases were categorized into a mixed infection group. Other identified species included M. xenopi (n=7, with 3 developing CPA), M. kansasii (n=8, with 3 developing CPA), M.gordonae (n=1, with CPA), and M.scrofulaceum (n=1, with 1 case of CPA).

Compared with the non-CPA group, the CPA group demonstrated significant differ ences (P < 0.05) in age, sex, BMI, smoking history, interstitial lung disease (ILD), chronic obstructive pulmonary disease (COPD), corticosteroid use, NTM species, radiographic cavitation, dyspnea, fever and laboratory tests. The baseline clinical characteristics of the both groups are presented in Table 1.

3.2. Risk Factors for Aspergillus Coinfection

To determine the risk factors for NTM-PD with CPA coinfection, we compared the baseline data of 182 patients diagnosed NTM-PD without CPA and 66 patients with CPA. The univariate logistic regression analysis showed that Age>60, Male, BMI<18.5 kg/m^2, smoking, drinking, COPD, ILD, dyspnea, fever, cavity, diabetes, inhaled corticosteroids, oral corticosteroids, lower albumin and hemoglobin levels and elevated ESR and CRP levels were associated with the condition. In the multivariate analysis, male sex(p=0.041), dyspnea(p<0.001), cavity(p<0.001), oral corticosteroids(p=0.032), ILD(p=0.008) were identified as independent risk factors. [Table 2]

3.3. Survival Analysis for All-Cause Mortality

During the follow-up period, 20 patients (8.1%) died. Mortality was significantly higher in the NTM-CPA group compared to the NTM group (19.7% [13/66] vs. 3.8% [7/182]). Kaplan-Meier analysis revealed a statistically significant difference in survival between the two groups (log-rank test, p=0.00039). [Figure 3] Univariate Cox regression analysis demonstrated a significant association between CPA and higher mortality in NTM-PD patients (hazard ratio[HR] 4.63, 95% CI:1.83-11.71, p=0.001). However, this association was not statistically significant after adjustment for potential confounders (HR 2.01, 95% CI:0.66-6.12, p=0.217).[Table S1]

4. Discussion

In this single-centered retrospective study, we aimed to assess the clinical characteristics, risk factors and prognosis of NTM-PD coinfected CPA in China. The incidence of CPA was 26.6% (66/248). We identified male sex, ILD, the symptom of dyspnea, cavity on imaging, and oral corticosteroids as independent risk factors for CPA in NTM-PD patients. These findings hold significant clinical value for identifying high-risk populations and facilitating early diagnosis and intervention.

In our study, the observed comorbidity rate of CPA was 26.6%, which was substantially higher than that previously reported (2.3%-16.0%). [8,9,10,11,12,18,19,20] This discrepancy may be attributed to regional variations and inclusion standards. Our study included patients diagnosed with both NTM-PD and CPA simultaneously. As a large tuberculosis specialty hospital, Beijing Chest Hospital typically admits patients with more severe or refractory NTM-PD. Previous studies have reported cavity as a significant factor contributing to CPA. In our cohort, the prevalence of cavity (50%) was notably higher compared to rates documented in prior research (18.6%-33.6%).[8,9,10,11,20] This likely serves as the primary reason for the elevated prevalence of CPA in our cohort. Furthermore, the transfer of patients to local institutions for follow-up treatment could introduce bias, potentially contributing to the higher observed rate of CPA in our study.

Previous studies have identified several risk factors for CPA in patients with NTM-PD, including male sex, the use of systemic corticosteroids, cavity, chronic respiratory failure, and interstitial pneumonia. Corticosteroids suppress the activity and function of immune cells, thereby compromising the host’s ability to resist fungal infections. With prolonged or high-dose administration, the immune system’s capacity to recognize and eliminate fungi is diminished, allowing commensal or environmental fungi to initiate an active infection. In NTM-PD, the presence of cavities not only serves as a marker of disease severity but also creates a favorable niche for Aspergillus colonization and the subsequent formation of aspergillomas.[21] ILD is a well-established independent risk factor for CPA.[22] ILD causes extensive architectural distortion and pulmonary fibrosis, often accompanied by traction bronchiectasis. ILD provides the structural groundwork, while NTM infection may further exacerbate local inflammation and epithelial damage, with both processes acting in concert to promote the development of CPA. Dyspnea may reflect poorer baseline pulmonary function, broader disease extent, or greater structural damage in these patients. These findings suggest that these patients likely represent a subgroup with more severe NTM-PD, thereby exhibiting increased susceptibility to opportunistic infections such as CPA. Male sex emerged as a risk factor in our cohort, aligning with prior data; this may be attributable to factors such as sex hormones, a higher burden of smoking-related lung disease, and specific ILD subtypes in men. The exact pathophysiology requires further elucidation.

While several studies have identified COPD/emphysema, and MABC pulmonary disease as significant risk factors for CPA in NTM-PD patients, our analysis did not establish them as independent predictors in our cohort. [8,10,11] This discrepancy may be attributed to the broad diagnostic spectrum of emphysema as a heterogeneous entity, suggesting that our cohort may have included patients with relatively milder disease. Different types of underlying lung disease possess distinct predisposing potentials for CPA, and in our cohort, other factors may have outweighed the contribution of COPD and emphysema. Regarding mycobacterial species, there are two main points to consider. Firstly, the previous study only assessed the type of bacteria at the onset of treatment. Given that NTM-PD treatment is lengthy, the prolonged treatment itself may have altered the condition of the lungs and even the predominant mycobacterial species. [8] Secondly, our study had a relatively small sample size. Therefore, larger, meticulously designed studies that control for established strong confounders are necessary to definitively ascertain the independent role of specific NTM species.

In China, coinfection with NTM-PD and CPA has rarely been reported. This can be partly attributed to the fact that the Aspergillus IgG antibody test has only become widely available in many hospitals in recent years. The Aspergillus IgG antibody test demonstrated high sensitivity and specificity for diagnosing CPA.[23] In this study, the Aspergillus IgG antibody test was available for 212 patients (85.5%) out of a total cohort of 248.

Consistent with prior studies, our findings also indicate that patients with concurrent NTM-PD and CPA experience worse outcomes.[8,9,10,11,19] Therefore, early identification and treatment are particularly important. The therapeutic management of CPA includes antifungal therapy, surgical intervention, and interventional procedures such as intracavitary instillation and bronchial artery embolization. A course of voriconazole or itraconazole lasting six months or longer is recommended to control infection, delay pulmonary fibrosis, prevent hemoptysis, and improve quality of life.[17] In patients with tuberculosis and CPA, studies have reported that a six-month course of voriconazole is associated with superior efficacy and a lower one-year relapse rate. [24] Furthermore, the combination of antifungal therapy and surgery has achieved a cure rate as high as 93.02%, which is significantly higher than that in the nonsurgical group, along with a lower recurrence rate.

Our study has several limitations. Firstly, the retrospective, single-center design may introduce potential biases. Secondly, the follow-up period was relatively short. Given that both NTM-PD and CPA are chronic diseases, it is possible that some patients may develop CPA in the future. Thirdly, we excluded some patients with mild symptoms or those who did not undergo fungal testing—individuals who are generally less likely to develop CPA—which may have led to an overestimation of the infection rate. Finaly, due to the limited number of cases, we did not investigate the relationships among CPA subtypes, treatment regimens and patient prognosis. Future studies could focus on the aforementioned aspects.

5. Conclusions

In conclusion, our study revealed that male sex, dyspnea, cavity, oral corticosteroids and interstitial lung disease are independent risk factors for CPA coinfection in patients with NTM- PD. Additionally, concurrent CPA is associated with a significant increase in mortality. Clinicians should maintain a high index of suspicion for CPA to ensure early diagnosis and treatment, particularly in high-risk individuals.