ABSTRACT
Background and Aims
The optimal management strategy for newly diagnosed pulmonary ground‐glass nodules (GGNs) with suspected inflammatory etiology remains controversial in clinical practice. Empirical anti‐inflammatory therapy is commonly used, but its efficacy compared with that of follow‐up observation lacks high‐quality evidence. Therefore, this study aims to compare the effectiveness of empirical anti‐infective therapy and follow‐up observation for pulmonary GGNs in real‐world settings.
Methods
This study intends to include 254 participants with newly discovered pulmonary ground‐glass opacities (GGOs) suspected to be related to inflammation but without current radiographic features suggestive of malignancy. Antibiotics will be recommended when the doctor considers the GGOs may be infection‐related. Upon enrollment, all participants will be assessed with the Self‐Rating Anxiety Scale (SAS) and divided into either the intervention or observation group. A repeat CT scan and SAS assessment will be conducted with all participants after 1 month ( ± 2 weeks) following the initial discovery of the GGOs. The primary outcome is the participants' response rate at the first follow‐up CT. The secondary outcome is the GGO response rate and total scores of SAS at 1 month after enrollment. A non‐inferiority test will be conducted to compare the outcomes between the two groups.
Discussion
To date, the efficacy and necessity of using antibiotics for GGOs suspected to be inflammatory upon primary CT screening remain controversial. This protocol describes the rationale and methodology to address this unmet clinical need using real‐world data, aiming to bridge the gap between clinical guidelines and real‐world practice.
Trial Registration: ChiCTR2200056975.
Keywords: anti‐inflammatory therapy, follow‐up observation, ground‐glass nodules, real‐world data
Summary
This is a novel, prospective observational study focusing on a relatively underexplored area in the management of ground‐glass opacities (GGOs) with suspected inflammatory etiology.
In this study, we aim to address the potential benefits of empirical anti‐infective treatment in reducing unnecessary surgical interventions and antibiotic misuse in patients with inflammatory GGOs.
We employed a comprehensive approach in designing this study, incorporating not only the clinical effectiveness of the intervention but also the psychological impact on patients.
1. Introduction
The recent widespread application of spiral computed tomography (CT) in chest examinations has facilitated the identification of ground‐glass opacities (GGOs). Reports suggest that the detection rate of GGOs in asymptomatic individuals undergoing baseline CT screening is approximately 9.2% [1]. Based on the degrees of uniformity of the internal components of GGOs on CT images, GGOs are divided into pure GGOs (pGGOs) without solid components and mixed GGOs (mGGOs) with solid components [2]. The differential diagnoses of GGOs include infection, bleeding, focal fibrosis, organizing pneumonia, and lung neoplasm [3]; approximately 85% of primary lung cancers present as GGOs [4]. One study reported that, in approximately 45% of detected opacities, GGOs either shrank or disappeared after a follow‐up of 3 months [5]. Additionally, in Asian populations, 30% of GGOs identified during initial screening and 78.9% of new GGOs nodules detected during re‐examination resolved spontaneously [6]. These cases were predominantly considered to be inflammation‐related [5]. Therefore, assessing the nature of these GGOs, that is, whether they are benign or malignant, is crucial for pulmonary nodule management. Surgery is the main treatment method for malignant pulmonary nodules (PNs) [7]. However, surgery often brings many postoperative symptoms and interferes with daily functioning [8, 9, 10, 11]; hence, distinguishing benign from malignant PNs as accurately as possible is necessary [9, 12, 13, 14].
The role of antibiotics in the clinical management of newly identified GGOs remains controversial. In cases where an inflammatory diagnosis cannot be excluded, several guidelines in China have recommended that these patients should first receive anti‐infective treatment, followed by re‐examination 1 month later [15, 16]. However, these guidelines do not further elaborate on relevant studies to support the implementation of such recommendations. The Clinical Practice Consensus Guidelines for Asia support using an empirical anti‐infective treatment for GGOs [17] despite a lack of high‐level evidence to support this approach. Furthermore, other guidelines do not mention the use of anti‐infective treatment in managing GGOs [18, 19, 20].
Previous studies have investigated the effects of antibiotic treatment on GGOs, but their results have been inconsistent and limited by methodological weaknesses, such as the absence of control groups and the retrospective nature of the studies [21, 22, 23]. Moreover, these studies have not addressed the potential risks of antibiotic misuse, which is a serious concern [21, 22, 23].
Therefore, our study aims to investigate the effects of observation versus the use of anti‐infective treatment on GGOs detected de novo by chest CT. We hypothesize that an observational strategy will not be inferior to the use of anti‐infective therapy in terms of clinical outcomes, and the findings of this study will contribute to a more evidence‐based approach for managing newly identified GGOs. Furthermore, we hope to clarify the appropriate role of antibiotics in managing GGOs, thereby minimizing the risk of antibiotic misuse.
2. Methods
2.1. Study Design and Patients
This multicenter prospective cohort study uses a non‐inferiority design in real‐world settings. We will enroll patients with GGOs (including patients with pGGOs and mGGOs) newly identified on chest CT and with suspected inflammatory characteristics. The enrolled patients will have GGOs with features suggestive of a possible inflammatory etiology, and the malignant nature of the nodules will not be considered at this stage. This criterion will provide clinicians with a rationale for using antibiotics to manage these patients.
2.1.1. Inclusion Criteria
Age ≥ 18 years;
GGOs (including pGGOs and mGGOs) were first detected by chest CT, with a GGO diameter > 5 and ≤ 20 mm;
Clinically advised for observation and follow‐up;
Willing to participate in the study; and
Having or not having comorbidities, including past respiratory infections.
2.1.2. Exclusion Criteria
GGOs identified for the first time > 2 weeks before screening and
Antibiotic use within 2 weeks before enrollment.
2.1.3. Withdrawal Criteria
Failure to cooperate or complete the study as planned,
Requesting withdrawal from the study,
Antibiotics use for < 5 days in the anti‐infective group or antibiotic use during the follow‐up period in the observation group,
CT images with severe respiratory movement artifacts preventing measurement of GGOs, and
Any condition that necessitates withdrawal from the study as deemed appropriate by the investigator.
2.2. Study Setting
This study was initiated at Jiangyou People's Hospital and has since commenced in five tertiary hospitals in China, including one county hospital (Jiangyou People's Hospital), three prefecture‐level hospitals (The Third People's Hospital of Chengdu, Chengdu Seventh People's Hospital, and Zigong First People's Hospital), and one provincial hospital (Sichuan Cancer Hospital). The study enrolled its first participant on March 14, 2022, and is expected to be completed in December 2024.
2.3. Ethical Approval
The study will be conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics committees of Jiangyou People's Hospital (No. JY‐2022‐0003), the Medical Research and New Medical Technology of Sichuan Cancer Hospital, Third People's Hospital of Chengdu, Seventh People's Hospital of Chengdu, and Zigong First People's Hospital. Written informed consent was obtained from all individual participants.
2.4. Sample Size Calculation
A non‐inferiority test was used to calculate the sample size using data from existing literature [22]. The non‐inferiority margin was set as 0.1, α as 0.05, β as 0.2, the anti‐inflammatory effectivity rate as 33%, and the effectivity rate in the observation group as 27%, yielding a sample size requirement of 101 participants per group. Considering a 20% loss to follow‐up, a total of 254 participants (127 per group) need to be enrolled.
2.5. Group and Intervention Allocation
Specific criteria, including radiological features (e.g., presence of centrilobular nodules, tree‐in‐bud pattern), laboratory infection markers (e.g., elevated white blood cell count, C‐reactive protein levels), and relevant medical history (e.g., recent respiratory infection, fever), will be applied to determine the likelihood of infection‐related GGOs. Patients who fulfill the eligibility criteria and present GGOs with features suggestive of a possible infection will be requested to provide written informed consent and allocated either to the intervention or to the observation group, according to the individual participant's choice. This approach ensures that both groups have a similar distribution of infection‐related GGOs, minimizing the risk of bias in comparing intervention outcomes. In the intervention group, empirical anti‐infection treatment is administered after group allocation [21]. In the observation group, patients will receive regular follow‐ups without anti‐infective treatment. Data for both the intervention and observation groups will be obtained through the same standardized methods to ensure consistency.
In this study, we have established more specific guidelines for antibiotic use in the intervention group. Because this is a real‐world observational study, the type and duration of antibiotics used will be determined jointly by the patient's attending doctor and the patient, following relevant national and international clinical guidelines and expert consensus. The commonly used antibiotics include oral levofloxacin hydrochloride (500 mg once daily for 7–10 days) and oral cephalosporins, such as cefuroxime axetil (250–500 mg twice daily for 10 days) or cefdinir (300 mg twice daily for 10 days). The dosage will be determined by doctors based on the specific type of drug used, as well as the patient's age, height, weight, and liver and kidney function. Patients will be provided with enough oral antibiotics for the entire treatment duration and instructed on how to use them. Patients will take these antibiotics home and return to the hospital 1 month later. We will instruct patients mainly by phone and messaging application (WeChat). The time and type of antibiotics used will be recorded and included in the final analysis. The observation group will undergo follow‐up observation without receiving any antibiotic treatment. Patients requiring alternative antibiotic treatment outside the study's predetermined options will not be included. This approach ensures strict indications and standards for the use of antibiotics, minimizing the risk of antibiotic misuse. A flowchart of this study is presented in Figure 1.
Figure 1.
Study flow diagram.
2.6. Outcome Measures
The measurement parameters for the scheduled CT will be as follows: reconstructed image section thickness of 0.625−1.25 mm; lung window widths of 1500−1600 HU and window levels of −650 to −600 HU; and mediastinal window widths of 350−380 HU and window levels of 25−40 HU. The longest diameter of the pGGOs and solid components on CT images will be measured in the lung window, whereas the longest diameter of the solid components will be measured in the mediastinal window.
In all patients in this study, anxiety will be evaluated using the Self‐Rating Anxiety Scale (SAS) at the time of enrollment and reassessed 1 month after enrollment. All patients will also undergo a repeat chest CT at 1 month ( ± 2 weeks) after enrollment. The scores of SAS in the initial and repeat assessment and the size of GGOs and their solid components in the initial and repeat CTs will be compared. Each GGO will be described as either increasing or decreasing in size, unchanged, or completely resorbed. When multiple nodules are noted upon enrollment, only the characteristics of the three largest nodules will be assessed. One attending thoracic surgeon and an attending radiologist will independently assess each nodule follow‐up result; a senior radiologist will resolve any disagreement.
Treatment of the GGOs with antibiotic therapy will be deemed effective (“GGO response”) if any of the following three criteria are met [6]: (1) a ≥ 2 mm decrease in the maximum diameter of the GGOs (lung window measurement); (2) a ≥ 2 mm decrease in the maximum diameter of the solid component in mGGOs (lung window measurement); or (3) disappearance of the solid component in mGGOs (mediastinal window measurement). Otherwise, treatment for GGO will be considered as “failed to respond.” If a participant had only one GGO requiring evaluation, a “responder” will be defined similarly to a “GGO response.” In contrast, if a participant has two or more GGOs for evaluation, then “responder” will be defined as having any GGO that meets the criteria of “GGO response.”
The SAS will be used to assess the anxiety state of the patients. The SAS adopts a four‐grade score, which mainly evaluates the frequency of symptoms defined by the items. The scoring points are “1” for no or little time, “2” for a small part of the time, “3” for a considerable amount of the time, and “4” for most or all of the time. The SAS applies to adults with anxiety symptoms and has a wide range of applicability [24, 25]; the main statistical indicator of the SAS is the total score. After being assessed by self‐evaluation, the scores of each of the 20 items will be added together and then multiplied by 1.25 to obtain a whole number, and the standard score will be obtained. The cutoff value of the SAS standard score is 50 points, with scores of 50–59 classified as mild anxiety, 60–69 as moderate anxiety, and 70 or more as severe anxiety [24, 25] The primary outcome measure is the patients' response rate (number of responders/total number of participants), whereas the secondary outcome measure is the GGO response rate (number of responded GGOs/total number of evaluated GGOs) and the total SAS score.
2.7. Data Collection, Management, and Monitoring
The data to be collected include demographic information, baseline clinical information, date of CT scan, date of clinical assessment, clinical symptoms, size of the target nodule(s) (maximum diameter of the largest slice), density (partially solid and non‐solid), change in nodule appearance on CT (including nodule size and density), final diagnosis of each nodule, type and duration of antibiotic use, and SAS scores at enrollment and first review. Data for both the intervention and observation groups will be obtained from electronic medical record systems or via telephone follow‐up. SAS data will be collected via paper questionnaires, electronic questionnaires, or telephone follow‐ups according to the participants' preferences. Participants will be instructed to complete questionnaires independently unless they require assistance.
This study will use an electronic data capture (EDC) system for data management [26]. Each site and research staff member will have separate accounts, permissions, and passwords. All data will be entered and tracked in the EDC system. The data manager will organize the trial design, establish the database, prepare the standard operating procedure (SOP), train the investigator, manage data daily, and ensure data security.
2.8. Quality Control
To ensure the quality and consistency of the study across multiple centers, research personnel will be trained in following standardized treatment protocols and operating procedures before the study begins. Research personnel at all sites will receive online or on‐site guidance, process monitoring, and supervision from quality control personnel regularly. This will ensure that all participating institutions and researchers adhere to the same treatment plans and quality control mechanisms.
Quality control personnel will be responsible for performing data checks every 3 months, including checks for data integrity and accuracy. After patient follow‐up, the quality control personnel will check the entire database. In addition to data quality, they will monitor the implementation of standardized treatment protocols and ensure that all participating centers comply with the established guidelines.
The quality control personnel will also be responsible for independently supervising the study's conduct and for monitoring the study's progress to ensure that the study's methods, content, and data collection are performed in strict accordance with the study protocol. The responsible investigator will assess study data that deviate from the study plan to ensure that alterations are subsequently made to meet the study requirements. This comprehensive quality control approach will help minimize inconsistencies in treatment and data collection across participating centers, ensuring reliable and accurate statistical results.
2.9. Data Analysis
All data included in the analysis will be collected from patients who meet the inclusion criteria. Continuous variables with a normal distribution will be presented as mean ± standard deviation, whereas those without a normal distribution will be presented as median and interquartile range. Categorical variables will be presented as counts, percentages, or proportions. Baseline characteristics and other relevant data will be compared between the intervention and observation groups.
For continuous variables, the t‐test will be employed to analyze normally distributed data, whereas the Mann−Whitney U test will be utilized for data that does not follow a normal distribution. Chi‐square tests and Fisher's exact tests will be used for comparing categorical variables, and adjustments will be made for potential confounders during data analysis.
A one‐sided p < 0.05 will be considered statistically significant. All analyses will be conducted using SAS 9.4 (SAS Institute Inc., Cary, NC) software.
Author Contributions
Study conception and design: Wenhong Feng, Tao He, Yuanqiang Zhang, Wei Dai, Qiuling Shi, Rui Zhang, and Xing Wei. Drafting of the abstract: Wenhong Feng, Tao He, Yuanqiang Zhang, Rui Zhang, and Xing Wei. Critical revision of the article for important intellectual content: Wenhong Feng, Tao He, Yuanqiang Zhang, Yunfei Mu, Yang Pu, Ying Liu, Zhangning Ouyang, Hangao Song, Yuanqiang Zhang, Hong Lu, Yanglin Zhou, Ping Zou, Gang Yang, Honggang Tian, Jianglin Jin, Gaoyu Liang, Lin Yang, Laian Zhang, Ying Liu, Wei Dai, Haomiao Qing, Jingyu Zhang, Qiuling Shi, Qiang Li, Ding Yang, Rui Zhang, and Xing Wei. Final approval of the version to be published: Wenhong Feng, Tao He, Yuanqiang Zhang, Yunfei Mu, Yang Pu, Yangjun Liu, Zhangning Ouyang, Hangao Song, Yuanqiang Zhang, Hong Lu, Yanglin Zhou, Ping Zou, Gang Yang, Honggang Tian, Jianglin Jin, Gaoyu Liang, Lin Yang, Laian Zhang, Ying Liu, Wei Dai, Haomiao Qing, Jingyu Zhang, Qiuling Shi, Qiang Li, Ding Yang, Rui Zhang, and Xing Wei. Funding acquisition: jingyu Zhang and Xing Wei. Administrative, technical, or material support: Ying Liu, Wei Dai, Haomiao Qing, Qiuling Shi, Qiang Li, Rui Zhang, and Xing Wei. All authors have read and approved the final version of the manuscript.
Conflicts of Interest
The authors declare no conflicts of interest.
Transparency Statement
The lead author Rui Zhang, Xing Wei affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.
Acknowledgments
We would like to thank Changping Liu from the Department of Thoracic Surgery of Jiangyou People's Hospital for his support in writing this study protocol. We would also like to thank Dong Yuan for his supporting in the revision of this protocol. This work was supported by the Natural Science Foundation of Sichuan Province (No. 2023NSFSC1047). The funding bodies played no role in the design of the study.
Wenhong Feng, He Tao, and Yuanqiang Zhang are co‐first authors.
Dr. Xing Wei and Dr. Rui Zhang contributed equally to this work as co‐corresponding authors.
Contributor Information
Rui Zhang, Email: richard9047@qq.com.
Xing Wei, Email: xing.wei@scszlyy.org.cn.
Data Availability Statement
The authors are willing to share data, analytic methods, and study materials related to this article with other researchers provided that all of the above will not be used for commercial or profit purposes. Other researchers can contact the corresponding author of this article by email and indicate the required research materials and purpose. We will be glad to provide relevant materials for this study after approval and discussion. Wenhong Feng and Xing Wei had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The authors are willing to share data, analytic methods, and study materials related to this article with other researchers provided that all of the above will not be used for commercial or profit purposes. Other researchers can contact the corresponding author of this article by email and indicate the required research materials and purpose. We will be glad to provide relevant materials for this study after approval and discussion. Wenhong Feng and Xing Wei had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.