Abstract
Background
Cryobiopsy is used in addition to conventional sampling during endobronchial ultrasound (rEBUS)-guided bronchoscopy for peripheral pulmonary lesions (PPLs) to improve diagnostic yield. However, the incremental risk of procedure-related pulmonary infection remains poorly quantified in routine clinical practice.
Methods
We retrospectively analyzed consecutive patients who underwent rEBUS-guided bronchoscopy for PPLs between January 2019 and March 2022. Patients were categorized into those undergoing combined conventional biopsy and cryobiopsy and those undergoing conventional biopsy alone. Pulmonary infectious complications occurring within 4 weeks after bronchoscopy were assessed. Propensity score matching was performed to adjust for baseline differences and to evaluate the impact of cryobiopsy on pulmonary infectious complications. Sensitivity analyses using overlap weighting were also conducted.
Results
After propensity score matching, 756 patients were included in the matched cohort (combined cryobiopsy group: n = 252; conventional biopsy group: n = 504). Pulmonary infectious complications occurred more frequently in the combined cryobiopsy group than in the conventional biopsy group (4.8% vs. 1.8%). Adding cryobiopsy was associated with an increased risk of pulmonary infectious complications (odds ratio, 2.84; 95% confidence interval, 1.15–6.99; P = 0.023), corresponding to an absolute risk increase of 3.0% and a number needed to harm of 33. These findings were consistent in sensitivity analyses using overlap weighting.
Conclusions
Adding cryobiopsy to conventional sampling in rEBUS-guided bronchoscopy is associated with a higher risk of pulmonary infectious complications. These findings provide quantitative evidence to guide patient selection and procedural planning.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12931-026-03715-1.
Keywords: Bronchoscopy, Cryobiopsy, Peripheral pulmonary lesion, Post-bronchoscopy pulmonary infection, Radial endobronchial ultrasound
Background
Bronchoscopic techniques for diagnosing peripheral pulmonary lesions (PPLs) have evolved substantially [1, 2]. Cryobiopsy has gained increasing attention as a tissue sampling technique for PPLs, as it enables the retrieval of specimens that are larger and less crushed than those obtained through conventional forceps biopsy. In clinical practice, cryobiopsy is often combined with other bronchoscopic sampling techniques to enhance diagnostic yield, and it is useful for molecular analyses, including next-generation sequencing and programmed death-ligand 1 expression assessment [3–9].
Despite these advantages, cryobiopsy is associated with procedure-related complications, particularly bleeding and pneumothorax, owing to the greater tissue volume obtained compared with conventional biopsy techniques [10, 11]. In contrast, pulmonary infectious complications following cryobiopsy have received relatively little attention, and available data regarding their incidence and risk factors remain limited. Post-bronchoscopic pulmonary infections are clinically significant because they may delay the initiation of lung cancer treatment or necessitate modification or interruption of planned therapy.
Previous studies of rEBUS-guided transbronchial biopsy have reported pulmonary infectious complication rates ranging from 0.5% to 6.1% [12–16]. However, whether the addition of cryobiopsy to conventional biopsy techniques increases the risk of post-procedural pulmonary infection remains unexamined. Moreover, no previous study has directly compared biopsy strategies while accounting for differences in patient and lesion characteristics encountered in routine clinical practice.
This study aimed to evaluate the risk of pulmonary infectious complications following rEBUS-guided bronchoscopy for PPLs and determine whether adding cryobiopsy to conventional biopsy techniques is associated with an increased risk of post-procedural pulmonary infection.
Methods
Study design and population
This retrospective observational study was conducted at the National Cancer Center Hospital, Tokyo, Japan. We reviewed consecutive patients who underwent rEBUS-guided bronchoscopy for PPLs between January 2019 and March 2022, using a prospectively maintained bronchoscopy registry. Patients were excluded if follow-up data were insufficient to ascertain pulmonary infection status within 4 weeks of bronchoscopy, or if antibiotics had already been initiated for a pre-existing pulmonary infection before the procedure.
The study period partially overlapped with several previously published studies from our institution [17–20]. However, those studies focused on diagnostic efficacy or procedural safety outcomes of cryobiopsy, such as diagnostic yield, performance in ground-glass opacity lesions, use of a single-use cryoprobe, or outcomes in older patients. None of these prior studies evaluated pulmonary infectious complications as a primary or secondary endpoint or assessed the incremental risk associated with adding cryobiopsy to conventional biopsy techniques. Therefore, the objectives and analytic framework of the present study are distinct.
This study was approved by the Institutional Review Board of the National Cancer Center Hospital (No. 2018 − 354) and registered in the Japan Registry of Clinical Trials (jRCT1032190168). The requirement for written informed consent was waived due to the study’s retrospective design.
Data collection
Clinical data were obtained from two sources: a prospectively maintained bronchoscopy registry and electronic medical records. From the bronchoscopy registry, we extracted patient demographics (age, sex, smoking history, and smoking index), radiologic characteristics of the target lesion on chest computed tomography (CT) (lesion size, lobar location, and lesion location from the hilum), bronchoscopic findings at the responsible bronchus (including bronchial stenosis, tumor exposure, and suspected bronchial invasion), and procedure-related variables. Procedure-related variables included biopsy strategy (conventional biopsy alone or combined conventional biopsy with cryobiopsy), rebiopsy status, sampling devices used, number of biopsy specimens obtained, use of a guide sheath, and final diagnoses.
Additional radiologic and clinical variables not captured in the registry were extracted from electronic medical records. These included the presence of a low-density area (LDA) within the lesion, cavitation, and obstructive pneumonic consolidation distal to the lesion on chest CT, as well as comorbidities (chronic obstructive pulmonary disease and interstitial lung disease), use of systemic corticosteroids or other immunosuppressive agents, ongoing anticancer therapy within 3 weeks before bronchoscopy, and pre-procedural laboratory data, including white blood cell (WBC) count, C-reactive protein (CRP) level, and serum albumin level. Detailed clinical courses were reviewed for patients who developed pulmonary infectious complications.
Definitions
Pulmonary infectious complications were defined as events occurring within 4 weeks of bronchoscopy that met al.l of the following criteria: (1) new onset or worsening of respiratory or systemic symptoms lasting ≥ 24 h; (2) elevation of WBC count or CRP compared with baseline; and (3) new or progressive infiltrative findings on chest radiography or CT requiring antibiotic treatment [14].
Pulmonary infectious complications were classified as intratumoral infection, lung abscess, pneumonia, pleurisy, or pyothorax according to previously defined criteria [14]. Intratumoral infection was defined as lesion enlargement accompanied by internal LDA or cavity expansion. Lung abscess was defined as newly developed perilesional consolidation progressing to cavitation or LDA formation. Pleurisy was defined as a neutrophil-predominant pleural effusion without lung parenchymal abscess formation, whereas pyothorax required microbiological evidence of infection within the pleural space. Pneumonia was defined as new infiltrative or consolidative changes around the target lesion.
Rebiopsy was defined as a biopsy performed after systemic anticancer therapy to assess histological or molecular changes.
Bronchoscopic procedures
All bronchoscopic procedures were performed under moderate-to-deep sedation with intravenous sedatives (midazolam or propofol) and/or opioids (fentanyl or pethidine), as previously described [3, 17–20]. An endotracheal tube (Portex® Uncuffed Ivory PVC, Oral/Nasal Tracheal Tube 8.0-mm; Smiths Medical, Minneapolis, MN, USA) was routinely placed in patients undergoing cryobiopsy. A flexible bronchoscope (BF-P260F, BF-P290, BF-1T260, or BF-1TQ290; Olympus, Tokyo, Japan) was advanced to the target bronchus. Lesion localization was confirmed using a 1.4- or 1.7-mm rEBUS probe (UM-S20-17 S or UM-S20-20 S; Olympus) under X-ray fluoroscopic guidance. Conventional biopsy, including forceps biopsy, transbronchial needle aspiration, and bronchial brushing, was performed at the discretion of the bronchoscopist. Cryobiopsy was performed using a 1.7-, 1.9-, or 2.4-mm cryoprobe in combination with ERBECRYO®2 (ERBE, Tübingen, Germany), with a freezing time of 3–5 s. Bleeding after cryobiopsy was managed using the 2-scope technique [11]. The selection of biopsy devices, the number of biopsy specimens, the use of a guide sheath, and the administration of prophylactic antibiotics were determined at the bronchoscopist’s discretion. Patients were routinely followed up 5–14 days post-bronchoscopy, with additional evaluations performed if infectious symptoms were suspected.
Statistical analysis
In this study, two complementary analyses were performed: an evaluation to identify risk factors for pulmonary infectious complications among patients who underwent cryobiopsy, which informed covariate selection, and a comparison between conventional biopsy alone and combined conventional biopsy and cryobiopsy to evaluate the impact of adding cryobiopsy. Categorical variables are presented as numbers (%) and continuous variables as medians (interquartile range [IQR]). Group comparisons were performed using Pearson’s chi-square test or Fisher’s exact test for categorical variables, and the Mann–Whitney U test for continuous variables.
To identify risk factors for pulmonary infectious complications among patients who underwent cryobiopsy, univariable logistic regression analysis was conducted. Given the limited number of pulmonary infectious events, multivariable analysis using Firth penalized logistic regression was performed as a sensitivity analysis to reduce small-sample bias. Covariates were selected a priori based on clinical relevance and previous literature, and included LDA on CT, abnormal bronchoscopic findings, lesion size (continuous), rebiopsy, and prophylactic antibiotic use as potential effect modifiers [12–16].
To determine whether adding cryobiopsy to conventional biopsy increased the risk of pulmonary infection, patients who underwent conventional biopsy alone were compared with those who underwent combined conventional and cryobiopsy. Propensity scores were estimated using a multivariable logistic regression model including age, sex, smoking index, lesion size, CT features (LDA, cavity, and obstructive pneumonic consolidation), abnormal bronchoscopic findings, comorbidities (chronic obstructive pulmonary disease and interstitial lung disease), immunocompromised status (use of systemic corticosteroids or other immunosuppressive agents, ongoing anticancer therapy), rebiopsy status, WBC count, CRP level, and albumin level. Patients were matched at a 1:2 ratio using nearest-neighbor matching with a caliper width of 0.2 standard deviations of the propensity score. Covariate balance was assessed using standardized mean differences (SMDs), with values < 0.1 indicating adequate balance. The association between biopsy strategy and pulmonary infectious complications was assessed using conditional logistic regression. As a sensitivity analysis, overlap weighting based on the propensity score was additionally performed to estimate the average treatment effect in the overlap population.
All statistical analyses were performed using EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). A two-sided P-value < 0.05 was considered statistically significant.
Results
Study population
A total of 1,999 patients who underwent rEBUS-guided bronchoscopy during the study period were identified after excluding patients with insufficient follow-up or pre-existing pulmonary infection requiring antibiotics (Fig. 1). Among these patients, 268 underwent combined conventional biopsy with cryobiopsy, and 1,497 underwent conventional biopsy alone (Additional file 1). For analyses focusing on post-cryobiopsy pulmonary infectious complications, all 502 patients who underwent cryobiopsy were identified and evaluated.
Fig. 1.
Study flowchart and cohort selection. Flowchart illustrating patient selection for the analysis of pulmonary infectious complications following rEBUS-guided bronchoscopy for peripheral pulmonary lesions. Patients were categorized according to biopsy strategy (conventional biopsy alone or combined conventional biopsy plus cryobiopsy). Propensity score matching was performed to create comparable groups for assessment of the incremental infection risk associated with adding cryobiopsy. rEBUS: radial endobronchial ultrasound
Pulmonary infectious complication risk factors
Among the 502 patients who underwent cryobiopsy, pulmonary infectious complications occurred in 21 patients (4.2%). Baseline characteristics of patients with and without pulmonary infectious complications are summarized in Additional file 2.
In univariable logistic regression analysis, several factors were significantly associated with infectious complications following cryobiopsy, including smoking history, receipt of anticancer therapy, rebiopsy, elevated CRP levels, larger lesion size, the presence of an LDA on CT, and abnormal bronchoscopic findings (Additional file 3).
Given the limited number of infectious events, a Firth penalized multivariable logistic regression analysis was performed as a sensitivity analysis (Additional file 4). In this model, LDA on CT remained independently associated with pulmonary infectious complications (adjusted odds ratio [OR] 5.35, 95% confidence interval [CI] 1.37–19.15, P = 0.016), whereas prophylactic antibiotic use showed a significant protective association (adjusted OR 0.21, 95% CI 0.04–0.81, P = 0.024).
Pulmonary infection risk and cryobiopsy
Baseline characteristics of patients who underwent combined conventional biopsy and cryobiopsy (combined cryobiopsy group) and those who underwent conventional biopsy alone (conventional biopsy group) are shown in Table 1. Several clinically relevant variables differed between the two groups before adjustment. After 1:2 propensity score matching, a well-balanced cohort of 756 patients was generated (combined cryobiopsy group, n = 252; conventional biopsy group, n = 504), with standardized mean differences < 0.1 for all covariates.
Table 1.
Baseline characteristics of patients undergoing conventional biopsy alone and combined conventional biopsy with cryobiopsy
| Variables | Total cohort (N = 1,765) | Propensity score–matched cohort (N = 756) | ||||||
|---|---|---|---|---|---|---|---|---|
| Combined cryobiopsy group (n = 268) | Conventional biopsy group (n = 1,497) | P-value | SMD | Combined cryobiopsy group (n = 252) | Conventional biopsy group (n = 504) | P-value | SMD | |
| Age, years | 67 (53–74) | 69 (60–75) | 0.001 | 0.267 | 68 (54–74) | 66 (56–74) | 0.699 | 0.006 |
| Sex, male | 133 (49.6) | 838 (56.0) | 0.062 | 0.127 | 125 (49.6) | 234 (46.4) | 0.440 | 0.064 |
| Smoking index, pack-years | 13.0 (0–33.25) | 20.0 (0–47.00) | 0.003 | 0.210 | 12.55 (0–36.55) | 6.50 (0–36.25) | 0.758 | 0.060 |
| Chronic obstructive pulmonary disease | 54 (20.1) | 421 (28.1) | 0.007 | 0.187 | 52 (20.6) | 99 (19.6) | 0.773 | 0.025 |
| Interstitial lung disease | 5 (1.9) | 77 (5.1) | 0.017 | 0.179 | 5 (2.0) | 8 (1.6) | 0.769 | 0.03 |
| Receiving corticosteroids or immunosuppressants | 8 (3.0) | 23 (1.5) | 0.124 | 0.098 | 6 (2.4) | 13 (2.6) | 1.000 | 0.013 |
| Receiving anticancer therapy | 20 (7.5) | 209 (14.0) | 0.003 | 0.211 | 18 (7.1) | 29 (5.8) | 0.523 | 0.057 |
| Rebiopsy | 16 (6.0) | 295 (19.7) | < 0.001 | 0.420 | 16 (6.3) | 35 (6.9) | 0.878 | 0.024 |
| WBC, count/µL | 6,000 (4,900–7,825) | 6,200 (5,100–7,600) | 0.835 | 0.115 | 6,000 (4,900–7,700) | 6,100 (5,100–7,525) | 0.993 | 0.022 |
| CRP, mg/dL | 0.07 (0.03–0.29) | 0.11 (0.04–0.38) | 0.008 | 0.132 | 0.07 (0.03–0.26) | 0.08 (0.03–0.35) | 0.062 | 0.152 |
| Albumin, g/dL | 4.3 (4.0–4.5) | 4.2 (3.9–4.4) | < 0.001 | 0.132 | 4.3 (4.0–4.5) | 4.3 (4.0–4.5) | 0.766 | 0.004 |
| Lesion size, mm | 25.6 (17.8–40.1) | 25.6 (17.2–37.5) | 0.345 | 0.124 | 24.5 (17.5–36.6) | 24.9 (16.8–37.7) | 0.923 | 0.033 |
| LDA on CT | 51 (19.0) | 407 (27.2) | 0.005 | 0.194 | 44 (17.5) | 98 (19.4) | 0.554 | 0.052 |
| Cavity on CT | 3 (1.1) | 119 (7.9) | < 0.001 | 0.333 | 3 (1.2) | 8 (1.6) | 1.000 | < 0.001 |
| Obstructive pneumonic consolidation on CT | 5 (1.9) | 71 (4.7) | 0.033 | 0.161 | 5 (2.0) | 12 (2.4) | 0.801 | 0.027 |
| Abnormal bronchoscopic findings | 46 (17.2) | 276 (18.4) | 0.668 | 0.033 | 40 (15.9) | 86 (17.1) | 0.756 | 0.032 |
| Prophylactic antibiotics | 37 (13.8) | 222 (14.8) | 0.708 | 0.029 | 31 (12.3) | 54 (10.7) | 0.542 | 0.050 |
Data are presented as n (%) or as median (interquartile range)
SMD Standardized mean difference, WBC white blood cell count, CRP C-reactive protein, LDA low-density area, CT computed tomography
In the matched cohort, pulmonary infectious complications occurred more frequently in the combined cryobiopsy group than in the conventional biopsy group (4.8% vs. 1.8%), corresponding to an absolute risk increase of 3.0% and a number needed to harm (NNH) of 33 (Fig. 2a). Conditional logistic regression analysis demonstrated that the addition of cryobiopsy was significantly associated with an increased risk of pulmonary infectious complications (OR 2.84, 95% CI 1.15–6.99, P = 0.023; Fig. 2b). This association remained consistent in a sensitivity analysis using overlap weighting (OR 3.20, 95% CI 1.31–7.81).
Fig. 2.
Risk of pulmonary infectious complications associated with the addition of cryobiopsy. a Incidence of pulmonary infectious complications in the propensity score-matched cohort. Patients who underwent combined conventional biopsy and cryobiopsy had a higher absolute risk of pulmonary infection than those who underwent conventional biopsy alone, corresponding to an absolute risk increase of 3.0% and a number needed to harm of 33. b Forest plot showing the association between biopsy strategy and pulmonary infectious complications. In conditional logistic regression analysis of the matched cohort, the addition of cryobiopsy was associated with a significantly increased risk of pulmonary infectious complications. This association remained consistent in sensitivity analyses using overlap weighting. Odds ratios and 95% confidence intervals are shown on a logarithmic scale. NNH: number needed to harm, OR: odds ratio, CI: confidence interval
Clinical characteristics and outcomes
Clinical characteristics and outcomes of pulmonary infectious complications in the total and matched cohorts are summarized in Table 2. The distribution of infection types and the severity of infectious complications did not differ significantly between the two groups in the matched cohort. Although the median time to onset and initiation of antibiotic therapy tended to be shorter in the combined cryobiopsy group, these differences were not statistically significant after matching. The impact of pulmonary infectious complications on subsequent cancer treatment, including treatment delay or modification, was comparable between groups.
Table 2.
Characteristics and outcomes of pulmonary infectious complications in the total and propensity score-matched cohorts
| Variables | Pulmonary infectious complications in the total cohort (N = 70) |
Pulmonary infectious complications in the propensity score–matched cohort (N = 21) |
||||
|---|---|---|---|---|---|---|
| Combined cryobiopsy group (n = 14) | Conventional biopsy group (n = 56) | P-value | Combined cryobiopsy group (n = 12) | Conventional biopsy group (n = 9) | P-value | |
| Type of infectious complications | 0.011 | 0.229 | ||||
| Intratumoral infection | 6 (42.9) | 16 (28.6) | 6 (50.0) | 2 (22.2) | ||
| Pyothorax | 3 (21.4) | 5 (8.9) | 2 (16.7) | 1 (11.1) | ||
| Lung abscess | 2 (14.3) | 17 (30.4) | 1 (8.3) | 4 (44.4) | ||
| Pleurisy | 2 (14.3) | 0 (0) | 2 (16.7) | 0 (0) | ||
| Pneumonia | 1 (7.1) | 18 (32.1) | 1 (8.3) | 2 (22.2) | ||
| Clinical course | ||||||
| Time to onset, days | 4 (2.00–6.75) | 7.5 (3.00–15.00) | 0.070 | 3 (2.00–6.25) | 5 (2.00–12.00) | 0.345 |
| Time to antibiotic initiation, days | 7.5 (4.75–16.00) | 12 (7.75–18.00) | 0.109 | 7.5 (6.25–17.25) | 12 (11.00–15.00) | 0.455 |
| Severity | ||||||
| Oral antibiotic treatment only | 5 (35.7) | 19 (33.9) | 1.000 | 4 (33.3) | 5 (55.6) | 0.396 |
| Intravenous antibiotic treatment required | 9 (64.3) | 37 (66.1) | 1.000 | 8 (66.7) | 4 (44.4) | 0.396 |
| Chest tube drainage required | 3 (21.4) | 8 (14.3) | 0.681 | 3 (25.0) | 1 (11.1) | 0.603 |
| Surgical treatment required | 1 (7.1) | 3 (5.4) | 1.000 | 1 (8.3) | 1 (11.1) | 1.000 |
| ICU admission | 0 (0) | 1 (1.8) | 1.000 | 0 (0) | 0 (0) | NA* |
| Mortality | 0 (0) | 0 (0) | NA* | 0 (0) | 0 (0) | NA* |
| Influence on subsequent cancer treatment | ||||||
| No influence | 3/13 (21.4) | 12/53 (24.0) | 1.000 | 2/12 (16.7) | 2/8 (25.0) | 1.000 |
| Delayed | 11/13 (78.6) | 37/53 (66.1) | 0.524 | 10/12 (83.3) | 6/8 (75.0) | 1.000 |
| Anticancer drug treatment | 9/13 (64.3) | 25/53 (44.6) | 0.238 | 8/12 (66.7) | 5/8 (62.5) | 1.000 |
| Surgery | 2/13 (14.3) | 10/53 (20.0) | 1.000 | 2/12 (16.7) | 1/8 (12.5) | 1.000 |
| Radiation therapy | 0/13 (0) | 2/53 (3.6) | 1.000 | 0/12 (0) | 0/8 (0) | NA* |
| Cancelled | 0/13 (0) | 1/53 (1.8) | 1.000 | 0/12 (0) | 0/8 (0) | NA* |
Data are presented as n (%) or as median (interquartile range)
WBC white blood cell count, CRP C-reactive protein, LDA low-density area, CT computed tomography, ICU intensive care unit, NA not applicable
*Statistical comparison not performed due to zero events
Discussion
In this study, we investigated pulmonary infectious complications following rEBUS-guided bronchoscopy for PPLs, with a specific focus on the incremental risk of adding cryobiopsy to conventional sampling. We demonstrated that pulmonary infectious complications occurred at a clinically relevant frequency after cryobiopsy and, importantly, the risk of infection was significantly higher when cryobiopsy was added to conventional biopsy techniques. This association remained robust after propensity score matching and was consistently observed in sensitivity analyses using overlap weighting, providing quantitative evidence that the addition of cryobiopsy confers a meaningful increase in procedure-related pulmonary infection risk in routine clinical practice.
First, we evaluated risk factors for pulmonary infectious complications in patients undergoing cryobiopsy. In our cohort, the overall incidence of pulmonary infection after cryobiopsy was 4.2%, higher than that previously reported (0%–3.0%) [3–11, 17–20]. This difference may be attributable to variations in patient selection, procedural strategies, and post-procedural surveillance. In particular, the systematic follow-up for up to 4 weeks after bronchoscopy in the present study might have facilitated the detection of clinically relevant pulmonary infections that could have been underestimated in earlier studies, which were primarily focused on diagnostic yield or immediate procedural safety [17].
Consistent with prior findings of post-bronchoscopic pulmonary infection, radiologic and bronchoscopic features reflecting a locally infection-prone environment–specifically, LDA on CT and abnormal bronchoscopic findings–were strongly associated with pulmonary infectious complications [13–16, 21, 22]. These features likely reflect underlying intralesional inflammation, necrosis, or airway obstruction; conditions that may predispose patients to infection following tissue sampling. Rebiopsy was associated with an increased risk of pulmonary infection in univariable analyses, suggesting that previously treated or biologically altered lesions may be particularly vulnerable to infection, regardless of biopsy modality.
The most important and novel finding of this study is the quantitative demonstration that adding cryobiopsy to conventional biopsy is associated with an increased risk of post-procedural pulmonary infection. In the propensity score-matched cohort, the combined biopsy strategy was associated with an approximately 2.7-fold increase in the odds of pulmonary infectious complications, corresponding to an absolute risk increase of 3.0% and an NNH of 33. These estimates indicate that adding cryobiopsy is associated with a higher risk of pulmonary infection and should be considered when weighing diagnostic benefit against procedural risk in routine practice.
Several mechanisms may underlie the increased risk of pulmonary infection observed with the combined biopsy strategy. The addition of cryobiopsy requires repeated instrumentation and causes more extensive tissue injury than conventional sampling alone, potentially exacerbating local inflammation and impairing host defense mechanisms. The observed trend toward earlier onset of pulmonary infection in the combined cryobiopsy group further supports a procedure-related effect, even though the overall severity of pulmonary infectious complications did not substantially differ between groups.
The role of prophylactic antibiotics in preventing post-bronchoscopic pulmonary infection remains controversial. Current guidelines do not recommend routine antibiotic prophylaxis following bronchoscopy [23]. In the present study, prophylactic antibiotics were administered in approximately 10% of cryobiopsy cases. Although no clear preventive effect was observed in unadjusted analyses, Firth penalized multivariable analysis suggested a potential protective association. While this finding should be interpreted cautiously, given the limited number of events, it suggests that prophylactic antibiotics may be beneficial in carefully selected high-risk patients, particularly those with radiologic or bronchoscopic features suggestive of infection-prone lesions [16, 22]. Further prospective studies are warranted to clarify this issue.
This study has some limitations. First, its retrospective single-center design limits causal inference and generalizability. In addition, a 1.1 mm cryoprobe was not used; therefore, caution is warranted when extrapolating our findings to clinical settings in which a 1.1 mm probe is employed, because the associated risk of infection may differ. In our study, all patients undergoing cryobiopsy were intubated, whereas those undergoing conventional biopsy were not, which may have influenced the risk of pulmonary infection; however, the direction of this effect remains uncertain. The relatively small number of infectious events restricted the complexity of multivariable modeling; however, we addressed this limitation by using penalized regression and multiple sensitivity analyses. Because pulmonary infection was defined partly by the initiation of antibiotic therapy, mild infections may have been overestimated. Nevertheless, a previous study from our institution has shown that microbiological cultures are frequently negative in post-bronchoscopic pulmonary infectious complications, supporting the clinical relevance of this pragmatic definition [24]. Finally, unmeasured confounding cannot be excluded despite careful adjustment using propensity score methods.
Conclusions
Pulmonary infectious complications after cryobiopsy for PPLs occur at a clinically relevant frequency, and the risk is significantly higher when cryobiopsy was added to conventional biopsy techniques. These findings provide quantitative evidence to guide patient selection and procedural planning. They may help clinicians balance diagnostic benefit against infection risk in routine practice.
Supplementary Information
Supplementary Material 1: Additional file 1. Baseline characteristics of patients undergoing combined cryobiopsy and conventional biopsy versus conventional biopsy alone. Additional file 2. Baseline characteristics of patients with and without pulmonary infectious complications among all cryobiopsy cases. Additional file 3. Univariable logistic regression analysis of risk factors for pulmonary infectious complications following cryobiopsy (N = 502). Additional file 4. Firth penalized multivariable logistic regression analysis of risk factors for pulmonary infectious complications following cryobiopsy.
Acknowledgements
We thank Editage Inc. for editing a draft of the manuscript.
Abbreviations
- PPLs
Peripheral pulmonary lesions
- NGS
Next-generation sequencing
- rEBUS
Radial endobronchial ultrasound
- WBC
White blood cell
- CRP
C-reactive protein
- CT
Computed tomography
- LDA
Low-density area
- IQR
Interquartile range
- CI
Confidence interval
- OR
Odds ratio
- SMD
Standardized mean difference
Authors’ contributions
T.I., Y.M., K.U., and F.H. contributed to the development of the study design; T.I., Y.M., and F.H. conducted data curation. T.I. conducted the statistical analyses. T.I. wrote the first draft of the paper and acted as the guarantor of the manuscript. T.I., Y.M., K.U., H.F., K.N., and T.T. commented on the manuscript drafts. All authors have read and approved the final version.
Funding
This study was partially supported by the National Cancer Center Research and Development Fund (29-A-13, 2020-A-12, and 2023-A-15).
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study was approved by the Institutional Review Board of the National Cancer Center Hospital (No. 2018 − 354) and registered in the Japan Registry of Clinical Trials (jRCT1032190168, registration date: December 23, 2019, https://jrct.mhlw.go.jp/en-latest-detail/jRCT1032190168).
Consent for publication
Not applicable.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Supplementary Material 1: Additional file 1. Baseline characteristics of patients undergoing combined cryobiopsy and conventional biopsy versus conventional biopsy alone. Additional file 2. Baseline characteristics of patients with and without pulmonary infectious complications among all cryobiopsy cases. Additional file 3. Univariable logistic regression analysis of risk factors for pulmonary infectious complications following cryobiopsy (N = 502). Additional file 4. Firth penalized multivariable logistic regression analysis of risk factors for pulmonary infectious complications following cryobiopsy.
Data Availability Statement
No datasets were generated or analysed during the current study.