Honeycomb wall thickening during acute deterioration of idiopathic pulmonary fibrosis: clinical, imaging and prognostic characteristics

Introduction

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease (ILD), accounting for approximately 20% of all ILDs (1). It is characterized by progressive dyspnea, decline in lung function and respiratory failure, often associated with a poor prognosis. The 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and AsociaciÓn Latinoamericana de TÓrax (ATS/ERS/JRS/ALAT) clinical practice guidelines indicate that typical high-resolution computed tomography (HRCT) signs of IPF are basal and peripheral honeycomb and reticular opacities accompanied by mild ground-glass attenuation (GGO) (2). While IPF typically progresses insidiously, acute exacerbations cause rapid and fatal deterioration characterized by a median survival of 3–4 months (3,4) and in-hospital mortality exceeding 50% (5-7). In the 2016 International Working Group Report, the presence of bilateral GGO/consolidation superimposed on bibasilar subpleural reticular abnormality and honeycomb on HRCT is an important feature of acute exacerbation of IPF (AE-IPF) (8). Akira et al. categorized the newly appeared parenchymal abnormalities on HRCT into three patterns: peripheral, multifocal and diffuse. Worse survival is associated with patients with diffuse type compared to patients with multifocal and peripheral types (9).

In clinical practice, we observed that some IPF patients experienced acute respiratory deterioration, including dyspnea and/or significant lung function decline in less than 30 days, yet their computed tomography (CT) scans did not show typical new GGO or consolidations. Instead, the radiological finding showed increased attenuation around the honeycomb walls, manifesting as “honeycomb wall thickening”. Strictly speaking, it does not meet the definition of AE-IPF. Most clinicians tend to classify it as fibrosis progression without giving sufficient attention to its potential for progressive aggravation in these patients. This study aims to investigate the clinical features of patients with worsening dyspnea alongside honeycomb wall thickening on HRCT. We further assess whether their prognosis differs from patients with the three typical AE-IPF patterns. This work seeks to determine whether honeycomb wall thickening represents a new CT sign of acute deterioration of IPF. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2625/rc).

Methods

Study patients and data collection

The retrospective study included patients with IPF who were admitted to West China Hospital for acute deterioration between April 2012 and February 2023. AE-IPF was diagnosed based on the 2016 AE-IPF International Working Group Report criteria (8). The inclusion criteria were: (I) concurrent or previous diagnosis of IPF; (II) worsening or development of dyspnea within 30 days; (III) chest CT findings demonstrating new bilateral GGO or consolidations superimposed on a background reticular or honeycomb pattern consistent with usual interstitial pneumonia (UIP). We concurrently enrolled patients with IPF manifesting worsening dyspnea and the honeycomb wall thickening pattern on CT. Exclusion criteria included: (I) poor-quality CT images precluding analysis; (II) comorbid conditions contributing to dyspnea, such as pulmonary embolism, pneumothorax, pleural effusion, significant mediastinal emphysema, heart failure or fluid overload. All diagnoses were confirmed through consensus by pulmonologists and radiologists. A total of 142 patients were enrolled, categorized as follows: 129 patients with AE-IPF [comprising peripheral (n=38), multifocal (n=75) and diffuse (n=16) patterns] and 13 patients with the honeycomb wall thickening pattern (Figure S1). Clinical data, laboratory results and chest CT findings were extracted from the hospital electronic medical record system. All patients underwent chest CT on the day of admission. Second CT scans were obtained 7 to 16 days (median 9 days) after initial CT of acute deterioration. Due to severe dyspnea, only 83 patients completed pulmonary function tests (PFTs), which were performed approximately six months before acute deterioration. The study was approved by the Medical Ethics Committee of West China Hospital of Sichuan University (No. 2018-572) and all participants signed written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

CT examination

All chest CT scans were performed in the supine position during full inspiration. Scans were acquired using various CT scanners, predominantly the Siemens Somatom Definition (Siemens Healthcare, Erlangen, Germany) and GE Revolution (GE Healthcare, Chicago, IL, USA). The scanning protocol included standard-dose CT with a slice thickness of approximately 1 mm. Image reconstruction utilized convolution kernels (e.g., I70f, B10f, B30f, B80f, B31f). In addition, the visual semi-quantitative assessments of abnormal lung involvement and CT subtypes were assessed visually on all CT scans by two experienced thoracic radiologist blinded to other clinical information. If there is any dispute, the final decision will be made after discussion by two chest radiologists. The classification of the CT pattern was described according to the method previously published by Akira et al. (9,10). GGO was defined as hazy increased lung attenuation with preservation of bronchial and vascular margins. Consolidation was defined as opacification with obscuration of margins of vessels and airway walls. Reticulation was defined as interlacing linear opacities forming a mesh-like pattern. Honeycomb was characterized by clustered cystic airspaces with thick fibrous walls. Based on the spatial distribution of newly developing parenchymal opacities on HRCT during acute exacerbation, patients were stratified into three distinct patterns, including peripheral, multifocal and diffuse.

The peripheral pattern was characterized by parenchymal opacities occurring adjacent to pre-existing subpleural honeycombing or increasing within areas of prior peripheral interstitial opacity (Figure 1A). The multifocal pattern exhibited opacities in both central and peripheral lung regions although these abnormalities were scattered and limited (Figure 1B). In contrast, the diffuse pattern showed widespread pulmonary involvement with noticeable regional heterogeneity (Figure 1C). In patients identified with the honeycomb wall thickening pattern, HRCT was characterized by pronounced thickening of honeycomb cyst walls (Figure 2). Based on comparing CT scans obtained before acute clinical worsening or after treatment, the honeycomb wall thickening pattern is characterized by new lesions predominantly localized around pre-existing honeycomb cysts, manifesting as wall thickening with or without minimal accompanying consolidation or ground-glass opacities (Figure 3). Using anatomical landmarks including level below aortic arch for upper lobes and inferior pulmonary vein for lower lobes, lungs were partitioned into six regions: right upper (RU), right middle (RM), right lower (RL), left upper (LU), left middle (LM) and left lower (LL). Two independent thoracic radiologists subjectively estimated the percentage volume of abnormal involvement per region. To correct for volumetric disparities among regions, a stratified random sampling of three patients per pattern group underwent volumetric measurement of all six regions using dedicated software, calculating region-specific volumetric coefficients (RU%, RM%, RL%, LU%, LM%, LL%) relative to total lung volume. These coefficients were then applied to all patients to compute the volume-adjusted percentage of total lung involvement. Previous studies have shown that a higher main pulmonary artery-to-aorta diameter ratio (mPA/Ao ratio) is associated with poor prognosis in IPF patients mainly due to increased right ventricular end-diastolic pressure (11,12). As a result, the mPA/AO ratio should also be documented.

Figure 1 Images of three classic patterns of AE-IPF on HRCT. (A) The peripheral pattern was characterized by parenchymal opacities occurring adjacent to pre-existing subpleural honeycombing or increasing within areas of prior peripheral interstitial opacity. (B) The multifocal pattern exhibited opacities in both central and peripheral lung regions although these abnormalities were scattered and limited. (C) The diffuse pattern showed widespread pulmonary involvement with noticeable regional heterogeneity. AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; HRCT, high resolution computed tomography.

Figure 2 Scheme of computed tomography patterns (9). (A) Peripheral pattern; (B) multifocal pattern; (C) diffuse pattern; (D) honeycomb wall thickening.

Figure 3 Honeycomb wall thickening pattern of the acute deterioration on HRCT. Images in a 78-year-old man with IPF. (A) HRCT scan taken during acute deterioration shows thickening of honeycomb cyst walls. (B) HRCT scan taken 11 days after treatment shows significant resolution of honeycomb wall. HRCT, high resolution computed tomography; IPF, idiopathic pulmonary fibrosis.

Patient and public involvement

This study did not involve patients or the public in the design, conduct, reporting or dissemination plans.

Statistical analysis

Continuous variables were expressed as mean ± standard deviation (SD) or median [interquartile range (IQR)], categorical variables as numbers. Data analysis was performed using commercial software (SPSS version 27; SPSS Inc., Chicago, IL, USA). Comparisons between the before treatment and post-treatment phases were conducted using either paired t-tests or non-parametric tests based on the normality distribution of the data. Intergroup differences across CT patterns were assessed via multifactorial analysis of variance (ANOVA) or nonparametric rank-sum tests, with statistical significance defined as P<0.05. Survival curves stratified by CT patterns were generated using the Kaplan-Meier method and compared via log-rank testing. Survival analysis incorporated Kaplan-Meier estimates with Wilcoxon testing. Cox proportional hazards regression models examined associations between CT patterns and mortality, adjusting for demographic characteristics (age, sex, smoking status), physiological parameters [forced vital capacity (FVC), diffusing capacity for carbon monoxide (DLco)], serum lactate dehydrogenase (LDH), partial pressure of arterial oxygen/fraction of inspired oxygen (PaO₂/FiO₂) ratio, mPA/Ao ratio, albumin and CT-quantified disease extent.

Results

Clinical characteristics of patients with honeycomb wall thickening pre-treatment versus post-treatment

We identified 13 cases with IPF admitted to our hospital for acute deterioration, presenting with the honeycomb wall thickening pattern on CT. Comparison of pre- and post-treatment data revealed a significant improvement in the PaO₂/FiO₂ ratio (P=0.01), whereas no significant changes were found in laboratory parameters (Table 1). Semi-quantitative visual assessment of CT scans showed virtually no new, isolated GGO or consolidations. Although some patients presented with minimal GGO or consolidation accompanied by traction bronchiectasis/bronchiolectasis, the extent of these findings did not change significantly following treatment (P>0.05).

Clinical characteristics of patients with different CT pattern at acute deterioration

Of the 129 patients with AE-IPF, they were categorized by CT findings into 38 with a peripheral pattern, 75 with a multifocal pattern and 16 with a diffuse pattern. Clinical characteristics, laboratory findings and treatment profiles were compared between 129 patients with AE-IPF and 13 patients exhibiting the honeycomb wall thickening pattern (Table 2). There were no statistically significant differences in baseline laboratory parameters between the two groups, including procalcitonin, sputum cultures or C-reactive protein (CRP). However, the mPA/Ao ratio was significantly higher in AE-IPF patients than in those with the honeycomb wall thickening pattern (P=0.03). Interestingly, every patient in the honeycomb wall thickening group was treated with both corticosteroids and antimicrobial agents. Patients with the honeycomb wall thickening pattern received a higher total corticosteroid dose than those with AE-IPF, although the difference was not statistically significant (P=0.056). Nevertheless, survival analysis revealed no significant difference in overall survival between the groups (P=0.19; Figure 4A).

Figure 4 Kaplan-Meier curves showing survival of patients with AE-IPF and honeycomb wall thickening pattern. (A) Show no significant difference between patients with the honeycomb wall thickening pattern and AE‑IPF patients after acute deterioration (P=0.19). (B) Comparison of survival outcomes between the honeycomb wall thickening pattern and CT subtypes of AE‑IPF. Survival in patients with the peripheral pattern was significantly better (P=0.01), while survival in those with the multifocal pattern (P<0.001), tended to be better than in those with the diffuse pattern. Survival in patients with the honeycomb wall thickening pattern was significantly better than the diffuse pattern (P<0.001). Survival in patients with the honeycomb wall thickening pattern was similar to that in those with the peripheral pattern (P=0.96) and multifocal (P=0.08). AE-IPF, acute exacerbation of idiopathic pulmonary fibrosis; CT, computed tomography.

Furthermore, among the AE-IPF subtypes (peripheral, n=38; multifocal, n=75; diffuse, n=16), the diffuse pattern was associated with significantly elevated CRP and LDH levels, reduced serum albumin, lower PaO₂/FiO₂ ratios and a higher mPA/Ao ratio compared to the peripheral pattern (Table 3). In contrast, the honeycomb wall thickening pattern showed no significant differences from the peripheral or multifocal patterns in these laboratory and physiological parameters. On semi-quantitative CT evaluation, the honeycomb wall thickening pattern was primarily characterized by consolidation with traction bronchiolectasis/bronchiectasis and minimal GGO with bronchiolectasis/bronchiectasis, whereas the diffuse pattern exhibited a significantly greater extent of both GGO and GGO with traction bronchiolectasis/bronchiectasis compared to the multifocal and honeycomb wall thickening groups.

Prognostic analysis of different CT patterns

Among the 142 enrolled patients, 110 (77.5%) succumbed to respiratory failure, including 7 of 13 (53.8%) with the honeycomb wall thickening pattern who died at a median survival of 48 months. Median survival times significantly differed across CT patterns: 5.5 months for diffuse, 16 months for multifocal, 40 months for peripheral patterns and 48 months for honeycomb wall thickening pattern. Kaplan-Meier curves demonstrated substantial survival disparities among the four CT phenotypes (Figure 4B). Cox regression confirmed significantly elevated mortality risk for diffuse pattern versus multifocal, peripheral and honeycomb wall thickening patterns. Multifocal pattern carried higher risk than peripheral but comparable to honeycomb wall thickening patterns. Peripheral and honeycomb wall thickening patterns showed no difference. Univariate analysis identified lower FVC, reduced PaO₂/FiO₂ ratio, elevated LDH, increased mPA/Ao ratio, CT pattern classification and disease extent as significant predictors of post-exacerbation mortality. After adjusting for age, sex, smoking status, PFTs, LDH, albumin, PaO₂/FiO₂ ratio, mPA/Ao ratio, CT pattern remained an independent mortality predictor, with diffuse pattern portending significantly worse prognosis than honeycomb wall thickening patterns [adjusted hazard ratio (HR) =15.026, 95% confidence interval (CI): 2.493–90.545; P=0.003; see Table 4].

Discussion

AE-IPF is a catastrophic clinical event characterized by severe symptom escalation and progressive quality-of-life deterioration. Prognostic stratification in AE-IPF is therefore clinically imperative for guiding therapy and improving outcomes. CT patterns serve as a critical discriminative feature for predicting prognosis and accurate classification is pivotal for guiding therapy and improving outcomes (9,10,13,14). This study identifies honeycomb wall thickening as a previously unclassified imaging pattern during respiratory deterioration in IPF. Compared with AE-IPF patients, those with the honeycomb wall thickening pattern showed similar clinical characteristics and laboratory findings. Patients with honeycomb wall thickening on HRCT exhibit prognoses comparable to AE-IPF. The honeycomb wall thickening pattern does not fulfill the current imaging criteria for typical AE-IPF and its pathophysiological basis remains unelucidated. Thus, we presently refrain from classifying it as AE. Rather, it may represent an imaging entity observed during acute deterioration in IPF, characterized predominantly by thickening of pre-existing honeycomb cyst walls. This phenotype appears to respond to antimicrobial or corticosteroid therapy and a favorable treatment response may be associated with improved long-term outcomes. Therefore, this pattern should be recognized by clinicians.

Prior studies demonstrates that the presence of extensive GGO in patients with UIP or the development of rapidly progressive new ground-glass opacity away from areas of fibrosis should raise the possibility of acute exacerbation (8,9,15). This study identifies a critical diagnostic feature highly suggestive of acute deterioration in IPF patients. The feature consists of new-onset or worsening cough, sputum and dyspnea, accompanied by HRCT findings of thickened honeycomb cyst walls without adjacent GGO. We define it as the honeycomb wall thickening pattern. Importantly, these patients exhibited improved PaO₂/FiO₂ ratios and radiographic reversal of wall thickening following corticosteroid and antimicrobial therapy. Given severe dyspnea in AE-IPF patients, previous established evidence indicates that bronchoscopy or lung biopsy may exacerbate the patient’s condition, thus leading to an increased risk of death (8,16-19). No biopsies were performed in our cohort, so our study lacks direct pathological characterization of the honeycomb wall thickening pattern. However, negative sputum cultures (positive rate: 2/13, with Candida albicans isolated) and normal procalcitonin levels (procalcitonin <0.5 ng/mL; single outlier: 1.35 ng/mL) in most patients with honeycomb wall thickening pattern in our cohort suggest bacterial infection is unlikely the primary driver of acute deterioration, indicating antibiotic therapy may be ineffective in promoting lesion resolution for patients in our cohort. Glucocorticoids exert anti-inflammatory effects through multimodal mechanisms including inhibiting leukocyte trafficking and tissue infiltration, disrupting functional crosstalk among leukocytes, fibroblasts and endothelial cells and suppressing pro-inflammatory cytokine release (20,21). In addition, latest research indicates that patients with a higher lymphocyte fraction in bronchoalveolar lavage fluid is associated with a significant improvement in respiratory symptoms within one year and the presence of consolidation, but not with ground-glass opacities on HRCT (22). All patients with the honeycomb wall thickening pattern in this study demonstrated significant radiographic regression of cyst wall thickening on early follow-up CT post-glucocorticoid therapy. Collectively, the rapid therapeutic response to glucocorticoids and absence of infectious biomarkers provides inferential evidence that the histopathological substrate of the honeycomb wall thickening phenotype likely involves organizing pneumonia (OP) or lymphocytic-predominant inflammatory infiltrates. This treatable phenotype contrasts with the common misinterpretation of such findings as irreversible fibrotic progression, which may delay intervention and contribute to excess mortality. Our findings redefine the honeycomb wall thickening pattern may not as irreversible fibrosis, but as a responsive form of AE-IPF amenable to timely treatment. Therefore, early recognition and treatment of patients with the honeycomb wall thickening pattern may improve their symptoms and enhance clinical outcomes. Dedicated prospective trials stratifying patients with honeycomb wall thickening pattern to targeted anti-inflammatory versus antimicrobial therapy arms are imperative to elucidate differential treatment responses and thereby infer the underlying histopathological features of this phenotype.

In our study, patients with the honeycomb wall thickening pattern exhibited baseline clinical and laboratory profiles largely similar to those meeting formal AE-IPF criteria. The two groups were comparable in demographics presenting symptoms and key laboratory indices, including inflammatory markers. However, a salient differentiating feature was the significantly lower mPA/Ao ratio in the honeycomb wall thickening group. This may indicate a lower burden of concomitant pulmonary vascular disease, potentially contributing to their more favorable prognosis. Despite a higher proportion of honeycomb compared to patients with peripheral and multifocal patterns, those with the honeycomb wall thickening pattern exhibited a similar prognosis, which warrants further mechanistic consideration. We hypothesize that this dissociation between structural fibrosis extent and outcome may reflect a distinct pathophysiological process. Unlike the diffuse pattern, which is strongly associated with diffuse alveolar damage (DAD) and a high mortality rate (9,23), the honeycomb wall thickening pattern may represent a more localized, airway-centered acute inflammatory response superimposed on advanced fibrotic lung. This is supported by its defining CT features: new wall thickening confined to pre-existing honeycomb cysts, accompanied by minimal ground-glass opacity. The significant radiographic and physiological improvement observed following anti-inflammatory therapy further suggests a reversible, exudative component rather than pure fibrotic progression. Consequently, even within lungs exhibiting greater architectural distortion (higher honeycomb proportion), an acute exacerbation driven by this more confined, treatment-responsive pathology could result in a survival trajectory comparable to, or even better than, other non-diffuse AE-IPF subtypes.

Acute exacerbations of IPF are associated with high mortality, historically demonstrating a median survival of 3–4 months (3,4,24). In contrast, our cohort exhibited a substantially prolonged median survival of approximately 18 months, though with survival curve trajectories consistent with prior reports. We attribute this survival disparity to several factors. First, the widespread availability and cost-effectiveness of HRCT in China enabled prompt chest imaging upon initial presentation at our center, facilitating early recognition of acute exacerbation and initiation of treatment, which may have improved outcomes in some patients. Second, infection may have been a primary trigger for acute exacerbation in a subset of individuals. Early antimicrobial intervention likely contributed to their improved survival. Third, the use of antifibrotic druges including pirfenidone or nintedanib in some patients may have extended survival. Additionally, although high-dose methylprednisolone has been used in earlier studies, recent evidence indicates no survival benefit with pulse glucocorticoid therapy compared to conventional dosing and it may increase infection-related mortality (25-28). In our cohort, the predominant use of moderate-dose glucocorticoids may have contributed to lower mortality and longer survival. Further studies are needed to confirm these observations.

There are several limitations in this study. First, owing to its single-center retrospective design and the low incidence of AE-IPF in the general patient population, the sample size was limited. Larger and multicenter studies are warranted to confirm these findings. Second, histopathologic confirmation was precluded by respiratory failure and critical illness prevented pulmonary function testing in some patients, resulting in missing pathologic and lung function data. Third, CT severity was assessed subjectively, which may affect comparability with studies using quantitative criteria. Nonetheless, consistent internal assessment standards were applied across all patient subgroups. Finally, because all patients with the honeycomb wall thickening pattern received both corticosteroids and antimicrobial therapy, our study cannot determine whether clinical and radiographic improvement was driven primarily by anti-inflammatory effects, antimicrobial activity or their combination. Prospective trials with stratified treatment arms are required to clarify the respective contributions of each intervention.

Conclusions

In conclusion, this study identifies honeycomb wall thickening pattern as a distinct and previously underrecognized CT phenotype of IPF patients with worsening respiratory symptoms. This pattern is often missed in practice, which may delay treatment. However, patients showing this pattern exhibited symptomatic and prognostic improvement after anti-inflammatory and antimicrobial therapy. These findings suggest that early recognition and targeted treatment could improve outcomes and offer actionable insights for risk stratification and management.

Acknowledgments

We would like to thank the other researchers for useful discussion.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2625/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2625/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2625/prf

Funding: This study was supported by grants from the National Key Technologies R&D Program of China (Nos. 2021YFC2500700 and 2016YFC0901100), 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. ZYGD23009) and Chengdu Science and Technology Program (No. 2025-YF09-00061-SN).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1-2625/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was approved by the Medical Ethics Committee of West China Hospital of Sichuan University (No. 2018-572) and all participants signed written informed consent before enrollment. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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