Disease progression in patients with usual interstitial pneumonia and probable UIP patterns on computed tomography with various underlying etiologies: a retrospective cohort study

Background Usual interstitial pneumonia (UIP) is a pattern of interstitial pneumonia that is caused by different etiologies. This study aimed to investigate the transplant-free survival (TFS) and the decline in forced vital capacity (FVC) of the patients with UIP and probable UIP patterns on CT caused by various underlying conditions. Methods A retrospective cohort study was conducted, enrolling patients with interstitial lung disease exhibiting a CT pattern consistent with UIP or probable UIP. Clinical and prognostic data of patients categorized by the etiology were compared. Results A total of 591 patients were included and classified into the following groups: idiopathic pulmonary fibrosis (IPF) (n = 320), connective tissue disease (CTD)-UIP (n = 229), asbestosis-UIP (n = 28), and hypersensitivity pneumonitis (HP)-UIP (n = 14). Advanced age, elevated levels of serum cytokeratin fraction 21-1 and percentage of neutrophils in bronchoalveolar lavage were observed in all groups. IPF patients showed a more rapid decline in FVC (133.9 mL/year) compared to CTD-UIP (24.5 mL/year, p = 0.001) and asbestosis-UIP (61.0 mL/year, p = 0.008) respectively. Sub-analysis of CTD-UIP revealed that patients with rheumatoid arthritis (RA)-UIP (88.1 mL/year) or antineutrophil cytoplasmic antibody-associated vasculitis (AAV)-UIP (72.9 mL/year) experienced a faster deterioration in FVC compared to those with primary Sjögren’s syndrome (pSS)-UIP (25.9 mL/year, p < 0.05). Kaplan–Meier curves showed that IPF had the poorest TFS (median 55.9 months), followed by HP-UIP (57.5 months), CTD-UIP (66.7 months), and asbestosis-UIP (TFS not reached). RA-UIP or AAV-UIP did not exhibit any prognostic advantages compared to IPF, while asbestosis-UIP and pSS-UIP showed better survival rates. Conclusion Patients with UIP caused by different underlying conditions share certain common features, but the trajectories of disease progression and survival outcomes differ.


Introduction
Usual interstitial pneumonia (UIP) is a commonly observed pattern of interstitial pneumonia characterized by heterogeneous fibrosis in the lung parenchyma, along with architectural distortion, fibroblast foci, and honeycombing.While UIP is diagnosed through pathology, extensive evidence supports the high specificity of typical and probable UIP patterns on high-resolution computed tomography (HRCT) for histopathologic UIP, eliminating the need for surgical lung biopsy.Idiopathic pulmonary fibrosis (IPF) represents the primary form of UIP with an unknown cause, but other interstitial lung diseases (ILDs), including connective tissue disease (CTD)related, hypersensitivity pneumonitis (HP)-related, and asbestosisrelated ILDs, can also exhibit a UIP pattern (1).UIP stands out from other ILD patterns, such as nonspecific interstitial pneumonia (NSIP), organizing pneumonia (OP), and lymphocytic interstitial pneumonia (LIP), due to its predominant fibrosis and minimal inflammation, which contribute to higher mortality rates, irrespective of whether it is idiopathic or secondary (2,3).
Recent discussions have proposed the unification of UIP as a single diagnostic entity due to the presence of similar disease progression behaviors and underlying mechanisms.This unified approach has the potential to expedite antifibrotic trials for secondary UIP and trials of novel therapeutic agents (4).However, there is a scarcity of data on secondary UIP types, apart from CTD-UIP.Furthermore, previous analyses examining the disparities in survival rates between IPF and CTD-UIP have yielded inconsistent findings (5,6).In this study, we conducted a comprehensive review of patients with UIP and probable UIP patterns on HRCT over a 10 years period at our hospital.The objective was to determine the transplantfree survival (TFS) and the decline in forced vital capacity (FVC) of the patients with different etiologies of UIP patterns and probable UIP on HRCT.

Study design and patient selection
This study was an observational, retrospective cohort study conducted at Beijing Chao-Yang Hospital, China, which serves as a regional medical center specializing in ILD.We screened all the in-patients consecutively admitted to our hospital between January 2012 and December 2021 with newly diagnosed ILDs.Considering the limitations imposed by the local medical insurance policy and taking into account the patient's individual preferences, hospitalized patients provide a more comprehensive set of clinical data for evaluating diseases, especially in terms of systemic organ involvement.The inclusion criterion was the presence of a UIP or probable UIP pattern on HRCT.Exclusion criteria included: (1) prior treatment with immunosuppressive or antifibrotic agents, (2) unclear diagnosis, (3) active infections, (4) malignancy or suspected malignancy at the time of diagnosis or within 1 year of diagnosis, (5) pneumothorax or pulmonary embolism at the time of diagnosis, (6) inadequate sample size for analysis, and (7) incomplete data or loss to follow-up.The study adhered to the principles of the Helsinki Declaration and its subsequent amendments and was approved by the Ethics Committee of Beijing Chao-Yang Hospital.

Diagnosis and image evaluation
All patients included in the final analysis underwent reevaluation and discussion by a multidisciplinary team comprising a pulmonologist, rheumatologist, and radiologist.The diagnosis of IPF was based on the 2018 ATS/ERS/JRS/ALAT guideline (7).CTD was diagnosed if the patients fulfilled the established classification criteria for each specific type of CTD (8)(9)(10)(11)(12)(13).Asbestosis was diagnosed using the International Labor Organization classification criteria (14), the patients included all had a history of exposure to chrysotile asbestos.HP was diagnosed following the 2020 ATS/JRS/ALAT guideline (15).
All patients underwent chest HRCT with a 1 s scan time, 1.25 mm slice thickness, and 5 mm interval from the lung apex to the base, encompassing both lungs within the field of view.The CT patterns and signs of the patients were assessed by a radiologist and pulmonologist who were blinded to the clinical data.In patients of disagreement between the pulmonologist and radiologist after the initial assessment, consultation was sought from a ILD specialist.The presence of all the following features, as outlined in the 2018 ATS/ERS/JRS/ALAT guidelines (7), defined the UIP and probable UIP patterns: heterogeneous subpleural/basal predominance, reticular abnormalities, honeycombing (reticular pattern for probable UIP), with or without traction bronchiectasis, and the absence of features inconsistent with the UIP pattern (mild ground-glass opacity may be present in probable UIP).Positive emphysema findings were visually defined as the presence of areas of low attenuation indicating a lack of a distinct alveolar wall threshold comprising more than 10% of the lung volume (16).Pulmonary hypertension (PHT) was defined as a pulmonary artery systolic pressure exceeding 35 mmHg on echocardiography (17).

Data collection and follow-up
Demographics, smoking history, parameters of pulmonary function tests, and laboratory findings at the time of ILD diagnosis were extracted from the medical records.Prebronchodilator FVC, forced expiratory volume in the first second (FEV1), and single-breath diffusing capacity of the lung for carbon monoxide (DLCO SB) were measured according to the criteria set by the ATS/ERS (18, 19), and the percentages (%) of the normal predicted values for these parameters were recorded.The gender-age-physiology (GAP) score Blood leukocytes, neutrophils, lymphocytes, monocytes, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), immunoglobulin G (IgG), cytokeratin fraction 21-1 (CYFRA21-1), carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9, and CA 125 were recorded.The recommended normal ranges for each tumor marker are as follows: CYFRA21-1 ≤2.08 ng/mL, CEA ≤5 ng/ mL, CA19-9 ≤37.00 U/mL, and CA125 ≤35.00 U/mL.Bronchoscopy with bronchoalveolar lavage (BAL) was performed following the guidelines of the ATS (22), and the results of the cellular analysis of the BAL fluid (BALF) were recorded.Normal BAL cell differential counts are as follows: macrophages ≥80%, lymphocytes ≤15%, neutrophils ≤3% and eosinophils ≤1%.
Longitudinal data on FVC, medication, and vital status were obtained by reviewing outpatient follow-up records and conducting phone interviews with patients or their family members.Patients were considered to have received immunosuppressive or antifibrotic therapy only if the medication was maintained for more than 6 months.For each patient, the decline in lung function was calculated as (last FVC − FVC at baseline)/duration of follow-up (in years) (23).The primary endpoint of the study was TFS, defined as the time from ILD diagnosis to the occurrence of either lung transplantation or death, up until August 2022.

Statistical analysis
Statistical analyses were conducted using the Statistical Package for the Social Sciences (SPSS) software, version 23 (IBM Corp., Armonk, NY, United States).Categorical baseline characteristics were presented as frequencies and percentages, while continuous characteristics were reported as mean ± standard deviation or median (interquartile range, IQR).Intergroup differences for continuous variables were assessed using one-way analysis of variance or the Mann-Whitney U test, while categorical data were analyzed using the chi-square test.Survival analysis was performed using Kaplan-Meier curves and log-rank test.When the log-rank test was significant, Bonferroni correction for multiple comparisons was applied and the alpha level was set at 0.0083 (0.05/6 tests).Univariate and Cox proportional hazard regression analyses were then conducted to determine the predictor variables for mortality or lung transplantation, presenting hazard ratios (HRs) and 95% confidence intervals (CIs).Statistical significance was set at a p-value <0.05.

Demographics and clinical characteristics
The average age of the patients was 65.5 years, with an average body mass index (BMI) of 24.2 kg/m 2 .Among the patients, 430 (72.8%) were male, and 351 (59.4%) had a smoking history.

Subgroup analysis
A subgroup analysis was conducted specifically for patients with CTD-UIP.Most demographic and laboratory characteristics were comparable among patients with RA-UIP, pSS-UIP, AAV-UIP, and other CTD-UIP.However, there were notable differences in age and levels of blood inflammatory markers, including leukocytes, neutrophils, ESR, and CRP levels, which were higher in AAV-UIP patients.The rates of decline in FVC varied among the patients.Both RA-UIP (88.1 mL/year) and AAV-UIP (72.9 mL/year) patients exhibited significantly faster FVC decline compared to pSS-UIP (25.9 mL/year) and other CTD-UIP patients (20.7 mL/year), with a significance level of p < 0.05 (Supplementary Table S1).
Additional comparisons were conducted between patients with or without emphysema, and those with or without PHT in the IPF and CTD-UIP groups.Patients with emphysema presented slower median annual FVC decline than those without emphysema, both in the IPF group (50.7 mL/yr vs. 177.3mL/yr, p = 0.047) and the CTD-UIP group (-35.6 mL/yr vs. 38.9mL/yr, p = 0.024).Patients with PHT, however, presented significantly shorter TFS than those without PHT in the IPF group (35.9 vs. 65.2month median TFS, p < 0.001) and the CTD-UIP group (28.5 vs. 80.9 month median TFS, p < 0.001) (see Supplementary Tables S2,S3).

Blood cytology
Leucocytes, ×10 9 /L 6.7 ± 1.9 6.6 ± 1.6 6.9 ± 2.3 b,c 6.1 ± 1.4   group exhibited the poorest prognosis (median TFS: 55.9 months), followed by the CTD-UIP group (median TFS: 66.7 months) and HP-UIP group (median TFS: 57.5 months).The asbestosis-UIP group demonstrated the best survival, with the median TFS not being reached.Pairwise comparisons revealed significant differences between the IPF and asbestosis-UIP patients (log-rank p < 0.001).While the difference did not reach statistical significance after Bonferroni correction, a marginal trend towards better survival was observed in the CTD-UIP group compared to the asbestosis-UIP group (p = 0.017).Furthermore, differences in TFS were observed within the CTD-UIP patients (p = 0.006) (Figure 2B).The AAV-UIP group (median TFS: 49.3 months) and RA-UIP group (median TFS: 59.0 months) had the poorest prognoses, while the pSS-UIP group (median TFS: 92.8 months) and other CTD-UIP group (median TFS: 69.1 months) exhibited better TFS.A significant difference was found between the AAV-UIP and pSS-UIP patients (log-rank p < 0.001), and a trend towards better survival was observed in the pSS-UIP group compared to the RA-UIP group (p = 0.017).When the IPF group was used as a control, neither the RA-UIP nor AAV-UIP patients showed a survival advantage, whereas a significant survival advantage was found in the pSS-UIP group (p = 0.017), and a marginal survival advantage was observed in the other CTD-UIP group (p = 0.066) (Figures 2C-F).

Discussion
This study focused on patients with ILD exhibiting UIP and probable UIP patterns on HRCT.Our findings revealed significant heterogeneity in disease progression and some shared characteristics among UIP patients with different etiologies.
In the current study, we observed significant heterogeneity in FVC decline rates and TFS among patients with UIP of different etiologies.Asbestosis, characterized by irregular and/or linear opacities with basal preponderance, ground-glass opacities, and mosaic attenuation accompanied by pleural abnormalities, is caused by repeated asbestos inhalation (24).Our recently published data showed that 9.8% (20/204) of patients with asbestosis manifested a UIP pattern on HRCT (25).Limited data are available regarding the survival of asbestosis-UIP patients.In our study, asbestosis-UIP patients demonstrated a slowly progressive disease course and better survival outcomes compared to IPF patients, despite the two groups being indistinguishable in terms of clinical and laboratory features.Another disease entity in our cohort, UIP associated with pSS also exhibited a prognostic advantage over IPF.Pathological comparisons revealed that fibroblast foci, a characteristic feature of IPF, are infrequent and sporadically observed in pSS-UIP and asbestosis patients, whereas interstitial inflammation, plasma cell infiltration, lymphoid follicles with germinal centers, cysts, bronchiolitis, and pleuritis were significantly more pronounced in the lungs of pSS-UIP patients (26,27).Recent studies utilizing artificial intelligence to quantify fibroblast foci have demonstrated that a large area occupied by fibroblast foci predicts a poor prognosis in IPF (28).Similarly, data from patients with chronic HP have indicated that the presence of fibroblast foci is an independent predictor of time to death or transplantation (29).Thus, we consider the number of fibroblastic foci to be at least one of the crucial factors contributing to the differences in fibrosis progression and mortality among patients with UIP.However, the factors influencing the presence and number of fibroblastic foci remain unknown.
In contrast to pSS-UIP, both the decline rate in FVC and TFS in patients with RA-UIP and AAV-UIP were similar to those observed in IPF.This finding could help explain the conflicting evidence regarding prognostic differences between CTD-UIP and IPF, as the composition of CTD patients varies across studies (5,6).Studies comparing survival between RA-UIP and IPF, as well as AAV-UIP and IPF, have reported results consistent with our findings (30,31).Interestingly, in a study by Watanabe et al. (32), while the decline in lung volume and median survival time were similar between AAV-UIP and IPF patients, the causes of death differed.AAV-UIP patients more frequently experienced deaths related to anti-immune therapy (infectious complications) or vasculitis itself (alveolar hemorrhage and potentially cardiovascular disease), whereas in IPF, most deaths were related to respiratory system issues.Nevertheless, considering the potential benefits, early initiation of antifibrotic therapy may be considered in patients with RA and AAV exhibiting a UIP pattern.Moreover, due to the evident heterogeneity, it may be inappropriate to treat CTD-ILD as a unified entity when conducting analyses related to ILD progression and survival.Furthermore, we recommend considering the specific etiology before conducting clinical trials, as therapeutic effects may diverge among patients with different progression patterns.
It is worth to mention that the annual decline rate of FVC observed in IPF patients from the current study appears to be slower than that reported in several large-scale clinical trials.In the TOMORROW trial, the annual decline rate of FVC was 60 mL in the 150 mg twice daily nintedanib group and 190 mL in the placebo group (33).In the INPULSIS trial, adjusted rate of decline in FVC was 112.4 mL/year with nintedanib and 223.3 mL/year with placebo (34).We noticed that the baseline FVC% (85.4%) of the patients in this cohort was higher than that in the TOMORROW (80.2%) and INPULSIS trials (80%).Besides, a portion of patients in the current study had received antifibrotic treatments during the study period.These could be the possible reasons for the different FVC decline rate in our study.
Despite the heterogeneities, the clinical and laboratory data of patients with UIP from various causes display remarkable similarities, shedding light on the shared underlying mechanisms   41).Thus, it is plausible that the association with aging might be more closely related to the fibrosis behavior itself rather than specific ILD patterns.Another noteworthy shared characteristic among patients with UIP is the presence of elevated levels of CYFRA21-1 in the serum and neutrophils in BALF.The significance of CYFRA21-1 in ILDs has been increasingly recognized in recent years.CYFRA21-1 is a cytoskeletal protein expressed in type 1 and type 2 pneumocytes, as well as respiratory bronchiolar epithelial cells, and its release is triggered by lung injury (42).Notably, Molyneaux et al. (43) discovered that baseline concentrations of CYFRA21-1 could potentially identify individuals at risk of disease progression within 12 months and predict overall mortality in patients with IPF.In our study, we observed comparably elevated levels of CYFRA21-1 in both IPF and secondary UIP patients.
Similarly, previous investigations have underscored the importance of neutrophils in the immune pathogenesis of IPF (44,45), and our data revealed that BALF neutrophils were equally elevated in IPF and secondary UIP, indicating analogous immune pathogenesis in UIP caused by various underlying conditions.However, the elevation in BALF neutrophils does not appear to be exclusive to UIP (46).One possible explanation is that BALF neutrophils are associated with lung fibrosis in general rather than specifically with the UIP pattern, which is supported by the increase in neutrophils and decrease in lymphocytes observed in the BALF during the transition from acute to chronic hypersensitivity pneumonitis (39).
The similarities between IPF and other ILDs with "IPF-like" behaviors gave birth to the concept of progressive pulmonary fibrosis (PPF), which indeed, has its clinical values, especially on drug development and application.However, precise and personalized medication should not be neglected.Thus, "smarter lumping and smarter splitting" maybe advocated for these patients The current study had several limitations that should be mentioned.Firstly, being a retrospective single-center study, it may be prone to selection bias, and the number of asbestosis-UIP and HP-UIP patients was relatively small.In the real world, the cases of HP-UIP and asbestosis are limited, a previous published study by our team showed that 9.8% (20/204) of patients with asbestosis and 10.8% (8/74) of patients with fibrotic HP manifested a UIP pattern on HRCT (25).However, this limitation may affect the accuracy of our assessments and result in an insufficient statistical power to detect existing differences, thus, some of the results must be interpretated with caution.Secondly, not all patients underwent a multidisciplinary team (MDT) assessment at the time of ILD diagnosis, although we conducted retrospective MDT discussions for each patient and excluded those with unclear diagnoses, there remains a possibility of misjudgments regarding the etiology in a few patients.Thirdly, the majority of the pathological results were derived from transbronchial lung biopsies, which prevented the comprehensive analysis of pathological features in this study.Fourthly, the assessment of the likelihood of developing PHT relied on echocardiography rather than right heart catheterization (RHC), which may have compromised accuracy.However, it is important to note that echocardiography offers the advantage of being non-invasive.RHC is an invasive procedure associated with potential risks for patients, and its benefits for patients with ILD are limited.Studies have demonstrated that in patients with PHT, the measurement of tricuspid regurgitation velocity (TRV) correlates significantly with pulmonary artery systolic pressure (PASP) obtained through RHC.Echocardiography has consistently proven to be a reliable method for diagnosing PHT (49).Last, the cause of death was not analyzed due to the fact that most deaths occurred outside the hospital, thus the specific reasons for the observed survival disparities among patients remain unknown.
In conclusion, this respective cohort study demonstrates that patients with UIP stemming from various etiologies exhibit common features such as advanced age, elevated serum levels of CYFRA21-1, and increased neutrophil counts in BALF.However, there are notable differences in the decline rate of FVC and TFS among these patients.Specifically, UIP associated with asbestosis and pSS-UIP exhibit slower disease progression and improved survival rates compared to IPF.

TABLE 1
Baseline demographics of UIP patients in various etiology groups.
Data were presented as mean ± SD or median (IQR) or n (%).UIP, usual interstitial pneumonia; IPF, idiopathic pulmonary fibrosis; CTD, connective tissue disease; HP, hypersensitivity pneumonitis; BMI, body mass index; FVC, forced vital capacity; FEV1, forced expiratory volume in the first second; DLCOsb, single-breath diffusing capacity of the lung for carbon monoxide; GAP, gender-age-physiology; CPI, composite physiologic index.a p < 0.0083 versus the IPF group.

TABLE 2
Laboratory data of UIP patients in various etiology groups.

TABLE 3
Comorbidities, treatment, FVC decline and transplant-free survival of UIP patients in various etiology groups.

TABLE 4
Risk factors associated with death or lung transplantation in UIP patients.As for UIP patients, on the one hand, exploring the common biological pathways during UIP development may provide broader directions for therapy; on the other hand, tailored therapies based on precision medicine urge deeper investigations for the causes of heterogeneity in disease progression and prognosis of these patients.