Differences in pulmonary nodular consolidation features among drug-sensitive pulmonary tuberculosis and multidrug/extensively-resistant pulmonary tuberculosis: a multi-national multi-center study

Introduction

The emergence of drug-resistant (DR) tuberculosis (TB) increases the burden of TB control. Multidrug-resistant (MDR) TB refers to TB infection resistant to at least two first-line anti-TB drugs, isoniazid and rifampicin. Extensively drug-resistant (XDR) TB is defined as TB that has evolved resistance to rifampin and isoniazid, as well as to any member of the quinolone family and at least one of the second-line injectable drugs: kanamycin, amikacin, and capreomycin. Of all MDRs, XDR accounts for 4–20% of these infections (1-3). When resistant mutants arise during treatment with anti-TB drugs, it is considered as acquired resistance (previously treated MDR-TB). Patients infected with an already drug-resistant strain develop primary resistance (new MDR-TB), which is observed in newly diagnosed TB patients. It has been estimated that globally 3.5% (which can be much higher in some regions) of newly diagnosed TB patients, and 20.5% of previously treated patients, are MDR-TB (1,4). There have been interests to use chest imaging as a supporting tool to suggest the diagnosis of drug-resistant (DR) [DR in this article refers to rifampicin-resistant (RR) pulmonary TB, MDR pulmonary TB, and XDR pulmonary TB] (5). A number of published articles described the potential chest imaging feature differences between drug-sensitive (DS) and DR (5-17). It has been suggested that MDR cases tend to have more extensive disease, more likely to be bilateral, to have pleural involvement, to have bronchiectasis, and to have lung volume loss (5). XDR overall appears even more aggressive than MDR, with a greater number of cavities, larger cavities, and cavities of thicker wall (5,15). However, these signs alone are considered not sufficient for the differential diagnosis of MDR/XDR from DS (5). Moreover, there have been concerns that reported radiological feature differences between DS and MDR are confounded by that MDR cases tend to have a longer history prior to being diagnosed as MDR, thus the radiological features shown in MDR may not be intrinsic to MDR pathology. The variation in imaging manifestations across the studies could be a consequence of differential time intervals between disease onset and chest imaging (5).

Based on earlier literature and our own initial data (7,18,19), we hypothesized that pulmonary nodular consolidation (PN) represents a potential imaging sign useful in differentiating DR from DS, and conducted two studies (20,21). In the ‘Dalian study’ conducted in 2022 (20), we analysed the lung CT feature differences of DS vs. DR patients from a well-defined urban region in Dalian, China. There were 33 consecutive new DR cases (inclusive of RR and MDR cases), with 19 cases having a history of <1 month and 8 and 6 cases having a history of 1–6 and >6 months respectively. To pair the MDR cases according to the disease history length, disease history length matched 33 DS patients were included. The first computed tomography (CT) exams prior to treatment were analyzed. It was found that, compared with DS cases, DR cases had a higher prevalence of PN (75.76% vs. 45.45%) and a higher number of PN per positive case for PN (6.2 vs. 1.53). In the ‘Guangzhou study’ conducted in China in 2024 (21), we retrieved CT data of consecutive new DR cases (n=46, inclusive of RR and MDR cases), and according to the electronic case archiving system records, the TB history was ≤3 months till the first CT scan was taken. To pair the MDR-pulmonary tuberculosis (PTB) cases with assumed equal disease history length, we retrieved data of 46 DS patients. PN prevalence was slightly higher among DR cases than among DS cases (69.6% vs. 63.0%). For positive cases, DR cases had a higher PN number than DS cases (mean number of positive cases: 2.63 vs. 2.28). To further study the potential differences of the lung imaging feature PN between DS and DR, hereby we carry out an additional study, analyzing a large number of DS, MDR, and XDR cases collected from multiple nations. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-832/rc).

Methods

Data resource

All Eastern European TB patient data were from the NIAID (National Institute of Allergy & Infectious Diseases, USA) TB Portals Program (TBPP, https://tbportals.niaid.nih.gov/) dataset (all patients registered in the database before January 2019 and with lung CT data) (22). In this article, eastern European countries refer to Belarus, Moldova, Romania, Azerbaijan, and Georgia. Chinese patients were obtained from the Third People’s Hospital of Shenzhen and the Shenzhen Center for Chronic Disease Control, Shenzhen, China, treated between April 2017 and February 2019. The study was approved by ethics boards of the Third People’s Hospital of Shenzhen and the Shenzhen Center for Chronic Disease Control. Informed consent was not needed due to the retrospective nature of this study. We excluded patients with unsatisfactory images or without drug susceptibility test (DST). We also excluded patients with human immunodeficiency virus (HIV) (+) status, as patients with compromised immunofunction have been noted to have altered t chest CT presentations (5,17). Finally, 743 eligible patients from six countries (489 men and 254 women, mean age, 40.0±14.8 years) were included in our study. According to the history of the previous anti-TB treatment, the patients were categorized into new cases (446 cases) and previously treated cases (297 cases). The Chinese patients were all new cases. For new patients, the interval days between the first CT chest scan and anti-TB treatment starting date were recorded, and the new patients were further classified into three groups: (I) the first CT was done before anti-TB treatment; (II) the first CT was done after anti-TB treatment started but the interval between CT scan and treatment initiation was ≤14 days; (III) the first CT was done after ant-TB treatment started and the interval was >14 days. The patient enrolment process and patient baseline are shown in Figure 1 and Table 1.

Figure 1 PTB patient data utilized in the current study. CT, computed tomography; CT after tr, first CT scan was acquired after the anti-TB treatment started; CT before tr, first CT scan was acquired before the anti-TB treatment started; DS, drug-sensitive; DST, drug susceptibility test; HIV, human immunodeficiency virus; MDR, multidrug-resistant; pts, patients; PTB, pulmonary tuberculosis; pre-treated, previously treated; TB, tuberculosis; tr, anti-TB treatment; tr-CT, the interval time in days between the anti-TB treatment initiation and the first CT scan was acquired; XDR, extensively drug-resistant.

Chest CT reading

For all the patients, the first CT scan images were used and read initially in consensus by two radiology trainees (S.N.T. and X.L.H.) both with over 2 years’ experience in chest image reading. The reading results were then double-checked case-by-case by a specialist radiologist (Y.X.J.W.). Consensus was achieved for the final reading results. This study focused on the CT feature of PN. As described earlier (20,21), a PN was rounded or oval with a relatively clear boundary measuring between 6 and 30 mm in diameter. The number was counted for each patient. The diameter for each nodular consolidation (NC) was measured on axial CT images showing the largest size. Aggregation of smaller nodules (<6 mm) was not counted as a nodular consolidation. When a nodule and a cavity coexist, we consider it to be a thick wall cavity when the cavity accounts for more than 60 per cent of the volume of the nodule; otherwise, we consider it a nodule combined with cavity. Examples of the PN are shown in Figure 2. Cases with apparent calcified lesions in the lungs were also recorded. Location of each NC was also recorded based on the natural anatomy of lung lobes. In addition to the comparison of PN features among DS, MDR, and XDR patients, a comparison was made between DS patients from China and DS patients from Eastern Europe. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 2 Examples of chest PN in tuberculosis patients with maximum diameter labeled (A-T). (B) The lower nodule with dotted line was not counted because the diameter did not reach 6 mm. In (J) and (Q), cavitation is present within the nodule, but no more than 60%, so it is still counted as nodules. (R) A nodule adjacent to a thick-walled cavity. PN, pulmonary nodular consolidation.

Statistical analysis

Data analysis was processed using GraphPad Software (GraphPad Software Inc., San Diego, CA, USA). Categorical and continuous variables were analyzed by the Chi-squared test and Mann-Whitney U test, respectively. A two-sided P value <0.05 was considered statistically significant, >0.1 as not significant, and between 0.05 and 0.1 as with a trend of significance. Receiver operating characteristic (ROC) curve analysis was used to determine the diagnostic performance, reporting the area under the ROC and optimal cut-off values with sensitivity and specificity.

Results

The PN prevalences were the same between Chinese DS patients and Eastern European DS cases (Figure 3). The mean PN number was slightly and statistically non-significantly higher among Eastern European patients than among Chinese patients (Figure 3). However, calcification on lung CT was also slightly more common among Eastern European cases than among Chinese patients (16.2% vs. 13.9%), suggesting the higher PN number among Eastern European cases could be due to those Eastern European cases had a longer disease history.

Figure 3 DS patient comparison of Eastern European cases and Chinese cases for PN prevalence according to PN number per positive case (A) and the lung calcification prevalence (B). The prevalence of PN is similar between Eastern European cases, however, for the positive cases, a trend is noted that Eastern European had higher PN number per case (A). The prevalence of lung calcification is slightly higher among Eastern European patients (B), which suggests that the Eastern European patients might have had a longer disease history. Overall, this graph shows the CT data of Eastern European patients and Chinese patients are broadly comparable. CT, computed tomography; DS, drug-sensitive; PN, pulmonary nodular consolidation.

For the new DS cases, the PN prevalence and mean PN number per PN positive case were almost the same for cases without anti-TB treatment, cases with ≤14 days anti-TB treatment, and all new DS cases, being slightly over 39% for prevalence and 2.40 for mean PN number (Table 2, Figure 4). For the new DR cases, the PN prevalences were almost the same for cases without anti-TB treatment, cases with ≤14 days anti-TB treatment, and all new DR cases, being around 71%. Mean PN number per PN positive case was slightly higher for DR cases with >14 days anti-TB treatment, but there was little difference for new DR cases without treatment and new cases with ≤14 days anti-TB treatment (Table 2, Figure 4). Therefore, in the following analysis, the treatment history was not considered for new patients.

Figure 4 A comparison for new patients with first CT image taken (I) before anti-TB treatment (≤0 pts), (II) with anti-TB treatment ≤14 days (≤14 d pts); (III) all-inclusive new patients. (A) The mean number of PN per PN positive patient was nearly the same regardless of the treatment status. (B) The comparison of PN number for PN positive DS patients with first CT image taken before anti-TB treatment (n=68) and with anti-TB treatment ≤14 days (n=73). X-axis in B is the ranked patient order. CT, computed tomography; d, day; DS, drug-sensitive; MDR, multidrug-resistant; PN, pulmonary nodular consolidation; pt, patient; TB, tuberculosis; XDR, extensively drug-resistant.

The prevalence, mean number and diameter of PN for DS and DR cases are shown in Table 3 and Figures 5,6. For new patients, the PN prevalence was higher for DR cases than for DS cases (around 70% vs. around 39%). PN prevalence increased for DS cases from around 39% for new patients to 59% for treated patients, but the increases for MDR/XDR cases were minimal. For new patients, the median PN numbers for positive cases were the same for DS and DR cases (=2/PN positive case), while the mean PN number for positive cases was slightly higher for DR cases (DS =2.38, MDR =2.89, XDR =2.72). For treated cases, the median PN number for positive cases was higher for XDR cases (=3/PN positive case), while the mean PN number for positive cases was higher for DR cases and being even higher for XDR cases (DS =2.54, MDR =3.91, XDR =4.99). For new patients, there was no difference in TB lesion calcification between DS cases and MDR cases. For previously-treated patients, TB lesion calcification was more prevalent in DR cases (DS =38.5%, MDR =48.3%, XDR =52.8%, Table 3), suggesting that the severity of PN lesion could be partially explained by that the DR patients had a longer disease history.The ROC analysis results for using PN numbers to suggest a diagnosis for DR are shown in Table 4. For new patients, PN No. ≥2 had a specificity of around 79.3% and a sensitivity of 45.5% suggesting the diagnosis of MDR/XDR. For both new patients and treated patients, PN No. ≥3 had a specificity of around 85% suggesting the diagnosis of XDR/XDR. For new patients, PN No. ≥4 had a specificity of >95.5 % suggesting the diagnosis of MDR/XDR.The lung field distribution of PN is shown in Table 5. For both DS and DR patients, PN was most commonly seen in the upper right lobe. The number of lung fields with PN lesion was higher for DR cases than for DS cases. PN was more commonly seen in the lower lobes for DR cases than for DS cases. DR cases were more likely to have bilateral PN lesions. PN lesions were even more widely spread in XDR cases than in MDR cases.

Figure 5 Prevalence of PN (A₁,A₂) and number of PN per PN positive case among DS and among DR patients (B₁,B₂: scatter plots; C₁,C₂: median and 95% CI; D₁,D₂: mean and SD). For DS cases, previously treated patients have higher PN prevalence while this difference between DR cases was minimal. The mean PN number was higher among DR cases, and this is more apparent with previously treated XDR patients. CI, confidence interval; DR, drug-resistant; DS, drug-sensitive; MDR, multidrug-resistant; PN, pulmonary nodular consolidation; SD, standard deviation; XDR, extensively drug-resistant.

Figure 6 Prevalence of PN of certain sizes in DS, MDR, and XDR patients. X-axis: NC diameter in mm. Y-axis: percentage prevalence of PN number of ≥1 (A), ≥2 (B), ≥3 (C), and ≥4 (D). Compared with DR cases, fewer DS patients had PN ≥2. DR, drug-resistant; DS, drug-sensitive; MDR, multidrug-resistant; NC, nodular consolidation; PN, pulmonary nodular consolidation; XDR, extensively drug-resistant.

Discussion

Since the publication of our earlier systematic review in 2018 (5), more articles on potential lung imaging feature differences between DS and MDR have been published. Most of these articles suggest a trend that the more extensive lesions seen with DR patients were also associated with a longer TB disease history of DR patients than that of DS patients, and this was more so with XDR patients. In a CT study conducted in China, Li et al. (23) studied 212 patients with MDR and 180 patients with DS. Previously treated patients accounted for 75.9% of the MDR cases and 35.0% of the DS cases. The duration of previous anti-TB treatment (months) was 8.0±12.0 for MDR cases and 1.0±2.0 for DS cases. The presence of cavities was seen in 74.1% of the MDR cases and 47.8% of the DS cases. Thick-walled cavities were seen in 34.9% of the MDR cases and 16.7% of the DS cases. Destroyed lungs were seen in 20.3% of the MDR cases and 7.8% of the DS cases. In a chest radiograph study in Indonesia, Zuhriyyah et al. (24) compared the chest radiograph findings of children (<18 years old) with 38 DS patients and 31 DR patients (RR =6, MDR =20, pre-XDR =4, XDR =1). More children with DR were classified as severe TB (50% DR vs. 19% DS). Cavity was observed in 29% (9/31) of DR patients, while in only 2% (2/38) of DS patients. In DR patients, 89% (8/31) of the cavity positive patients had multiple cavities. ‘Consolidation’ was observed in 68% (21/31) of DR patients, while in only 18% (7/38) of DS patients. Calcification was observed in 23% (7/31) of DR patients, while in only 5% (2/38) of DS patients. Fibrosis, a sign for chronicity, was observed in 42% (13/31) of DR patients, while in only 13% (5/38) of DS patients. The higher prevalences of calcification and fibrosis suggest that DR patients had a longer TB disease history. In a CT study conducted in Indonesia with 36 DS and 34 MDR patients, Messah et al. (25) reported a higher number of multiple cavity cases (cavity number >3, n=25 in MDR and n=11 in DS), a bigger diameter of cavity (median 38 mm in MDR and 17.5 mm in DR), and a thicker cavity wall (median 6 mm for MDR and 4.5 mm for DS), seen in MDR patients than in DS patients. In the meantime, bronchiectasis, a sign of chronicity, is more common in MDR patients (88.2%) than in DS patients (58.3%). Fibrosis distribution was also wider among MDR patients than among DS patients. In a CT study conducted in Korea, Shin et al. (26) investigated 90 patients with new MDR patients and 90 age- and sex-matched patients with new DS. Fibrotic scar was noted in 46.7% of MDR patients and in 36.7% of DS patients. Bronchiectasis was noted in 32.2% of MDR patients and in 20% of DS patients. These data also suggest that their MDR patients had longer TB disease history. Segmental to lobar consolidation (63.3% vs. 35.6%), cavity in consolidation (35.6% vs. 15.6%), cavitary nodule or mass (51.1% vs. 37.8%), and bilateral involvement (64.4% vs. 38.9%) were all more frequent in patients with MDR than in those with DS. In a CT study conducted in Iran, Mehrian et al. (27) compared CT findings of MDR (n=28) and XDR (n=17) patients. Patients with XDR had more parenchymal calcification (64.7% vs. 28.6%), suggesting higher chronicity for XDR cases. Lesions in nodule or mass pattern had a prevalence of 57.1% for MDR cases while 70.6% for XDR-cases. In a CT study conducted in China, Zhang et al. (28) reported a TB cavity prevalence of 76% in their 240 MDR patients. This lung cavity prevalence is high compared to the reported cavity prevalence for DS patients, but consistent with reported lung cavity prevalence for MDR patients (5). In a study on MDR cases in India, Jain et al. (29) described that, with the introduction of molecular diagnostic tools for the upfront diagnosis of all TB cases, there was a substantial reduction in the median time from the onset of symptoms to diagnosis between 2015 and 2020. In 2015, a higher frequency of cases exhibited cavitations, bronchiectasis, and fibrosis on chest radiograph compared to the findings in 2020. A higher occurrence of significantly advanced cases was noted in 2015 in contrast to 2020. The mean cavity size in 2015 measured 6.73 cm, while in 2020 it averaged 4.06 cm. Bronchiectasis was noted in 90% of the 2015 cohort, and in 64.3% of the 2020 cohort. All these reports described in the current paragraph suggest the more extensive lesions seen in MDR patients might be partly due to the fact that they had a longer TB disease history. Most existing literature cannot clearly establish whether MDR patients intrinsically have more extensive pathologies, or the higher prevalence and extent of lung lesions in MDR patients were purely due to MDR cases being associated with a longer disease history and less responsive to first line anti-TB treatment.

With the intent to solve the question discussed above, we have recently conducted two studies to compare lung CT features of DS patients and RR/MDR patients with matched disease history length (20,21). The results of these two studies tentatively suggested that MDR patients intrinsically have more extensive lung pathologies. For the current study, in new patients, there was no difference in lung lesion calcification (a sign of chronicity) prevalence among DS (16.9%), MDR (15.4%), and XDR (12%) patients. In previously treated patients, lung calcification prevalence was 38.5% for DS, 48.6% for MDR, and 52.8% for XDR. Thus, for previously treated cases, a high possibility existed that DR cases have a longer disease history than DS cases. In the current study, for new patients, PN prevalence was around 40% for DS cases while around 70% for DR cases. For previously treated patients, the PN prevalence for MDR was also the same (i.e., 74.4%), however, the PN prevalence for DS cases increased from 40% to 59%. For previously treated patients, it is also noted that XDR cases had a higher PN number per positive case than MDR. Compared with MDR cases, this study shows XDR had similar prevalence of PN, being around 70–75%. Thus, one notable result of the current study is that, despite calcification being slightly more common in DS new patients, PN is more common in MDR/XDR new patients. Overall, it is more likely that the MDR/DS number ratio for PN per positive case would be likely around 1.2–1.5 (Table 6). However, the current study showed there was no difference in PN diameter for DS and DR patients. The number of lung fields with PN lesion was higher for DR cases than for DS cases. DR cases were more likely to have bilateral PN lesions. PN lesions were more widely spread in XDR cases than in MDR cases (Table 5). Overall, the current study further supports our earlier studies that MDR patients intrinsically have more extensive lung pathologies (20,21).

To further clarify whether DR patients are associated with more extensive lung lesions, another analysis approach is to compare the lung imaging features among DS, RR, MDR, and XDR patients (Table 7). In our ‘Dalian study’ in China, there were 21 DS patients, 11 RR patients and 7 MDR patients with a disease history of <1 month. Median PN and cavity numbers for DS patients with a disease history of <1 month (n=21) were 0 and 1 (mean number: 0.53 and 1.2) respectively; median PN and cavity numbers for RR cases were 2 and 1 (mean number: 1.54 and 2.36) respectively; median PN and cavity number for MDR cases were 3 and 3 (mean number: 4 and 4), respectively [re-analyzed with raw data from (20)]. In a chest radiograph study conducted in Pakistan by Saifullah et al. (30), cavity was seen in 13.6% (27/198) of the DS patients, 35.2% (62/176) of the RR patents, 87.2% (170/195) of the MDR patients, and 90.9% (10/11) of the XDR patients. Among their patients, 75.3% of the DS were new patients, and 9.1%, 9.2%, and 9.1% of the RR, MDR, and XDR were new patients respectively. It is interesting to note that, though no major difference in history was identified between RR patients and MDR/XDR patients, RR patients had a much lower cavity prevalence than MDR/XDR patients (Table 7). In a chest radiograph conducted in Uganda, Oriekot et al. (31) analyzed chest radiograph findings of 139 DS and 26 RR TB cases. Consolidations were in 74.8% of DS patients and 88.5% of RR patients. Cavities were seen in 38.1% of DS patients and 46.2% of RR patients. For these patients, chronicity signs of fibrotic bands and bronchiectasis were slightly more prevalent in DS patients (30.9% and 31.7%) than in RR patients (26.9% and 23.1%). Taken together, the findings above suggest that, regardless of disease history, RR patients had less frequent PN and cavity lesions than MDR/XDR patients. For the lung lesion extent, the current study shows, DS had less lesion distribution than MDR even for new patients (Table 5), where the frequency of the chronicity sign of calcification is not lower among DS patients (16.09% for new DS patients, 15.04% for new MDR patients). XDR also had more lesion distribution than MDR for new patients (Table 5), where the frequency of the chronicity sign of calcification is not higher among XDR patients (15.04% for new MDR patients, 12.0% for new XDR patients). These results suggest that a trend may indeed exist that the frequency of some radiological features is DS < RR < MDR/XDR.

The general perception of many practicing radiologists is that there is no chest imaging feature difference between DS and MDR patients, and it is impossible to differentiate MDR from DS based on chest imaging. This study shows, consistent with our earlier results (20,21), PN number ≥3 offers reasonable specificity, being around 85%, for suggesting the diagnosis of MDR, though the corresponding sensitivity is low (being around 30%). The strength of this study is that the data were from multi-national multi-centers with relatively large sample sizes, particularly the sample size for XDR patients was unusually large. One limitation of the current study is that it was not possible for us to precisely quantify the disease history length for each patient. On the other hand, it is also possible that our sample may represent the real-world scenario we might encounter. Disease history length is a subjective measure by patients themselves. Patients from rural/remote areas might only present to the hospital until their discomforts reach a certain degree, or their discomforts have protracted for a long period of time. This study only investigated one particular sign of chest CT assumed related to DR status of TB patients, i.e., PN, other CT features, such as cavity prevalence, cavity size, and cavity wall thickness, will be further investigated in further studies.

Conclusions

In conclusion, this multi-national multi-center study further supports the earlier observation that the prevalence of PN is higher among MDR/XDR patients than among DS patients. In this study, among DS patients, PN prevalence was increased in previously treated patients than in new patients. When PN number is ≥3, then a possible diagnosis of DR should be suggested with an overall specificity of around 85%. This study further supports the notion that we should consider patient disease history length when analyzing the chest CT features of TB patients.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-832/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-832/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-832/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-832/coif). Y.X.J.W. serves as an unpaid editorial board member of Journal of Thoracic Disease from April 2024 to June 2026. The other 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. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by ethics boards of the Third People’s Hospital of Shenzhen and the Shenzhen Center for Chronic Disease Control. Informed consent was not needed due to the retrospective nature of this study.

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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