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A comparison of the chest radiographic and computed tomographic features of subclinical pulmonary tuberculosis

Subclinical pulmonary tuberculosis (PTB) is a recently described intermediate state of great interest, but about which little is known. This study sought to describe and compare the frequency of key radiologic features of subclinical PTB on chest radiograph (CXR) versus computed tomographic scan (CT), and to interpret the clinical and public health relevance of the differences. Diagnostic CXRs and CT scans of the thorax and neck in a 16-year cohort of subclinical PTB patients in Canada were re-acquired and read by two independent readers and arbitrated by a third reader. Logistic regression models were fit to determine how likely CXR features can be detected by CT scan versus CXR after adjustment for age and sex. Among 296 subclinical patients, CXRs were available in 286 (96.6%) and CT scans in 94 (32.9%). CXR features in patients with and without CT scans were comparable. Lung cavitation was 4.77 times (95% CI 1.95–11.66), endobronchial spread 19.36 times (95% CI 8.05–46.52), and moderate/far-advanced parenchymal disease 3.23 times (95% CI 1.66–6.30), more common on CT scan than CXR. We conclude that the extent to which CXRs under-detect key radiologic features in subclinical PTB is substantial. This may have public health and treatment implications.


Methods
Institutional approval was obtained from, and informed consent was waived by, the Health Research Ethics Board of the University of Alberta, proposal ID: PRO00108560. We performed a retrospective cohort study wherein we identified all adults (age > 14 years) who were diagnosed with culture-positive PTB in the Province of Alberta, Canada (population 4,464,170 in 2021 [Statistics Canada]), between January 1, 2005 and December 31, 2020 6 . Alberta Precision Laboratories, where all mycobacteriology in the province is performed, confirmed the culture status of each patient. Patients' symptom status, i.e. whether they had one or more TB-compatible respiratory (cough [dry or productive], hemoptysis, chest pain or dyspnea), or constitutional/systemic (weight loss, fever, night sweats, fatigue) symptom had been recorded by the public health nurse and/or the attending physician, at the time of diagnosis. Final determination of symptomatic versus asymptomatic was achieved through independent review of public health and hospital records by two members of the study team. Discrepancies were resolved by consensus. Patients with extrapulmonary TB who had no respiratory symptoms were considered asymptomatic for PTB, though they may have had symptoms localized to their other site(s) of disease. Symptomatic (hereafter 'clinical') and asymptomatic (hereafter 'subclinical') PTB patients were described according to age, sex, country of birth (Canadian-born vs foreign-born), and mycobacteriologic features. The latter included smear status, average time-to-liquid-culture positivity of pre-treatment sputum or other airway secretion specimens; i.e. those specimens collected on or up to 8 weeks before the start date of treatment, and first-line anti-TB drug resistance. Laboratory cross-contamination was systematically excluded in all patients with a single smear-negative culture-positive specimen 11 . Patients who were HIV-seropositive or HIV-unknown and patients with relapse/retreatment disease or whose disease type was unknown, were excluded due to the potential impact HIV coinfection and/or past TB may have on the chest radiograph. Finally, subclinical patients were further described according to their reason-for-assessment: (1) immigration referral if foreign-born including immigrants, refugees, and some temporary residents whose admission to Canada is conditional on compliance with TB surveillance; (2) a concomitant diagnosis of extrapulmonary TB; (3) positive tuberculin skin test (TST) or interferon-gamma release assay (IGRA) identified during contact tracing, employment screening, or screening of patients at increased risk of developing reactivation TB if infected; or, (4) miscellaneous other.
The name, date of birth and personal health care number of subclinical PTB patients was used to identify records in the provincial picture archiving and communication system (PACs). The date of the posterior-anterior (PA) and lateral (LAT) chest images closest to the start date of treatment were recorded and images acquired. The dates of all computed tomographic (CT) scans of the thorax, or neck in those with cervical lymph node TB, performed in close proximity to the diagnostic chest radiograph were recorded and images acquired. Data abstraction forms were used to report and categorize the chest radiograph and CT scan features of PTB (see Supplement 1 and 2) 12 . Images were independently read by two chest radiologists (with 25 and 15 years of experience, respectively); radiographic interpretations were blind to CT interpretations. Discrepant interpretations were resolved by a third chest radiologist (with 15 years of experience).

Chest radiographic features.
i) Category: radiographic findings were categorized as 'typical' for adult-type PTB (upper lung zone predominant disease, with or without cavitation, but no discernable adenopathy), 'atypical' for adult-type PTB (abnormalities inconsistent with the definition of typical), or normal. Lung zones were determined by visualizing a perpendicular line from the apex of the lung to the hemidiaphragm and dividing the lung in half; the superior segment of the lower lobe was considered part of the upper lung zone. ii) Laterality: bilateral, unilateral, or normal. iii) Cavitation: cavitary or non-cavitary disease (a cavity defined as a gas filled space within pulmonary consolidation, a mass or a nodule); whether cavities were single or multiple and the internal diameter of the largest cavity. iv) Endobronchial spread: acinar shadows (multiple ill-defined nodules 4-8 mm in diameter). v) Adenopathy: enlarged hilar and/or mediastinal lymph nodes. vi) Extent of parenchymal disease: normal, minimal, moderately-advanced, far-advanced, or miliary according to criteria established by the US National Tuberculosis and Respiratory Disease Association (see supplement 3) 13 . In this definition, the presence of cavitation automatically infers either moderately-or far-advanced disease.
Incidental note was also made of the presence of volume loss, pleural thickening/retraction or effusion. If adenopathy alone was identified, i.e. the lung parenchyma appeared normal, the category was reported as atypical and the laterality and extent of disease were reported as normal. When the only abnormality was a single small (< 1 cm) calcified nodule (granuloma), the radiograph was reported as normal. Normal radiographs included both PA and LAT views.

Computed tomographic features.
i) Category: typical, atypical, or normal as per the chest radiograph definition with the exception that when the only abnormality was enlarged lymph nodes and enlarged lymph nodes had not been reported on the corresponding chest radiograph the scan was reported as typical. ii) Laterality: unilateral or bilateral or normal. www.nature.com/scientificreports/ iii) Endobronchial spread: either centrilobular nodules or opacities (well defined lesions 2 to 4 mm separated by > 2 mm from the pleural surface or interlobular septa) with or without "tree-in-bud" (a branching linear structure with more than one contiguous branching site) or poorly defined nodules 5-8 mm in diameter 14 , or both. iv) Cavitation: as per the chest radiograph, whether single or multiple, the internal diameter of the largest cavity. v) Adenopathy: hilar or mediastinal lymph node enlargement defined as a node > 10 mm short axis diameter. vi) Extent of parenchymal disease: normal, minimal, moderately-advanced, far-advanced as per the chest radiograph definition; determination to include review of coronal sections.
The scan type (thorax or neck), date of performance, and parameters (i.e. enhanced or non-enhanced; collimation) were recorded. A CT of the neck was accepted in cervical lymph node TB patients if, (i) it extended to the main carina, and (ii) the only abnormality, if any, on the corresponding chest radiograph was above the level of the main carina. As per the chest radiograph, note was also made of the presence or absence of volume loss, pleural thickening/retraction or effusion. Statistical analysis. To assess differences between the demographic and mycobacteriologic features in subclinical and clinical patients, we used chi square or Fisher's exact test for categorical variables and t-test for continuous variables. To quantify the level of agreement between readers for radiographs and CT scans, we report generalized kappa statistics, and for the purpose of results, we report the arbitrated values. The difference in proportions of radiographic features present in patients who underwent a chest radiograph alone versus those who had both chest radiograph and CT scan were determined using chi square or Fisher's exact test. We fit logistic regression models to determine how likely radiographic features can be detected by the CT scan versus the chest radiograph, adjusted for universal confounders, age and sex. We use the conventional p value < 0.05 for statistical significance. Methods were performed in accordance with the relevant guidelines and regulations. All analyses were performed in STATA, version 14.0.  Table 2. Kappa statistics for the chest radiograph showed substantial agreement (0.61-0.80) for category, laterality, lymph node enlargement, and extent of parenchymal disease, and moderate agreement (0.41-0.60) for cavitation and endobronchial spread. Kappa statistics for the CT scan showed almost perfect agreement (0.81-0.99) for category, laterality, cavitation, and extent of disease, substantial agreement for lymph node enlargement, and moderate agreement for endobronchial spread. As previously reported (6), subclinical patients with relapse/retreatment PTB were significantly more likely to be smear-positive and have more extensive disease on chest radiograph; hence their chest images were excluded from further analysis.

Results
Typical adult-type PTB was present on chest radiograph in 68.2% of HIV-seronegative new-active subclinical PTB patients (82.2% of those whose radiograph was abnormal), see Table 3. Normal chest radiographs were not uncommon (17.5%); 15 or 30% of patients with a normal chest radiograph were TB contacts with a positive TST or IGRA. Bilateral disease was present in 24.5%. Cavitation and evidence of endobronchial spread (acinar shadows) were uncommon, 6.6% and 7.1%, respectively. Cavities, when present, were usually small (median internal diameter 13.0 mm; IQR 9.5-16.0 mm) and singular (73.7%). Most patients with cavitation on chest radiograph had a typical adult-type PTB pattern of disease (17/19 or 89.5%). Intrathoracic lymph node enlargement was rare (3.1%); in 2 (22.2%) patients it was associated with cervical lymph node TB. The "extent of parenchymal disease" was normal in 18.9% and minimally abnormal in 67.5%. Volume loss and pleural thickening/retraction were uncommon (15.9% and 10.6%, respectively), while pleural effusion was rare (2.8%), data not shown. Radiographic features in subclinical patients who had or had not undergone a CT scan were similar, with the exception of radiograph category which was more likely to be atypical in those who underwent a CT scan versus those who did not.
Of the 286 HIV-seronegative, new-active subclinical patients with chest imaging, 94 (32.1%) had undergone both a chest radiograph and a CT scan (Fig. 1). The median (IQR) time between the two studies was 10 (2 to 27) days. There were 86 scans of the thorax and 8 scans of the neck. The median (IQR) collimation was 1.0 (1.0 to 2.5); 68 scans (72.3%) were thin section (≤ 2 mm); 62 (66.0%) scans were enhanced. Going from one diagnostic imaging modality to another (chest radiograph to CT scan), the odds of having bilateral disease were 1  www.nature.com/scientificreports/ Of the 14 patients who had no lung parenchymal disease on chest radiograph (12 with completely normal chest radiographs, 2 with intrathoracic lymph node enlargement only), 7 had minimal and 1 had moderatelyadvanced disease (with cavitation) on CT scan (see Fig. 3). Endobronchial spread on CT scan was more likely in those with than those without lung parenchymal disease on chest radiograph (52/80 [65.0%] vs. 4/14 [28.6%], p < 0.02).

Discussion
After careful review of clinical and public health records by two independent reviewers and exclusion of laboratory case contamination, we found, as previously reported 6 , that 21.4% of incident HIV-seronegative, new-active culture-positive PTB patients in this high-income, low incidence setting were subclinical. Most HIV-seronegative, new-active subclinical patients were foreign-born persons whose disease was discovered during one or other active case-finding exercise. They were usually AFB smear-negative (90.5%) and had, on average, long times-toliquid-culture positivity (median [IQR] 18.0 [14.5-25.0] days). Most (86.4%) had minimal or no lung parenchymal abnormality on chest radiograph. But, importantly, as reported herein, from a public health and possibly a treatment perspective, the chest radiograph significantly under-detected key features of disease; cavitation was 4.77 times, endobronchial spread 19.36 times, and extensive lung parenchymal disease 3.23 times more likely to be present on CT scan than chest radiograph. While many of the classical features of adult-type PTB were present on plain chest radiograph in this cohort of HIV-seronegative, new-active subclinical PTB patients, others were notably absent. Most patients whose chest radiograph was abnormal had a typical pattern of adult-type PTB -upper lung zone predominant disease, with or without cavitation, but no discernable adenopathy 15 . Cavitation on the other hand, while previously reported to be present on chest radiograph in 30-50% of adult-type PTB patients [16][17][18] , was present in only 6.6% of subclinical PTB patients. Likewise, endobronchial spread (acinar shadows), known to be highly correlated with cavitation and smear positivity, and reported to be present on chest radiograph in approximately 20% of adult PTB patients 16,17 was present in only 6.7% of subclinical PTB patients. Remarkably, normal chest radiographs were present in 17.5% of subclinical PTB patients. They have previously been reported in a proportion of adolescents and adults with primary PTB 16 , but we found that only 30% of our subclinical patients with a normal chest radiograph could be linked to recent TB contact and thus be considered to have primary PTB. Moreover, Table 3. Chest radiographic features of subclinical pulmonary tuberculosis in patients with and without a computed tomographic scan Abbreviations: PTB pulmonary tuberculosis; CXR chest x-ray; CT computedtomography. The proportions of all patients ("total" column) with the features have been previously reported (see reference #6). † Information on acinar shadows on the chest radiograph was unavailable in three patients. www.nature.com/scientificreports/ intrathoracic adenopathy, another, albeit less common, feature of primary PTB in adolescents and young adults, was rare, present in only 9 (3.1%) subclinical PTB patients, none of whom could be linked to recent TB contact. That the CT scan was much more sensitive than the chest radiograph in the detection and characterization of both parenchymal disease and intrathoracic lymph node enlargement; cavitation (27.7% vs. 7.4%,), moderate to far advanced or miliary disease (42.6% vs. 19.2%), and lymph node enlargement (22.3% vs. 5.3%), was not surprising given the higher resolution of CT 19,20 . However, the magnitude of the differences in the frequencies of features on CT scan versus chest radiograph were larger than has been previously reported for adult-type PTB. For example, with respect to cavitation and endobronchial spread, differences of 58% vs 22% (2.6 fold) and 98% vs. 24% (4.1 fold), respectively, have been reported in the past using high resolution CT [14], whereas we saw 3.7 fold and 9.1 fold differences, respectively, in these two features in subclinical patients. While this may in part reflect improvements in CT scan performance characteristics (e.g. collimation, temporal resolution), it may also reflect a proportionately greater limitation of the chest radiograph in subclinical disease. We are aware of only one other study that has reported on the CT scan findings in subclinical PTB 21 . This study was performed in South Korea and although their inclusion criteria for subclinical patients differed somewhat from our own (their patients were older aged [> 18 years vs > 14 years in our study] and may or may not have been culture-positive [all of our patients were culture-positive]), the frequencies of key findings were only slightly higher than those we report; cavitation 44.4%, "tree-in-bud" (endobronchial spread) 69.1%, and multiple lobe involvement (more extensive disease) (29.6%).

Feature
Early reports of CT scan findings in adult-type PTB suggested that endobronchial spread was present on CT scan in virtually all active PTB patients, with the exception of those with miliary disease and a small fraction (10%) of those with sputum smear-negative PTB, regardless of CT scan collimation 14  www.nature.com/scientificreports/ above only 59.6% (28.6% of those with no lung parenchymal disease on chest radiograph) of our subclinical PTB patients had evidence of endobronchial spread on CT scan. While the presence of endobronchial lesions on high resolution CT may prove helpful in making a distinction between active and inactive PTB disease on chest radiograph 14,23 , their absence clearly does not rule out active subclinical PTB disease. The pathologic correlates of lung parenchymal disease in that subset of HIV-seronegative, new-active subclinical PTB patients with no evidence of endobronchial spread on CT scan, would be of special interest 14,27 . The global pandemic of COVID-19, caused by severe acute respiratory virus 2 (SARS-CoV2), has rekindled interest in the question of asymptomatic PTB transmission. COVID-19 has shown that asymptomatic infection can be important in disease transmission 28 . In our subclinical patients smear-positivity and evidence of cavitation on chest radiograph, known predictors of the infectiousness of PTB, were uncommon [29][30][31] . However, cavitation and more extensive disease were much more common on CT scan. And others have found that these same features, along with a typical pattern of disease on CT scan, have been associated with smear-positivity 24,26,32 . Although most of our patients were smear-negative, we have previously shown that shorter times-to-culture positivity, an indicator of a higher bacillary burden or more metabolically active bacteria 33,34 , and therefore, theoretically, a greater likelihood of transmission, were associated with more extensive disease on chest radiograph 6 . Almost certainly there is a radiologic/mycobacteriologic gradient of transmission risk within subclinical PTB source cases, as is known to be the case in PTB source cases in general. This same gradient may ultimately prove to be useful in determining the duration of treatment necessary to cure subclinical PTB 35,36 .
Strengths of our study include the size of the cohort, the quality and completeness of the epidemiologic, radiologic and mycobacteriologic data, and the prospective interpretation of the radiographs and CT scans by multiple highly qualified readers. Limitations include the study's retrospective design which meant that not all patients underwent a CT scan, thus raising a question about the representativeness of the sample. In support of its representativeness the chest radiographic features in those who had or had not been scanned were, for most part, comparable. The only exception was radiograph category, which likely reflected the greater probability that an atypical pattern would prompt the ordering of a CT scan. Some CT scans, specifically, those of the neck in patients whose chest radiograph had shown no abnormality below the main carina, only included the lung apices. In others,scanners and scan parameters such as collimation and enhancement, varied, though in this regard it is noteworthy that our inter-reader variability analysis suggested that there was little ambiguity about the findings. Finally, though most radiographs and CT scans were performed contemporaneously, this was not always so. Any changes that occurred in the interval separating the studies would compromise the comparison. These limitations could be overcome in a prospective study that included both CT scan and chest radiograph www.nature.com/scientificreports/ in all consenting subclinical patients, that used the same scanners and scan parameters in all patients, and that used a fixed, short, time interval between CT and radiographic imaging. www.nature.com/scientificreports/ We conclude that when strictly defined, most subclinical PTB patients in Canada have minimal or no lung parenchymal disease apparent on chest radiograph. However, when CT scans are performed in the same patients, the chest radiograph may be shown to significantly under-detect the presence of key features of potential importance to transmission risk and treatment duration.  Figure 3. Computed tomographic (CT) scan results in patients who had normal chest radiographs (patients #1-12) and in patients whose chest radiographs were abnormal but showed no lung parenchymal abnormality (patients #13 and 14). Positive findings are indicated by a black box . Back-shaded columns (3, 5, 6, 7) refer to patients who had a CT scan of the neck. Patients #3, 5, 6, 7, and 10 had concomitant cervical lymph node TB. Patients #9 and #12 were close contacts of smear-positive clinical patients. In Patient #8 (i.e. the patient whose chest radiograph was reported as normal and whose CT was reported as showing moderately advanced cavitary disease) the chest radiograph and CT scan were performed on the same day. Abbreviations: CXR chest X-ray; MOD moderately; ADV advanced.