After careful review of clinical and public health records by two independent reviewers and exclusion of laboratory case contamination, we found 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: the screening of immigration referrals, the screening of extrapulmonary patients for pulmonary disease, or the screening of TB contacts or others with a positive TST/IGRA. They were usually AFB smear-negative (90.5%) and had, on average, long times-to-liquid-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 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 . Cavitation on the other hand, while previously reported to be present on chest radiograph in 30–50% of adult-type PTB patients [16–18], 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 , 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, 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 . 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%).
Notably in the above South Korean cohort, where thin collimation was presumably used, and in our own cohort where thin collimation was mainly used, evidence of endobronchial spread was not a uniform finding. As noted 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. Early reports of CT scan findings in adult-type PTB suggested that evidence of endobronchial spread was present in virtually all active PTB patients, with the exception of those with miliary disease, regardless of CT scan collimation [14, 22, 23]. Closer scrutiny of that literature, however, suggests that when sputum smear-negative culture-positive PTB patients alone were studied, the proportion with evidence of endobronchial spread on CT scan was closer to 90% [24–26]. 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 . In our subclinical patients smear-positivity and evidence of cavitation on chest radiograph, known predictors of the infectiousness of PTB, were uncommon [29–31]. 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 . 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, though chest radiographic features in those who had or had not been scanned were 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 (those of the neck) only included the lung apices; scanners and scan parameters varied. Our inter-reader variability analysis, however, suggests that there was little ambiguity about the findings. Finally, though most radiographs and CT scans were performed contemporaneously, this was not always so.
We conclude that when strictly defined, most subclinical PTB patients in Canada have minimal or no lung parenchymal disease 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.