Tuberculosis (TB) and diabetes mellitus (DM) are both important global health issues. In addition, the link between TB and DM has been demonstrated, and these conditions may complicate each other at numerous levels. Concerning the epidemiology, approximately 70% of diabetics live in TB endemic countries [1], and the World Health Organization (WHO) reported that approximately 10% of TB cases worldwide are associated with DM [2]. In addition, the summary relative risk of TB in people with DM is 2.52 (95% CI: 1.53 to 4.03) in 4 cohort studies and 2.20 (ranged from 1.16 to 7.81) in 10 case-control studies [2,3]. In a cohort study by Leung et al, poor glycemic control was significantly associated with the occurrence of TB [4]. Another study from South Africa further demonstrated a correlation between active TB and the level of glycosylated hemoglobin (Hb_A1c) with a hazard ratio of 1.39 (95% CI: 1.18–1.63) per unit increase [5].

In addition to an increased risk of developing TB, DM increases TB disease severity [6] and may lead to an increased risk of delayed sputum conversion, treatment failure, and recurrence/relapse after TB treatment [6,7]. Therefore, diabetic TB patients can play a critical role of TB transmission.

The effect of DM on the radiological manifestation of pulmonary TB (PTB) using chest radiographs (CXRs) was investigated over the past 20 years. These studies demonstrated that diabetic PTB patients might exhibit an increased frequency of atypical features, including lower lobe disease [8,9], less reticulonodular opacities [10], and more extensive disease [9,11–13]. In contrast, several studies revealed no obvious radiological differences between diabetic and non-diabetic PTB patients [10,14–16]. A relatively small number of study cases, inconsistent consideration of the influence of age and gender and the effect of different glycemic control levels may partially explain the mixed results of these reported studies. In 2014, a study with a larger sample size enrolling 581 culture-positive PTB cases with DM and similar number of non-DM PTB cases by Chiang et al. demonstrated an increased frequency of lower lung field opacity and extensive parenchymal involvement in diabetic PTB patients [17]. Moreover, this study indicated that the risk of lower lung field disease is potentially correlated with glycemic control in DM.

On the other hand, the CT findings of PTB in diabetic and non-diabetic cases were only investigated in one study with a small number of cases (31 DM cases, 71 cases without underlying disease) by Ikezoe and colleagues [18]. The results revealed an increased prevalence of non-segmental distribution of lesions in DM patients, but no significant difference in disease location was noted compared with the controls. To the best of our knowledge, no study has investigated the relation between glycemic status and CT findings of PTB diabetic patients.

DM may exhibit a risk for PTB and impact radiological manifestations of PTB in diabetics. In this study, we intended to evaluate the differences of CXRs and thoracic CT findings of PTB between diabetics and non-diabetics and further address the impact of glycemic status on imaging features of PTB in DM patients.

Consistent with the results of previous reports [8–13,17,26], our results demonstrated that unusual manifestations on CXRs were more frequently noted in diabetics compared with non-diabetics. An increased frequency of unusual findings and unusual location of disease on thoracic CT scans were also noted in diabetic PTB patients. Therefore, diabetes may have potential effects on the radiological manifestations of PTB. Moreover, we found that diabetic patients had more extensive PTB disease on both CXRs and thoracic CT scans. Given the increased frequency of atypical radiological findings and unusual location of PTB lesions in our results, the relevant difficulty in image interpretation leading to a delay of diagnosis by clinicians may partly contribute to the more extensive lung involvement of PTB in diabetic subjects.

The mechanisms underlying atypical image findings of PTB in diabetic patients remain unclear. Immune derangements (or dysfunctions) were identified in the studies of both hyperglycemic mice [27,28] and diabetic individuals [29–31], which might play a vital role in their TB susceptibility. The predominant abnormalities affect the cell-mediated arm of the immune system. However, there was no definite correlation of dysfunctional immune process and radiological manifestations of PTB. In the study of Perez-Guzman et al [8], although a reduced number of non-lymphocyte leukocytes were observed in diabetic PTB patients, it did not statistically contribute to the atypical radiological images. Additionally, no difference of lymphocyte counts in peripheral blood was noted between diabetic and non-diabetic TB subjects. In terms of pulmonary physiology, Perez-Guzman and colleagues reported an increased frequency of lower lung lesions in elderly non-diabetic TB patients and in all ages of diabetic TB subjects [26]. Additionally, similar structural modifications of alveoli and pulmonary microvasculature were observed in the aging process and diabetes [32]. Accordingly, they postulated that similar physiological dysfunction with an increased ventilation/perfusion (V/Q) ratio and a consequent increased alveolar oxygen pressure (PAO₂) might predispose the growth of Mycobacterium tuberculosis in the lower lung fields of diabetic patients. However, in a small sample size study of ventilation-perfusion scintigraphy among diabetics exhibiting a high V/Q ratio in 40% of the patients (8 out of 20), only one case had this physiological change in the lower lobes [33]. Therefore, the correlation between pulmonary physiological dysfunction and atypical lower lung field TB in diabetics deserves verification through further studies.

Our study also explored the correlation between glycemic status and radiological manifestations of PTB in diabetic patients. Individuals of poor glycemic control with Hb_A1C > 8% were more likely to have unusual CXRs findings and more advanced disease. In contrast, the post-primary TB pattern was more frequent in those with Hb_A1C ≤ 8%. Our results were consistent with the findings of Chiang’s report [17]. Regarding thoracic CT manifestations, a statistically significant higher prevalence of unusual findings and lesions involving all lobes of the lung were noted in diabetics with Hb_A1C > 8%. Accordingly, glycemic status has a potential effect on radiological manifestations and disease extent in diabetic PTB patients.

In the 41 diabetic PTB patients with Hb_A1C > 8% exhibiting unusual CXRs findings, 11 of them received thoracic CT scans (Table 4). However, although the thoracic CT images were expected to provide more detailed and thorough diagnostic information, a straightforward diagnosis of PTB could only be made in four (cases 1, 2, 8, and 10) of the 11 patients by the reading physicians. Therefore, as a possibly limited role of thoracic CT scans in aiding the diagnosis of PTB in poorly controlled diabetic patients, a high index of suspicion with early clinical work-ups are absolutely critical for PTB detection in these subjects.

The study had some limitations. First, the retrospective nature and limited patient sample size in the current study may introduce a possible selection bias, which potentially limited our conclusions. Second, the image protocol could not be uniformly implemented in all cases due to the retrospective study design, especially in the thoracic CT scans. Third, the results of our findings may not be generalized to the areas or countries with non-endemic TB. Fourth, although our study demonstrated a possibly limited role of the thoracic CT scans in aiding the diagnosis of PTB in poorly controlled diabetic patients, a small sample size may not achieve a solid conclusion. Further studies with larger study populations are needed to clarify this issue. Finally, Mycobacterium tuberculosis strains were not studied. Our previous work indicated that Mycobacterium tuberculosis strains might affect the radiological presentation of PTB [34]. However, our results may still have clinical relevance. Given the increased frequency of unusual radiological findings and extensive disease on CXRs and thoracic CT scans of PTB observed in diabetics, those without appropriate glycemic control may have an even higher risk. Therefore, when interpreting chest images, radiologists and chest physicians should pay more attention to diabetic patients with poor blood sugar control to avoid underdiagnoses of PTB.

Unusual radiological patterns with atypical locations and extensive PTB disease were more frequently observed in diabetics. Among them, subjects with poor blood sugar control exhibit a higher risk. Awareness of these unusual radiological features of PTB on CXRs and thoracic CT scans in the diabetic patients as well as a high index of suspicion in those with poor glycemic control are of considerable value in establishing an early diagnosis of PTB and avoiding treatment delays. Further studies are needed to clarify these issues.