Tuberculosis (TB) is the leading cause of death from a single epidemic disease worldwide [1], and it remains a global health problem despite advances in its diagnosis and treatment. The global incidence of TB is currently declining 1.5% per year [1], and to achieve the World Health Organization (WHO) End TB Strategy targets, this reduction rate needs to be increased by 4% to 5% per year by 2020 [2].

To reach the goals of the WHO End TB Strategy, early diagnosis to prevent TB spread is one of the most important factors for reducing the incidence of TB [3]. To enable early detection and diagnosis, the sensitivity and specificity of TB diagnostic tools must be improved. Sputum smear microscopy has been used as a primary method for diagnosing TB [4]; however, the sensitivity of this method is reportedly only 50% to 60% [5].

Because it may take a long time before TB culture test results are confirmed, not initiating TB treatment until a positive culture report is received may result in delayed diagnosis. This, in turn, may delay optimal treatment, lead to poor treatment outcomes, and increase the risk of transmission in the hospital and community. For the rapid diagnosis of smear-negative pulmonary TB, TB polymerase chain reaction (PCR), which includes the Xpert MTB/RIF assay (Xpert, Cepheid, Sunnyvale, CA, USA), is performed; however, this assay is not sufficiently sensitive and not fully implemented in real-world settings. Therefore, delayed diagnosis and treatment of smear-negative pulmonary TB are major concerns for TB control in low- and intermediate-burden areas.

We, therefore, aimed to evaluate the clinical characteristics and radiologic findings of patients with smear-negative pulmonary TB whose diagnosis and treatment were delayed and to identify risk factors that may have contributed to the delayed diagnosis.

In this study, we found that the diagnosis of more than half of all patients with smear-negative pulmonary TB (53.2%) was delayed until the confirmation of positive culture results. Such a delay could contribute to disease transmission within the hospital [10] and community. Patients with a delayed diagnosis of TB were older, had higher BMIs, and were more likely to have negative PCR results. Thus, these were factors that could potentially delay diagnosis and treatment of smear-negative pulmonary TB.

Older age was an important factor associated with missed TB diagnosis, a finding consistent with the results of previous studies [11-13]. In elderly people, clinical symptoms and radiographic findings of TB are known to be less typical and less specific [12,14], making it easier for TB to be confused with other diseases [13]. Atypical clinical manifestations of TB in elderly patients may lead to delayed diagnosis and treatment, which may be associated with poor treatment outcomes. Furthermore, because adverse reactions are more common in elderly patients undergoing anti-TB treatment [15,16], clinicians are more likely to hesitate to initiate anti-TB treatment, which can cause a delay in the diagnosis and treatment of such patients with smear-negative pulmonary TB. Previous studies have shown that the mortality rate of TB increases with older age [17]. The higher mortality rate associated with TB in elderly patients was because of underlying comorbidities, deterioration of the immune system, and delays in initiating anti-TB treatment [18]. Therefore, efforts to improve early detection and treatment in the elderly population are needed. TB is often difficult to diagnose; thus, even if typical respiratory symptoms of TB are not present, clinicians should consider the possibility of TB in elderly patients living in areas with a considerable TB burden.

In our study, BMI was significantly higher in the missed TB group than in the control group. We, therefore, assumed that clinicians may be less likely to suspect TB in patients with higher BMI, although there is limited in-depth evidence to support this assumption. Although there were significant differences in BMI in the two groups, the mean BMIs in both groups were within the normal weight range according to the WHO guidelines.

According to the Korean TB guidelines [8], broad-spectrum antibiotics—except fluoroquinolones—could be used to rule out pulmonary TB in clinical settings. However, in our study, only 38% of patients who had a possible diagnosis of pulmonary TB were treated with broad-spectrum antibiotics before their diagnosis. This might be explained by the high performance rate of chest CT (98% in our study) and easy accessibility of bronchoscopy at our institution. At our facility, when a clinician suspects pulmonary TB through chest radiographs, they tend to perform chest CT and bronchoscopic examinations to achieve an accurate diagnosis, rather than initiate a trial of broad-spectrum antibiotics in our situation.

Rapid molecular diagnostic tools have improved the diagnostic yield of TB. Our analysis revealed that positive PCR results were associated with a faster diagnosis. However, we also found that the sensitivity of PCR testing was only 47.8%. This was probably related to the properties of smear-negative TB, i.e., paucibacillary TB with low bacillary load or enzymes in the sputum, which inhibits the amplification reaction. Previous studies reported that Xpert MTB/RIF results had a sensitivity ranging from 47% to 87% [19] in the setting of smear-negative pulmonary TB. However, in real-world practice, the sensitivity of Xpert for the detection of TB is inadequate when few bacilli are present in the clinical specimen. Therefore, various attempts have been made to increase the sensitivity of the diagnosis. Although a recent report showed that the sensitivity of the Xpert MTB/RIF Ultra assay (63%) was superior to that of the Xpert MTB RIF assay (46%), neither test’s sensitivity was sufficiently high in the setting of smear-negative pulmonary TB [20]. Thus, the development of further rapid and sensitive diagnostic tools for paucibacillary TB is warranted to prevent the delayed diagnosis of possibly infectious cases of pulmonary TB.

This study had some limitations. First, our study was a single-center trial, and the results may not be applicable to other settings. Second, the retrospective design of this study was limited to the review of medical records and our data may, therefore, not be as accurate as data collected within the context of a prospective study. Thus, further prospective studies are required to confirm our results.

In conclusion, we identified clinical characteristics and risk factors associated with missed TB diagnosis in patients who initiated anti-TB treatment after receiving confirmed positive culture results. These factors could provide clues and explain why the diagnosis of TB was delayed in the missed TB group. Carefully considering the possibility of TB in an elderly population, even when symptoms are atypical, and performing diagnostic tests—including radiological imaging and molecular assays—can help clinicians with the early detection of TB.