Delays in tuberculosis (TB) treatment have been reported to be a primary source of ongoing TB transmission because of the prolonged infectious period [1]–[3]. The World Health Organization (WHO) reported that China has made significant progress in TB control and prevention in the past decade, with prevalence being halved and mortality reduced by 78%, suggesting that case detection has improved in China as well [4]. As new diagnostic tools are introduced, treatment delay can be reduced, leading to earlier therapy and interruption of disease transmission [5]–[7]. Despite this, TB patients in China are generally identified passively when patients self-present with illness rather than through screening actively and therefore are generally not treated until illness [8].

Risk factors associated with a delay in the diagnosis and treatment of TB have been identified [1]–[3], [9], [10], but the impact of this treatment delay on TB transmission in the community, to our knowledge, has not been well studied in China. In this study, we aim to estimate the effect of treatment delay on the risk of transmission of TB. Data from this kind of study are important for TB policy making on an international scale [11].

The study included 48,441pulmonary tuberculosis patients, among whom median age was 27 years, 63% were male, and 78% were migrants (Table 1). Overall, 70% presented with symptoms of pulmonary TB, 62% were sputum smear positive, and 21% had a pulmonary cavity on chest x-ray identified at presentation. Among the 2261 (4.7%) patients identified by routine physical examination, 11% already had symptoms of pulmonary TB, 31% were already sputum smear positive, and 5% already had a pulmonary cavity on chest x-ray. The remaining 95.3% of patients self-presented to the healthcare system for medical evaluation of illness and were diagnosed with TB after a median duration of delay of 18 days. The proportion presenting sputum smear positive and with a pulmonary cavity increased significantly with increasing duration of delay () for sputum smear positive; () for pulmonary cavity positive).Yearly delay decreased over time from 1993–2010 (). Overall median duration of treatment delay declined significantly from 1993–2010 (, Figure 1B). The proportion of tuberculosis patients identified by physical examination remained stable from 1993–2008, then increased in 2009–2010 (, Figure 1C), with the decline primarily due to the decreasing proportion of patients with treatment delay ≥60 days (, Figure 1C).

In a 3-level multivariate logistic regression analysis, compared with patients identified by routine physical examination, the risk of patients presenting with smear positive tuberculosis was 2.6 fold () greater for delay <14 days, 3.9 fold () greater for delay 14–29 days, 5.4 fold () greater for delay30–59 days, and 7.6 fold () greater for delay ≥60 days (Table 2). Similarly, patients were 2.2 fold (), 3.3 fold (), 4.0 fold (), and 5.0 fold () more likely to present with a pulmonary cavity with delays of <14 days, 14–29 days,30–59 days, and ≥60 days, respectively, compared to those identified on routine physical examination (Table 2).

In a multivariate regression analysis of risk factors associated with treatment delay, women () were associated with longer treatment delay (Table 3). Those who presented with constitutional symptoms alone were diagnosed and started on treatment earlier than those with respiratory symptoms alone () or with both respiratory and constitutional symptoms (), suggesting that respiratory symptoms are often misdiagnosed, delaying appropriate TB treatment (Table 3).

In our retrospective study of 48,441pulmonary TB patients in Shenzhen, China from 1993–2010, 95.3% of TB patients self presented for medical evaluation after a median 18 days of illness. The remaining 4.7% of patients were diagnosed with TB during a routine physical examination. Overall, 61.6% presented sputum smear positive and 21.3% presented with a pulmonary cavity on chest x-ray, with the proportion sputum smear positive and pulmonary cavity positive both increasing significantly with increasing duration of treatment delay. Those with delays ≥60 days were 7.6 times () more likely to be sputum smear positive and 5.0 times () more likely to have a pulmonary cavity compared to those identified with TB during a routine physical examination. Because being sputum smear positive and having a pulmonary cavity are associated with a higher risk of TB transmission [20], [21], reducing treatment delay would thereby reduce the risk of TB transmission.

Many studies in multiple countries have assessed the factors associated with diagnostic and treatment delays, with the associated factors primarily related to patients or the healthcare system [22]–[28]. One common factor for delay across many of the studies was the lack of sufficient awareness of the symptoms and signs of TB among the general public and healthcare providers, causing either a delay in presentation or in diagnosis. In our analysis, due to its retrospective nature, we were unfortunately not able to analyze the specific reasons for delay. Instead, we analyzed the effect of the duration of treatment delay on the proportion sputum smear positive and pulmonary cavity positive. We used these two measures as a proxy for TB transmission risk because they have both been associated with TB transmission [20], [21]. Our analysis demonstrates the significantly increased risk of sputum smear positivity and proportion developing a pulmonary cavity with increasing duration of treatment delay, with those delaying more than 2 months having a 7–8 fold increased risk (Table 2). Additional studies are needed to understand not just how to incorporate individual interventions to reduce disease transmission, such as conducting physical examinations of migrants, patient and provider education, improved diagnostic tests, and active case finding, but how to incorporate a multi-factorial, combination strategy that not only seeks to reduce disease transmission but also aims to reduce disease progression from latent to active disease [29]. Both of these types of strategies will likely be needed to ultimately control the TB epidemic.

The duration of treatment delay in Shenzhen gradually decreased from 1993–2010, particularly among those with delays ≥60 days (Figure 1B), which is consistent with the global trend [30]. Although we were not able to identify specific reasons for this trend in our analysis, Shenzhen began providing free treatment for all TB patients in 2002 [16] and has systematically improved its overall TB control strategies [17], [18], especially for migrants [16], [18]. These policies may have played a significant role in reducing diagnostic and treatment delay. Our study identified no significant variance in treatment delay duration between migrants and non-migrants in Shenzhen. Although this is different from previous studies elsewhere in China [31], [32], other cities also do not consist of 80% migrants [14] and have not provided a similar level of support services to migrants as Shenzhen.

Our work is subject to certain limitations. First, the duration of treatment delay may be influenced by recall bias and may not be exactly accurate. However, this should not affect the overall trend and should also be the same for all patients, thus would not affect our finding an association between sputum smear positivity and having a pulmonary cavity with increasing duration of treatment delay. Second, we were not able to measure actual disease transmission and thus used two proxy measures. However, these two measures have been are well associated with TB transmission and have been used by previous studies [20], [21]. Finally, we were not able to identify specific factors, such as policy change, related to treatment delay from our data due to its retrospective nature. However, this question has been studied repeatedly by other groups and we have no reason to believe that treatment delay factors in Shenzhen would be any different.

Delays in TB diagnosis and treatment carry significant risks of worsening disease severity to the patient and increased risk of transmission to those around him/her. The challenge is to determine how to reduce this duration of delay, particularly in resource-limited settings where rapid diagnostic techniques may not be available or affordable. Shenzhen has done a commendable job already of reducing treatment delay duration ≥60 days and further studies are needed to understand the specific factors that contributed to this decrease.