The present study is the first nationwide report on the outcome of anti-TB treatment in advanced age. It has three crucial findings. First, the incidence rate of PTB is exponentially correlated with the age that elderly adults are the major reservoir of PTB infections in Taiwan. Second, although the anti-TB treatment completion rate has increased following the implementation of directly observed treatment, short course (DOTS) programme in Taiwan since 2006, elder patients with PTB remained to have longer treatment delays and worse outcomes, particularly those with underlying comorbidities. Third, the length of treatment delay is inversely correlated with the treatment completion rate. The treatment delay can be shortened by applying rapid molecular diagnostic tools such as the MTB–NAAT. The extent of benefit is even greater among the elder patients and those with smear-negative PTB. Given the increasing elderly populations worldwide, the findings of the present study can serve as a reference for policies regarding TB care.
According to a World Health Organization report, the TB notification rate increases with age worldwide . As a result of population ageing, the proportion of elder TB patients increased steadily from 1990 to 2015 . The gradual deterioration of the immune system (involving both the host’s capacity to respond to infections and the development of long-term immune memory as age increases, referred to as immunosenescence) may be the major contributor [18, 19]. Other factors, such as malnutrition, poverty, decreased access to health services, comorbidities, and iatrogenic immunosuppression, also contribute to the higher risk of infection in ageing populations [20,21,22]. However, the correlation between age and PTB incidence has never been calculated, and reports on advanced aged population are currently lacking. This is the first study showing that the risk of PTB not only increases but is exponentially correlated with age (R
2 = 0.962; Fig. 2).
Because of the high prevalence of underlying comorbidities, anti-TB treatment in elderly patients is frequently complicated by drug–drug interaction and adverse drug reactions, leading to an increased rates of regimen modification and default [8, 23]. Consequently, advanced age increases the mortality rate of TB significantly and eclipses the treatment completion rate [23,24,25,26,27]. In this study, the treatment completion rate among patients ≥65 years old was comparable to the two previous reports (71%–73%) [25, 26]. An even lower treatment completion rate was demonstrated among those with age ≥ 80 years.
Another crucial contributor to poor outcomes in elderly patients with PTB is the delay in anti-TB treatment. The clinical symptoms and radiographic findings of PTB in elderly people tend to be less specific [25, 28, 29]. Extrapulmonary TB including TB meningitis, osteomyelitis or urological involvement is more common with advancing age . Combined with decreased access to health services , the atypical manifestations of TB in elder people result in a delay in the diagnosis and treatment [24, 28, 29]. As shown in the present study, prescription of airway medications and antibiotics occurred early in the course prior to chest x ray examination as well as the diagnosis of PTB, suggesting that these cases are already symptomatic and may be infectious in the community and health care system for a long period. Moreover, even when chest radiography is ordered, the duration of treatment delay is still far from negligible, indicating that a high proportion of patients presented with non-diagnostic radiographic findings, particularly in elderly patients. Consistent with previous studies, treatment delay increases mortality rates in patients with PTB [31, 32].
A treatment delay may result from either a delay in seeking health service (patient delay) or failure in establishing diagnosis and starting treatment (provider delay) [6, 33]. In countries with a high TB burden, insufficient patients’ awareness for the TB disease and financial barrier are major contributors for delay in diagnosis . In countries with a low TB burden, the percentage of advanced pulmonary TB with positive sputum smear and cavitary lesions steadily increased due to declining clinicians’ vigilance to the presentations of TB and a lack of efficient diagnostic tools to diagnose TB in its early stage [34, 35]. Because of the built-in shortage of claims data, patient delay cannot be accessed in this study. However, the median of provider delay among patients aged 65–79 years was 32 days longer than that among those aged <65 years (53 vs 21 days). For those aged ≥80 years, the impact can be higher since the treatment delay is longer. In addition to the negative impact on treatment outcome, failure to recognise active PTB cases increases the risk of transmission , thus constituting a major hindrance to effective control for TB.
Because ageing is a well-known risk factor for adverse events during anti-TB treatment [8, 23, 37], for safety concerns, physicians are becoming increasingly hesitant to initiate anti-TB treatment unless solid bacteriologic evidence exists. Furthermore, because of the improved accessibility of health services in Taiwan, patients tend to seek medical help while their disease is minimal. This probably explains why an initial medical visit in an urban area is associated with a longer treatment delay than in a rural area. Implementing MTB–NAAT was shown to reduce treatment delay (Table 3), especially among the elderly and smear-negative PTB cases. These findings support the implementation of a rapid molecular assay for PTB diagnosis.
Most patient factors leading to treatment non-adherence can be eliminated with supervision, resulting in an improved treatment completion rate and reduction in unfavourable outcomes . Under Taiwan’s national TB programme, DOTS has been implemented countrywide since 2006. The findings of this study support the continuous government commitment to TB control and the necessity of continuing DOTS programme in Taiwan.
The present study has some limitations. First, because of the built-in shortage of claims data, the results of mycobacterial studies and radiographic findings were unavailable. Second, the disease severity, a critical determinant of patient outcome, was not known. Although hospitalisation and admission to intensive care unit were used as surrogates of disease severity in this study, they may not correlate 100%. Third, the impact of the MTB–NAAT on treatment delay may be confounded by the indication, resulting in an overestimation of it benefits. Lastly and importantly, though the overall delay was calculated by fulfilling two or more events indicating TB onset, they could be due to clinical conditions other than TB. However, it may not be a considerable bias since sensitivity tests showed that the model was consistent across the broader or stricter definitions of delay in treatment.