A systematic review of delay in the diagnosis and treatment of tuberculosis

Until the last part of the twentieth century, tuberculosis (TB) was a major cause of death in both developed and developing countries. Due to a range of factors such as the human immunodeficiency virus (HIV) epidemic, population growth, migration, socioeconomic changes, and broad spread of aggressive and resistant new strains such as the Beijing and W strains, a resurgence of TB has occurred, even in low endemic areas [1]. In 1993, the World Health Organization (WHO) declared a state of global emergency for TB due to the steady worldwide increase in the disease. Along with HIV and malaria, TB has been declared a global enemy. In 2005, 12 million new cases of tuberculosis were identified, a 58% increase from the 7.5 million estimated cases in 1990, and it was estimated that in 2005 the disease caused 1.5 million deaths worldwide [2].

The goal of TB control programs is to arrest transmission within the community. Achieving this goal takes considerable time, because most individuals in endemic areas are already infected, constituting a reservoir that continuously contributes to the pool of infectious cases. An effective TB control program requires early diagnosis and immediate initiation of treatment. Delay in diagnosis is significant with regard to not only disease prognosis at the individual level but also transmission within the community and the reproductive rate of the TB epidemic [3, 4]. Most transmissions occur between the appearance of cough and initiation of treatment. Madebo et al found that patients become more contagious as the delay progresses; the longest delays are associated with the highest bacillary numbers on sputum smears [5]. Because TB symptoms, particularly chronic cough with sputum, are so prevalent in most societies, early contact with health services causes delay rather than suspicion of TB. We found that in Ethiopia patients with TB symptoms contact an educated health worker on average after just 25% of the total delay period [6]. Thus, there is a fourfold-difference in the time of first contact and diagnosis.

Analysis of the factors leading to this delay between first contact and diagnosis is crucial to combatting the increasing TB epidemic. Although there are multiple studies of delayed TB diagnosis, no one has performed a systematic review.

The studies had different definitions of a range of variables, for example, debut of symptoms, first appropriate health care provider, time to diagnosis, and start of treatment, and they were not directly comparable or suited for a meta-analysis. Rather than excluding studies that failed to meet strict scientific criteria (like in a meta-analysis), we tried to extract the "solid findings" from all of them to arrive on a more global understanding of diagnostic delay in TB. Our detailed analysis demonstrates that the interacting factors affecting patients' health-seeking behavior and the availability of TB treatment can be categorized as involving either the patient or healthcare. Most factors influence both patient and health care delay, but some factors were more closely related to patient delay: alcohol or substance abuse, poverty, low access to health care facilities, rural residence, old age, belonging to an indigenous group and incomprehensive attitudes, beliefs and knowledge about TB. Other factors were evidently more linked to health care delay: coexistence of chronic cough and/or other lung diseases, having extrapulmonary or negative sputum smear TB, less severe and indifferent symptoms or absence of haemoptysis, poor health care infrastructure and seeking traditional and private practitioners first. As patients continue to go untreated, absent isolation, both components equally contribute to the infectious pool.

Our analysis revealed that the vicious circle of repeated visits at the same level is the core problem of diagnostic delay in most high endemic countries. TB is a rare disease, and more than 95% of patients with chronic cough seeking treatment at the level of primary healthcare do not have TB [43]. The delay in diagnosis on the part of health providers does not necessarily reflect inferior performance, but instead a lack of effective diagnostic tools and follow-up routines. Correct diagnosis requires both good training and available diagnostic facilities. The number of repetitions of this vicious cycle proved to be highly dependent on both the patient's beliefs and awareness of TB and the category of healthcare provider. In most countries, private practitioners are consulted first, and this pattern is significantly associated with a longer diagnostic delay. This pattern is also recognized as a source of bottleneck in low endemic countries. A New Zealand study observed that the first consulting doctor often did not perform an X-ray, ask about previous TB, or obtain a sputum smear – although the patients had classical symptoms [44]. The same observations were make by Ward et al in Australia [20]. Cough was treated symptomatically, and CXR were misdiagnosed.

A range of studies have shown that selection of a traditional practitioner for the first visit is associated with a prolonged delay in diagnosis [9, 10, 14, 26‐29, 32, 36, 37]. In Yimer et al's study from Ethiopia, patients who first visited a qualified medical provider experienced a 21-day delay before initiation of treatment. Patients who first visited a traditional healthcare provider waited 15 days before first seeking healthcare, but the period from first visit to initiation of TB treatment was 4-fold greater [6]. These findings are supported by studies of The Gambia [32], Tanzania [29], and Penang [21].

Many studies describe a bottleneck in reaching the local unit of the NTP. Multiple studies observed poor access to the NTP as one of the main factors in delayed diagnosis [6, 8, 10, 14, 18, 23, 25, 27‐30, 34, 42, 47, 48, 50]. In many high endemic countries, it appears crucial that a unit of the NTP is within a 1-day walking distance, as many patients have limited access to motorized vehicles. In addition to geographic distance, the studies identified several other barriers. One of the most important barriers is stigma [27]. Many patients were highly reluctant to visit the NTP facility, because it would mean disclosing to the public that they had TB. Even worse, in many countries, TB is so closely linked to HIV that patients fear they are revealing HIV status to their neighbors [37]. Also, many of the NTP personnel are unfriendly. Many patients feel deprived of both privacy and dignity. The widespread introduction of DOTS also means that patients must visit daily so that their consumption of medication can be directly observed; this is perceived as humiliating, time consuming, and a threat of a substantial loss of income [6, 51, 52]. A marginal farmer or a day laborer will often have to choose between treatment and placing food on the table for his family. Most of the studies from developing countries demonstrated a significant link between delayed diagnosis and poverty [7, 20, 21, 27, 28, 34, 37, 40, 47, 48].

Most of the studies in our review also demonstrate the nonspecific nature of symptoms and the disease's first natural history as a core problem [15, 18, 23, 31, 50, 53]. In the Gambia, TB is often misdiagnosed as malaria or viral infections [32].

Several studies also highlight the problem of self-treatment [6, 36, 42]. In the study in Pakistan, more than 50% of patients practiced self-treatment, and 42% first searched a pharmacy for their symptoms[27]. Many studies link this to the problem of stigma, in fact the unhappy triad of incomprehensive beliefs, low awareness, and stigma.

Our analysis is consistent with the findings of the WHO Eastern Mediterranean Region study. They concluded: "The private sector was the first choice for more than two-thirds of the patients. The main determinants of delay were: socio-demographic; economic; stigma; time to reach the health facility; seeking care from non-specialized individuals; and visiting more than one health care provider before diagnosis [3]." The core problem in delay of diagnosis and treatment seemed to be a vicious cycle of repeated visits at the same healthcare level, resulting in nonspecific antibiotic treatment and failure to access specialized TB services. Once generation of a specific diagnosis was in reach, TB treatment was initiated within a reasonable period of time.