Research TB Institute, Novosibirsk Medical University, Novosibirsk, Russia
Extrapulmonary tuberculosis (EPTB) is an important component of tuberculosis (TB) taken as a whole, but it is often underestimated. Before we can make a reliable estimation of the epidemiology of EPTB, and particularly urogenital tuberculosis (UGTB), unification of the terminology is necessary. The term “Urogenital tuberculosis” is obviously preferable to “Genitourinary tuberculosis”. Some authors understand the term “Extrapulmonary tuberculosis” as specific TB lesions of all organs, excluding bronchus, lungs, pleura and intrathoracic broncho-pulmonal lymph nodes. Others consider pleural TB as one form of EPTB – which is a reason why different authors conclude very different proportions in the spectrum of EPTB. Enigmatic tendencies were revealed also in the distribution of patients–in neighbouring regions the incidence rate may differ significantly. Many forms of EPTB are underdiagnosed: in fact, about 25 % of patients with pulmonary (PTB) and 77 % of those who died from all localizations of TB, had prostate TB – mostly having been overlooked for a lifetime. Absence of unique terms and classifications make it difficult to formulate an accurate picture of EPTB.
KeywordsEpidemiologyExtrapulmonary tuberculosisMycobacterium tuberculosisPrevalenceIncidence rate
Tuberculosis (TB) remains one of the world’s deadliest communicable diseases. In 2013, an estimated 9.0 million people developed TB and 1.5 million died from the disease, 360,000 of whom were HIV-positive. About 60 % of TB cases and deaths occur among men, but the burden of disease among women is also high. In 2013, an estimated 510,000 women died as a result of TB, more than one third of whom were HIV-positive. There were 80,000 deaths from TB among HIV-negative children in the same year. An estimated 1.1 million (13 %) of the 9 million people who developed TB in 2013 were HIV-positive (WHO 2014).
About one-third of the world’s population has latent TB, which means people have been infected by TB bacteria but are not (yet) ill with disease and cannot transmit the disease. People infected with TB bacteria have a lifetime risk of falling ill with TB of 10 %. However persons with compromised immune systems, such as people living with HIV, malnutrition or diabetes, or people who use tobacco, have a much higher risk of falling ill.
In 2012, about 80 % of reported TB cases occurred in 22 countries. Some countries are experiencing a major decline in cases, while cases are dropping very slowly in others. Brazil and China for example, are among the 22 countries that showed a sustained decline in TB cases over the past 20 years. In the last decade, the TB prevalence in Cambodia fell by almost 45 %. About 450,000 people developed multidrug-resistant (MDR)-TB in the world in 2012. More than half of these cases were in India, China and the Russian Federation. It is estimated that about 9.6 % of MDR-TB cases had extensively drug-resistant (XDR)-TB (WHO 2014).
Mycobacterium tuberculosis (Mtb) has, for thousands of years, existed on Earth alongside humankind: multiple traces have been found in the bones of ancient bison, who lived 17,000 years ago. For ages mankind has payed fatal tribute to tuberculosis, and even now it accounts for about 5000 human deaths daily.
TB is a multisystemic disease with myriad presentations and manifestations; it can affect any organ or tissue, excluding only hair and nails. TB (both pulmonary and extrapulmonary) leads to male and female infertility, possibly as a sexually transmitted disease (Tzvetkov and Tzvetkova 2006; Scherban and Kulchavenya 2008; Khanna and Agrawal 2011) that explains why TB is not only a medical, but also a big social problem.
1.2 Transmission of Mtb
Tuberculosis is mainly an airborne infectious disease, which means that the most common route of transmission of Mtb is respiratory. Infections can be spread by coughing, sneezing, laughing, singing, or just talking.
The second common route is alimentary transmission – usually through milk from ill cows.
Iatrogenic transmission, when BCG-induced TB has developed after instillation of BCG for therapy of superficial bladder cancer.
Direct and indirect physical contact, including sexual, are rarer ways of transmission of infection.
Transplacental transmission (very rare).
Independent of the route of infection, Mtb spreads through the bloodstream and lymphatic system throughout the body (so-called primary dissemination). Of course, direct contact more often leads to skin TB, an alimentary route – to intestinal TB, and prostate TB may be a cause of genital TB in a sexual partner etc. But after respiratory contamination, lungs may remain intact, kidney or lymphonodal TB may develop, and TB meningitis after alimentary contamination is possible.
1.3 Enigmas of Extrapulmonary Tuberculosis
TB as a whole consists of PTB and EPTB. While incidence, distribution and characteristics of pulmonary TB are subject to common laws, extrapulmonary TB has its own specific features.
Prevalence of TB naturally differs from region to region depending on economic and epidemic features, but if PTB in one region is about the same, EPTB is not. In any country the majority of PTB patients are young men with infiltrative PTB; this is explained by pathogenesis of the disease. But epidemiology of EPTB is an enigma of physiatria, where there are more questions than answers. Why is there such difference between prevalence of EPTB in neighboring regions? Why is the spectrum of EPTB different? What is EPTB indeed? Should we separate EPTB as a special part of TB as a whole?
The aim of our analysis was to clarify these points and try to explain them.
A Medline/PubMed research report was published with key words “epidemiology, extrapulmonary, tuberculosis urogenital”. This research resulted in a total of six titles with only key words “epidemiology, tuberculosis, extrapulmonary, urogenital”. The key words “epidemiology, extrapulmonary, tuberculosis” appeared in a total of 963 titles. Recent articles have analyzed them critically and revealed seven enigmas of EPTB.
1.3.1 First Enigma is Incomparable Epidemiologic Data on EPTB
We have no real picture of EPTB because we don’t know what EPTB actually is. One of the reasons for incorrect estimation of epidemiology on EPTB is a misadjustment in terminology. Some authors consider EPTB as TB of any organ, excluding only broncho-pulmonary lesions, so pleural TB and broncho-pulmonal lymph nodes were related to the one of the form of EPTB. Others think that division of lung and its cover pleura on two separate organs is incorrect, and ascribe both organs to PTB and instead of EPTB use a term Extrathoracal Tuberculosis (ETTB), or extrarespiratory tuberculosis. WHO has considered an extrapulmonary case of TB as a patient with TB of organs other than only the lungs (e.g. pleura, lymph nodes, abdomen, genitourinary tract, skin, joints and bones, meninges). The question is – what about bronchial TB? As pleural TB is EPTB (formally it is, of course) – bronchial TB is an extrapulmonary form too? I think this position is absurd, and pulmonary TB (or more correctly – TB of breathing system, respiratory TB) should include a disease of the lungs, pleura and bronchi – and all other organs we have to attribute as extrapulmonary ones. This opinion has been totally accepted by the Russian Federation as well as in some other countries with extensive experience dealing with TB. The absence of a unique suitable definition, absence of a unanimous understanding of what really EPTB is, leads to confusing estimations of the proportion of forms of TB.
1.3.2 Second Enigma – A Different Part of EPTB Among TB as a Whole in Different Times and in Different Regions
There was very unstable prevalence of EPTB in different times and regions. In 1984 EPTB remained a major health problem in Australia, where 24.3 % of all new TB notifications were of extrapulmonary origin (Dwyer et al. 1987). In the past century in Oklahoma a greater proportion of newly diagnosed cases of EPTB occurred in nonwhites (Snider 1975). In those days EPTB was frequent in Africa and was of great severity due to delayed diagnoses and multifocal forms (Aubry et al. 1979). In the 1980s in the city of Boston, EPTB represented 4.5 % of all new cases of active TB and tended to occur in older patients (Alvarez and McCabe 1984). In Spain EPTB increased from 30.6 % of cases in 1991–1996 to 37.6 % in 2003–2008 (García-Rodríguez et al. 2011). EPTB had an increasing rate in Turkey in 2001–2007. The reason remains largely unknown (Gunal et al. 2011). In 2009 in the USA, 73.6 % were PTB and 18.7 % were EPTB (Peto et al. 2009). In developed countries, from 2 – 10 % patients with PTB have also UGTB; in developing countries such proportion increases up to 15–20 % (Figueiredo and Lucon 2008). About 20 % of patients cured of PTB, had EPTB later, mostly–UGTB (Lenk and Schroeder 2001). We have to agree that incidence is changing depending on the country and time – but not so dramatically. I’m sure the main reason is a global mistake in the definition of the EPTB and different approaches to the diagnosis and confirmation of the disease.
1.3.3 Third Enigma – Different Spectrum of EPTB in Different Regions and in Different Time
In 1984 in Australia, the commonest sites of disease were the lymph nodes, urogenital tract, pleura and bone (Dwyer et al. 1987). In Oklahoma, the majority of EPTB forms were meningitis and lymphadenitis (Snider 1975). In the 1980s in the city of Boston, sites of involvement included lymph nodes, genitourinary tract, bone and articular sites, the meninges, peritoneum, adrenal glands, pericardium, and miscellaneous sites, in this order (Alvarez and McCabe 1984). In Spain in 2003–2008 TB lymphadenitis increased up to 27 % (García-Rodríguez et al. 2011). In Nepal common sites for EPTB were lymph nodes (42.6 %) and peritoneum and/or intestines (14.8 %) (Sreeramareddy et al. 2008). The most common types of EPTB in Turkey in 2001–2007 were UGTB (27.2 %) and meningeal TB (19.4 %) (Gunal et al. 2011). But other authors from the same region reported a little different data. Among 141 EPTB patients in Istanbul for 7 years, meningeal TB accounted for 23 %, TB lymphadenitis 21 % (Sevgi et al. 2013).
In 2009 in the USA, EPTB included lymphatic (40.4 %), pleural (19.8 %), bone and/or joint (11.3 %), genitourinary (6.5 %), meningeal (5.4 %), peritoneal (4.9 %), and unclassified EPTB (11.8 %) cases (Peto et al. 2009). In France in 2012 the most frequent clinical presentations of EPTB were lymphadenitis, pleuritis and osteoarticular TB (Mazza-Stalder et al. 2012). In some countries the rate of growth of bone&joint TB reached the leading position among EPTB (Kulchavenya et al. 2013a). Location of TB on the spine remains the most common form of skeletal TB, representing 62.2 % of all osteo-articulary locations (Didilescu and Tănăsescu 2012; Wiler et al. 2010).
In Bashkortostan, female genital TB (FGTB) prevailed in 1998–2006 years, but from 2007 the bone & joint TB was a leader among EPTB (29.5 %), then–FGTB (27.4 %), then – lymphonodal TB (17.9 %). The share of UGTB was 9.5 % only (Tuktamysheva et al. 2011). We support the idea to separate urological TB and gynecological TB (female genital TB) because it allows us to better estimate the epidemiology.
Throughout the world, high TB burden countries account for about 80 % of the world’s TB cases. Vietnam is one of such countries with the biggest prevalence of TB – 100 cases among 100,000 inhabitants (Do Chau Giang 2004). Among EPTB patients UGTB only was diagnosed in 77.2 %, combination of PTB and UGTB was found in 19.2 %, and UGTB and other forms of EPTB – in 3.5 % of patients (Nguyen Phuc Cam et al. 2009).
Navarro-Vilasaró et al. (2008) reported UGTB was the third most frequent EPTB infection, following pleural and nodal involvement in Spain in 2008. In the opinion of Abbara and Davidson (2011), UGTB is the second most common form of EPTB, with more than 90 % of cases occurring in developing countries. At the same time Goth and Joshi (2004) listed this form of EPTB as “others” due to low prevalence.
1.3.4 Fourth Enigma is a Non-stable Spectrum of EPTB During a Time Period
Within the last decade the spectrum of EPTB in Siberia has changed significantly (Kulchavenya et al. 2013b). TB of the central nervous system almost doubled from 4.9 to 8.7 %, mostly due to co-morbidity with HIV. Bone and joints TB increased by about half from 20.3 to 34.5 %, and among this group TB spondylitis with neurological disorders predominated. The proportion of UGTB decreased from 42.9 to 31.7 %. On the contrary, there was a decrease of peripheral lymph nodes TB from 16.7 % in 1999 to 11.2 % in 2011. At the end of the last century ocular TB accounted for 7.4 % and in 2008 (in 2009 listed in “others”) for 4.4 % of the patients with EPTB. Accordingly, in 1999 other forms of TB accounted for 7.8 % and in 2009 for 15.8 % (in 2011–13.9 %). The increase is partly due to inclusion of patients with ocular TB in this group, and partly due to better diagnosis of TB of the skin, abdominal organs, breast etc. (Kulchavenya et al. 2013a, b).
1.3.5 Fifth Enigma is the Different Prevalence of EPTB in Neighboring Regions
Fritjofsson and Kollberg (1973) analyzed the incidence of UGTB in Sweden, and found that the incidence showed geographical variation within the country. The same situation was in Hungary, where the number of new cases in one province was as high as 10 per 100,000 inhabitants per year, while in another part of the country only 2–3 cases had been reported. Unexplainable different prevalence of UGTB in the neighbor regions was found in Siberia too (Kulchavenya and Krasnov 2012)–multiple predominance of the number of EPTB cases in one regions relatively another in 20–50 km – and there is no idea for the reason of this phenomena.
1.3.6 Sixth Enigma – What Does UGTB Mean (Misunderstanding in Definitions)
The first note of urogenital TB was made by Porter in 1894 ; in 1937 Wildbolz  suggested the term genitourinary TB c The term urogenital TB is more correct, because kidney TB, which is usually primary, is diagnosed more often than genital TB. Actually the term “urogenital tuberculosis” is incorrect too as it collects many forms with its own clinical features and requiring its own therapy and management. UGTB joins kidney TB, urinary tract TB, male and female genital TB – and every form has its own features. The combined term “UGTB” does not allow estimation of a real epidemic picture – is it prevalence of male genital TB or kidney TB? Also a high incidence rate of kidney TB 1–2 stages is better than a low incidence rate, except when complicated forms are revealed.
1.3.7 Seventh Enigma – Different Sex and Age Ration in UGTB
Some authors have found that UGTB affects more men than women (Figueiredo and Lucon 2008; Benchekroun et al. 1998; el Khader et al. 1997; Tanthanuch et al. 2010; Nurkić 2006); others – exactly the contrary (Mazza-Stalder et al. 2012; Snider 1975; García-Rodríguez et al. 2011; Singh et al. 2011). It seems that renal TB, alike any other kidney disease, should be found more often in female patients, because menses, gravidity, and inflammation of female genitals may hinder the urine passage. Urinary stasis carries a possibility for fixation of M.tuberculosis to urothelium, and, so, for developing renal TB.