Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review

Abstract

Background

The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data.

Methodology and Principal Findings

To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis.

Conclusions

Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory.

About the Authors:

Edine W. Tiemersma

* E-mail: [email protected]

Affiliations KNCV Tuberculosis Foundation, The Hague, The Netherlands, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Marieke J. van der Werf

Affiliations KNCV Tuberculosis Foundation, The Hague, The Netherlands, Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

Martien W. Borgdorff

Affiliation: Cluster Infectious Disease Control, Municipal Health Service (GGD) Amsterdam, Amsterdam, The Netherlands

Brian G. Williams

Affiliation: South African Centre for Epidemiological Modelling and Analysis, Stellenbosch, South Africa

Nico J. D. Nagelkerke

Affiliation: Department of Community Medicine, Faculty of Medicine and Health Sciences, UAE University, Al Ain, United Arab Emirates

Introduction

Before the advent of chemotherapy, tuberculosis was one of the major causes of death in both Western [1] and also several non-Western countries [2]. While effective chemotherapy for tuberculosis has been available since the 1950s (isoniazid (INH) was introduced in 1952, the less effective para-aminosalicylic acid (PAS) and streptomycin slightly earlier [3]) the prognosis of untreated tuberculosis is still of great importance, as many patients will not receive appropriate treatment because their condition was never properly diagnosed as tuberculosis. For example, both the Cambodian [4] and Vietnamese [5] prevalence survey show that only about 20% of tuberculosis-patients identified in these surveys were on treatment at the time of the survey. This is especially true for smear-negative culture-positive pulmonary cases because in many places in the world Ziehl-Neelsen (Z-N) direct sputum smear, with low sensitivity for paucibacillary disease, is the only available diagnostic tool [6]. Also, many national tuberculosis programmes based on the DOTS (directly observed therapy, short course) strategy only offer free treatment to smear-positive cases in view of their disproportionate role in tuberculosis transmission and thus their large public health impact [7]. In addition, despite the availability of standard chemotherapy, with the recent increases in multi-drug resistant (MDR) and extensively drug resistant (XDR) tuberculosis [8] many patients will have a prognosis that is in all likelihood not very different from untreated tuberculosis. This also holds true for tuberculosis, both drug susceptible and resistant, in HIV-positive patients, most of whom live in Sub-Sahara Africa, where adequate diagnosis and treatment is unavailable in many (especially rural) areas. Since a substantial number of tuberculosis cases will not receive adequate treatment the prognosis in terms of duration and outcome of (untreated) tuberculosis is an important parameter in models used for estimating the disease and mortality burden caused by tuberculosis [9], [10].

The prognosis of untreated tuberculosis is difficult to study these days as leaving patients untreated, especially in a study setting, is unethical. As an alternative, one could consider, as an approximation, the prognosis of multi-drug resistant (MDR) tuberculosis treated with first line drugs. However, MDR-tuberculosis patients may benefit to some extent from first line therapy [11]–[14] and many of these patients may have a history of tuberculosis treatment and may thus suffer from a relapse with secondary (acquired) drug resistance with a prognosis that may differ from that of those who never received tuberculosis treatment. Furthermore, Mycobacterium tuberculosis strains resistant to rifampicin and INH might be less fit than drug susceptible strains and therefore lead to longer duration of disease with less mortality [15]. Therefore, to estimate the prognosis of HIV-negative tuberculosis, one inevitably has to rely on data collected in the pre-chemotherapy era even though many of those studies do not meet modern standards.

To estimate the duration and case fatality of untreated pulmonary tuberculosis, we reviewed studies from the pre-chemotherapy era. For tuberculosis in HIV infected patients there are, of course, no data from the pre-chemotherapy era. Thus the only data that are potentially relevant are those on MDR-tuberculosis HIV positive patients treated with (inadequate) first line tuberculosis drugs, as their prognosis would probably be similar to that of untreated HIV positive tuberculosis. However, it is clearly important to distinguish patients by stage of HIV disease and by treatment (ART, type of ART, or not [16]). The complexity of this far exceeds that of estimating the prognosis in HIV- negative patients and requires separate reviews.

We studied the duration until death or self-cure of untreated tuberculosis and 5- and 10-year survival probabilities in representative adult populations (>15 yrs of age) with pulmonary tuberculosis, identifiable as either smear-positive or smear-negative.

Methods

Eligibility criteria

Not a single study has measured the duration of disease directly, as this would require an exhaustive ascertainment of incident cases as well as a follow-up to either death, which is easy to establish, or cure, which is more difficult to establish, while withholding treatment, at least for some time. One thus has to rely on indirect information to estimate duration of disease, on the assumption that duration of disease (D) and case fatality (CF) are related to incidence (I), prevalence (P) and mortality (M): D = P/I and CF = M/I [17].

We defined four types of data sources which may contribute information on the natural duration and/or outcome of disease:

1. Follow-up (cohort) studies. Diagnosed patients are individually followed–up over time and their mortality and morbidity experience recorded. Inevitably there is some kind of selection (bias) involved in such studies as they exclude undiagnosed patients. Patients included may be those identified through the health system, or those who attended a specific institution (e.g. sanatorium), or patients may have been identified through a tuberculosis survey. These cohort studies provide key information on CF, but do not generally provide estimates of duration of disease, as the start of the tuberculosis episode is normally unknown and cure is usually not recorded.

2. Prevalence and incidence studies. A comparison between prevalent and incident cases would yield the duration immediately if the population is stable, i.e. no migration. However, if incidence is measured through repeated waves of surveys (instead of recorded continuously), one has to take into account the fact that incident cases occurring in-between surveys, but who recovered or died before the next survey wave, will be missed by the study. Although such studies are ideal for estimating the duration of disease they are less suitable for estimating the CF. In order to obtain an estimate of the CF one needs either follow-up of incident cases or estimates of the frequency with which disease ends in death among those patients for whom the end of disease is observed.

3. Notification and mortality studies. Studies that relate notification to mortality are also relevant. While such studies may provide little information on the duration of disease they do provide data on ultimate outcome (cure versus death) as CF = M/I although one cannot be certain that all incident cases are notified nor that all deaths occur among patients ever notified.

4. Prevalence and mortality studies. These compare the prevalence of tuberculosis to its (annual) mortality, but do not establish the fate of individual patients. To estimate the duration of disease, however, requires knowledge of the CF of (prevalent) tuberculosis cases, as well as an assumption of a stationary epidemiological situation. For then the ratio of the mortality rate and the CF estimates the incidence rate, and one can use the fact that the prevalence equals the product of the incidence and the duration (P = I*D) to obtain the duration. Conversely, estimating the CF would require knowledge of the duration of disease in addition to the prevalence and mortality rate, as the incidence would then equal the prevalence divided by the duration, and the ratio of the mortality and incidence rate would yield the CF.

Search strategy

We searched PubMed including OldMedline with publications from the early decades of the 20th century up to 17 December 2010 and EMBASE, including references from 1900 until 1966. The search strategy is summarized in Table 1. These searches did, for a variety of reasons (see below), not yield any eligible papers. Therefore, additionally a snowball sampling method was applied, using reference lists of various papers and books, starting with Hans Rieder's book “Epidemiological Basis of Tuberculosis Control” [18], supplemented with literature identified from the authors' personal libraries [19]–[23]. We also asked the members of the tuberculosis expert group of the Global Burden of Diseases, Injuries, and Risk factors study (see Acknowledgements for names) for suitable references. For practical reasons, we only included papers in English, French, German, Spanish and Dutch. Papers in other languages with English table and figure legends as well as an English summary were also included.

[Figure omitted. See PDF.]

Table 1. Search strategies used for searching electronic databases.

https://doi.org/10.1371/journal.pone.0017601.t001

Study selection

All references were first screened independently by two authors (ET and NN) on title and, if no title was available, in the snowball sampling method, on reference in the text to assess whether they potentially assessed the prognosis of untreated pulmonary tuberculosis in representative adult populations. Of potentially eligible papers, if available, abstracts were subsequently assessed for eligibility using the same strategy. If no abstract was available, papers were accessed in full text. Among the identified sources we selected those that would potentially provide estimates of CF and/or duration of pulmonary tuberculosis in adults (≥15 years) by any of the four methods outlined above. Studies were included provided: a) their methodology was sound (e.g. (near-to-)complete follow-up or making use of actuarial methods), considering populations that can be considered as more or less ‘population-based’ (thus not including only specific population subgroups or pre-selecting certain categories of patients), b) they contained original data (i.e., no editorials, opinion papers, minutes; reviews were only included if the literature these referred to was not found), c) we could decide whether patients included were smear-positive or smear-negative but culture-positive; in studies where patients were described as having “open” tuberculosis or “bacillary tuberculosis” before 1930 (when culture became available) we assumed that these patients were smear-positive, d) description of the available data was sufficient to enable calculation 5- and/or 10-year survival probabilities or disease duration, and e) the study population was not treated with chemotherapy or was treated with probably or proven ineffective therapy (e.g. collapse therapy, lung resection, short duration mono-drug therapy, etc.).

Data extraction

Eligibility and data extracted from all eligible sources were checked and discussed by two authors (NN and ET) using the criteria described above. The data sources were reviewed and summarized with respect to their information regarding the duration and outcome of untreated tuberculosis, and CF. Discrepancies between authors with respect to extracted data were resolved by discussing the differences and independently re-reviewing the data.

Methodological considerations

There are some important limitations to studying the duration and CF of untreated tuberculosis, since many of the included studies do not meet modern research standards. For example, the case definition, the onset of disease, or the beginning of follow-up in cohort studies (onset of symptoms, sputum positivity) are often ill-defined or poorly described in older publications, and many cases included in those studies would not meet modern diagnostic standards.

A large number of studies are based on passive case finding, which inevitably entails some selection bias, as diagnosed cases may well differ from undiagnosed ones. Some studies are limited to hospitalized (sanatoria) cases and therefore presumably exclude both the mildest and the most severe cases, as some of the latter probably died before they could have been hospitalized.

An additional methodological problem constitutes the way cases have been classified in old studies. Using the distinction of pulmonary tuberculosis into sputum smear-positive (smear-positive) and sputum smear-negative (smear-negative) cases, the most common classification used today, we must assume (highly unrealistically) that the sensitivity and specificity of direct smear has not changed. Especially the diagnosis of smear-negative cases is problematic as culture using the Löwenstein-Jensen (L-J) medium did not become available until the 1930s [24], [25] and thus all Z-N smear-negative tuberculosis was diagnosed on the basis of radiology and/or symptoms with uncertain specificity [26]. In some publications cases are reported as having “open” tuberculosis without explicit definition. This presumably depends on various non-standardized Z-N like procedures of directly demonstrating M. tuberculosis in sputum. A comparison between sputum smear microscopy used in those days with that currently in use is not available. Another methodological problem, also affecting many modern studies on tuberculosis, is the implicit assumption that pulmonary tuberculosis can reliably be classified as either smear-positive or smear-negative and that no transitions between these categories take place. This is almost certainly untrue, if only because of the poor sensitivity of sputum smear and its dependence on factors such as the number of repeat smears [14]. Yet, it is well established that many smear-positive patients who become smear-negative in the absence of adequate treatment subsequently relapse and become smear-positive again [12]. Whether they are still culture-positive while being smear-negative or temporarily “cured” (i.e. culture-negative) is largely unknown. Presumably, some smear-negative patients who die will become smear-positive prior to death, vitiating the assumption of stable categories. Yet how common this is, remains unknown. Nevertheless, the classification into smear-positive and smear-negative has become so widely established, and is so much part of the methodology of estimating the burden of tuberculosis, that it is impossible to avoid it.

A further methodological pitfall is that by combining different estimates one makes the implicit, and untested, assumption that the natural history of tuberculosis does not differ significantly among countries and periods. However, the risk of infection with M. tuberculosis and progression to tuberculosis disease is influenced by host factors and especially risk of progression depends on the hosts' immune status, which may be reduced due to concomitant HIV infection, diabetes, and other underlying diseases [27], [28]. Given these methodological challenges, it is clear that only by combining, often in an ad-hoc fashion, different sources of information can one probably get somewhat adequate or reasonable estimates of the “correct” duration and case fatality (CF) of various types of tuberculosis.

Summary measures and synthesis of results

Data were extracted into Excel sheets and survival probabilities re-calculated and provided with accompanying 95% Greenwood confidence intervals using the original paper's life table's information. Where insufficient details were available to recalculate survival probabilities, estimates as calculated by the studies' authors were taken. Duration of active pulmonary tuberculosis disease from diagnosis till death or cure could be assessed from two studies with a very different study design [20], [29].

Because of the above-described methodological problems with combining the results of such diverse studies, we did not attempt to do a formal meta-analysis here.

Results

Study selection

Using the methods described above we identified a wide range of studies on the prognosis of tuberculosis in the absence of chemotherapy (Figure 1). In total, 2256 references were identified of which 2171 (96%) were screened on title, abstract and/or reference in the text. Of the 193 references selected for full-text reading, 84, i.e. 43% (Note that.) were not available in consulted libraries. However, 32 of these references most probably do not contain any useful information, as they had a very general title including only “tuberculosis” and “mortality” or “research” or “annual report” and appeared in regional journals or were old text books. Another 87 were excluded after reading because they contained no original data [30]–[38] or the selection [39]–[46], description and/or classification of the patients included [21]–[23], [47]–[72], such as the number of smear-positive patients, or (the description of) the available data [73]–[109] were either insufficient, too rudimentary or different from current practice to be useful to us (Figure 1). For example, Elderton and Perry [47], [48] classified patients as “incipient”, “moderately advanced”, “arrested” etc. without providing sufficient details about these patients for us to decide what the operational definition of such classification may have been nor whether these patients were in all likelihood smear-positive or smear-negative culture-positive, or neither. Other authors (e.g., [55], [60]) classified tuberculosis according to three stages defined by Turban. Four papers were excluded because all or part of the patients were treated with chemotherapy. Most of these papers also did not contain sufficient follow-up time nor details to calculate 5-year survival or duration of disease [10], [110]–[112].

[Figure omitted. See PDF.]

Figure 1. Selection of papers.

Flowchart schematically showing inclusion and exclusion of papers. Those marked with a * were excluded either because they were referred to at places in the text that did not discuss duration of tuberculosis, tuberculosis mortality, case fatality, life tables or natural history, or because the title indicated that the paper was not about one of these topics; ** for two of these, data were included to the extent mentioned by Berg [115] (see legend of Table 3).

https://doi.org/10.1371/journal.pone.0017601.g001

Description of included studies

The sources we considered relevant to the natural (pre-chemotherapy) history of tuberculosis are listed in Table 2. The data sources cover different periods and different countries, but except for two studies [29], [113], all are from the pre-chemotherapy era. All included both sexes. Although sanatorium treatment and surgical therapy were available, these are unlikely to have affected mortality by much [114]. The type of patients included was highly variable in terms of diagnostic criteria (as explained above, diagnostic criteria were often unclear) and age composition (if reported). For example, the age distribution of the population included in the study of Berg was 36%, 50% and 14% for men in the age groups 15–24, 25–44, and 45 years and older, and 43%, 50% and 7% for women [115], whereas that of Drolet's population was 23%, 45%, 33% and 36%, 46% and 18% for men and women respectively [116].

[Figure omitted. See PDF.]

Table 2. Overview of studies included in our review*.

https://doi.org/10.1371/journal.pone.0017601.t002

Follow-up studies.

1. Berg's study [115] is probably the most comprehensive study of all the (retrospective) follow-up studies and has tried to include all patients (including those ascertained after death) with “open” tuberculosis from Gothenburg (Sweden) diagnosed between 1928 and 1934. He followed all patients who were ever found to have bacilli in sputum from diagnosis of tuberculosis. He identified various difficulties and biases (e.g. “ascertainment” biases) in doing so. Berg also reviewed earlier studies on the prognosis of tuberculosis and open tuberculosis more specifically. However, the starting point of follow-up of most of these patients is unclear and the studies usually included highly selected patients (e.g. sanatorium, tuberculosis dispensary), and are thus less representative than Berg's own material from Gothenburg [115]. We included the relevant studies that were not available to us in full text (Trail and Stockman (1931) [117], and Hartley, Wingfield and Burrows (1935) [118]), to the extent summarized by Berg [115]. Trail and Stockman carried out a cohort study in the UK among patients of the King Edward VII sanatorium in Midhurst (UK). Hartley and colleagues did a retrospective cohort study of cases treated for tuberculosis at Brompton Hospital. Only the pre-war (World War I) period is presented here, as Berg considered the results of the period 1915-1931 being less representative.

2. Sinding-Larsen [119] did a cohort study in Denmark among sanatorium patients, with the objective of evaluating the impact of collapse therapy.

3. Backer [120] followed patients notified to the Board of Health in Oslo, Norway, between 1911 and 1920 until 1931 and reported survival from date of notification, not date of diagnosis.

4. Krebs [121] considered pulmonary tuberculosis patients discharged from Barmelweid sanatorium in Switzerland treated from its opening in 1912 up to 1927. In his report patients are categorized according to different categories/stages, including whether tuberculosis is open or closed but he does not clarify the exact definitions of open and closed tuberculosis. It is also unclear whether all closed tuberculosis patients would meet the current definition of smear-negative culture-positive tuberculosis. Probably, the study included patients diagnosed on the basis of chest radiographs or clinical symptoms, as L-J medium was not yet available. Five- and 10-year mortality rates of all 1464 patients who were followed for at least 5 years (discharged between 1912 and 1924) were re-calculated by Fürth [122].

5. Tattersall [123], [124] included sputum-positive cases attending Reading (UK) dispensary between 1914 and 1940 from the time of their diagnosis until death or up to 31 December 1945.

6. Magnusson [125] studied cases admitted for treatment at the Vifillsstadir Sanatorium in Reykjavik, Iceland, recruited between 1916 and 1923 with a subsequent follow-up time reaching up to 1935. Cases of ‘closed’ and open tuberculosis were reported separately.

7. Rutledge and Crouch [19] reported on the follow up of tuberculosis patients discharged from a particular sanatorium in the United States of America (USA). Smear-positive and smear-negative (note: not necessarily culture-positive) cases were reported separately.

8. Münchbach [126] included sanatorium patients with open bacillary tuberculosis, which should probably be interpreted as smear-positive tuberculosis.

9. Braeuning and Neisen [127], [128] included tuberculosis dispensary patients from Szczecin, Poland (then known as Stettin, Germany) from two periods, 1920-21 and 1927-28 from the date of their first positive sputum.

10. Griep [129] followed-up all notified cases of open pulmonary tuberculosis occurring in The Hague, The Netherlands during a 18-year period (1920-1937). Although cultures were being performed, only those who had at least one positive sputum smear were included in his analyses. He estimated that about 62% of all tuberculosis patients were notified, with overrepresentation of those in the lowest socio-economic classes, since those in higher classes probably sought private care.

11. Baart de la Faille [130] explored the outcome of tuberculosis cases hospitalized in the Sanatorium “Berg en Bosch” in The Netherlands. He distinguished three different groups of patients based on sputum smear results at admission and during the last two months before discharge: positive/positive, positive/negative and negative/negative patients. Cultures were being done from 1931 onwards and smear-negative culture-positive patients were added to the negative/negative group, this group thus being a mixture of culture-positive and culture-negative patients. Results from 1936 show that 30% of the negative/negative group in fact had negative smear(s) but one or more positive cultures.

12. Buhl and Nyboe [131] reported on mortality among Danish tuberculosis patients diagnosed between 1925 and 1954. Only patients for whom bacilli had been demonstrated in sputum or gastric washings were included. However, it is not stated by which method bacilli were demonstrated. We therefore only used data from patients diagnosed between 1925 and 1929 (N = 314) as for this period L-J culture was not available yet and all the patients must have been smear-positive. The decline in mortality that they observe during the pre-chemotherapy era suggests that after 1930 some patients were smear-negative culture-positive.

13. Lindhardt [132] reported on tuberculosis mortality in Denmark between 1925 and 1934. All notified cases and all notified smear-positive cases were reported separately. As the category “all cases” may include cases for whom no smear result was available (in addition to smear-negative patients), we only considered smear-positive cases.

14. Thompson [133] included all sputum-positive tuberculosis patients occurring in a compact industrial area in Middlesex County, UK, diagnosed between 1928 and 1938.

Prevalence and incidence studies.

The study of the National Tuberculosis Institute, Bangalore, India (NTI) [29] involved a series of 4 waves of community surveys in the South of India. The study clearly documents its (more modern) methods and is based on systematic surveys. Pamra [113] and colleagues used very similar methodology in four survey waves following the National Sample Survey in New Delhi. Both studies looked at the (bacteriological) status of survivors during follow-up survey waves and included patients with any chest radiograph abnormalities (screening) who were either positive on direct smear (Z-N/fluorescence microscopy) and/or L-J culture. As such, these are the only studies that included smear-negative, culture-positive patients. In the NTI study, the fractions of smear-negative culture-positive patients were 53.4%, 53.0%, 55.1% and 41.4% in the subsequent 4 surveys. In the other study, the fraction of smear-negative culture-positive cases was lower in the first two surveys (24% and 30%) and similar in the subsequent surveys [113], which may suggest changes in tuberculosis epidemiology, capturing cases earlier in the development of active tuberculosis, or in practice of culturing.

Unfortunately, the reporting of both studies leaves much to be desired. For example, prognosis (death or cure) is not presented broken down by Z-N status (i.e. for smear-positive and smear-negative separately). Moreover, Pamra and colleagues did not give any information about treatment of tuberculosis [113], whereas the NTI study reported that no organized anti-tuberculous treatment was available in the area, and that the study did not provide chemotherapy (except for one month of INH monotherapy at the second and third survey) which was highly unethical given the fact that effective treatment was available at the time of the study. INH was definitely available to some patients in that part of India as the authors discovered a high percentage of INH drug resistance, which again clearly indicates that patients could have been provided with full chemotherapy in this study. In all likelihood treatment was only adequate in some exceptional cases and otherwise of such a low quality that its impact can be ignored [29].

Notification and mortality studies.

Drolet [116] reported overall mortality ratios (i.e. the ratio of mortality to notification as reported by the departments of Health of the various cities and states in the USA, and the Ministry of Health in the case of the UK) for New York (pulmonary), Chicago (all forms), Detroit (pulmonary), New Jersey (all forms), Philadelphia (all forms, including childhood tuberculosis), Massachusetts (pulmonary), and England and Wales (pulmonary) during the period 1915-35. Braeuning [134] similarly reported population rates, notification rates of new ‘open’ tuberculosis cases and tuberculosis mortality in Stettin between 1925 and 1929.

Prevalence and mortality studies.

The Framingham Community Health and Demonstration project [20], [135]–[137] was an extensive community based project on tuberculosis epidemiology and prevention initiated in 1916 in the same community that later became the focus of the famous Framingham Heart Study. Several publications report on its findings. Although we did not identify any systematic follow-up of patients, data on the relationship between prevalence and mortality are provided.

Analysis of Case Fatality

Follow-up studies.

Direct estimates are available from cohort studies. Table 3 shows 5- and 10-year survival rates from all cohort studies considered in this review. Only one study [125] provided follow-up findings for periods of more than 10 years and showed that mortality rate declined with time since diagnosis. Between 10 and 20 years, mortality for both open and closed tuberculosis dropped to 3.4%, which must have been close to the mortality of non-tuberculous persons. Thus, it seems plausible to assume that almost all mortality will occur within 10 years of onset of disease or diagnosis. Even if the mortality rate and self-cure rate (µ and γ respectively) were constant, i.e. independent of time since onset of disease, the fraction (self) cured among those still alive after 10 years would be (γ/(γ+µ))(1-exp(-(γ+µ)10))/{(γ/(γ+µ))(1-exp(-(γ+µ)10))+exp(-(γ+µ)10)} (which will be close to 1 for values of γ and µ that are consistent with observed 5- and 10-year CF of approximately 59% and 70% respectively (as for smear-positive tuberculosis, see below).

[Figure omitted. See PDF.]

Table 3. Survival rates for open (smear-positive) and closed (smear-negative, diagnosed in various ways including chest X-ray) pulmonary tuberculosis.

https://doi.org/10.1371/journal.pone.0017601.t003

In studies that reported on this (particularly Berg [115] who reports a 30.7% mortality during the first year of follow-up) mortality tended to be highest shortly after diagnosis. This decline in risk with time is also apparent from Table 3 as 10-year survival probabilities tend to be better than the square of the 5-year survival probabilities, as would be obtained with constant mortality rates (risk of dying among those still alive). As cures were not recorded, it is unclear whether this decline is due to a decline in the mortality rate among those still having active tuberculosis, or whether this is due to a decline in the number of people still diseased, so that the denominator gets progressively inflated by cured patients.

Nevertheless, although mortality rates decline, long-term survivorship (of 10 years or more) is much poorer (a 10-year CF of 70% or more) than 5-year survival showing that tuberculosis can be a very long-lasting, chronic disease. Taking the crude unweighted average of all studies one arrives at a 5-year case fatality of 58% and a 10-year case fatality of 73% for open (smear-positive) tuberculosis. Taking an average weighted by sample size these numbers are 55% and 72% respectively. Of course, these mortality data are somewhat distorted by mortality from other causes, as most studies do not record cause of death, and all-cause mortality rates may have been somewhat higher in the pre-antibiotic era than they are now. On the basis of the above data, especially the studies by Berg [115], Thompson [133], and Buhl and Nyboe [131] which – unlike studies on sanatorium patients – appear to be mostly population based, a 30% 10-year survival for smear-positive patients, i.e. a 70% CF, as used by WHO and others in their estimates of the burden of tuberculosis [27], seems a reasonable ballpark figure. As tuberculosis is mostly a disease of young to middle-aged adults the distortion by other causes of death is probably small.

A single, aggregate, CF for all smear positive patients is only justified if in most studies the differences in mortality between the sexes and age groups are rather small. This appears to be the case for sex, but higher ages appear to have somewhat poorer prognosis. For example, in Berg's study (providing the most detailed data), age- and sex specific 10-year mortality rates were 66% for men aged 15–29 years, 70% for men aged between 30 and 49 years, and 94% for men of 50 and older. For women, these rates were 70%, 69%, and 92% respectively [115]. Similar patterns are apparent in other studies providing age (but often using different age-groups) and sex specific mortality.

Notification and mortality studies

Braeuning [134] reported a ratio of mortality to notification (RMN) for ‘open’ tuberculosis of 70%. This was adjusted for mortality arising from not-previously notified tuberculosis cases by identifying the number of tuberculosis deaths that had been notified as tuberculosis cases previously, but not for changes in either population or incidence over time.

Drolet [116] reported RMNs of approximately 43% for New York City and Detroit, approximately 32% for Chicago, 51%–52% for both New York State and New Jersey, and 55% for Philadelphia. For Massachusetts and England/Wales mortality to notification ratios of 54% were reported. Percentages in all areas were approximately stable over the period for which data are provided, with the possible exception of England and Wales where declines in RMNs were observed. Cases in New York City, Chicago, and England/Wales (from 1923 onwards) also include those first identified from death certificates, all others areas include “primary” notifications only. As this was a period of general decline in tuberculosis incidence, RMNs may slightly overestimate CF as the deaths occur among tuberculosis patients who were incident cases several years earlier and thus the number of deaths in any year would exceed the number of future deaths that would (ultimately) occur among incident cases in that year. In addition, some additional overestimation may be possible if mortality data were more complete than notification data. Pulmonary forms were diagnosed by Z-N smear and chest X-ray and/or clinical symptoms and do not necessarily only include L-J culture-positive cases. The proportion of smear-positive cases was not presented. Variations in CF among regions may well be due to differences in diagnostic methods, reporting systems, inclusion of cases from death certificates, etc., rather than true heterogeneity in prognosis. The only conclusion that stands out from these data is that the prognosis of all forms of (pulmonary) tuberculosis is much better that that of smear-positive cases only.

Prevalence and incidence studies.

The CF of pulmonary tuberculosis, smear-positive and/or culture-positive, can also be estimated from the NTI study [29] which comprised 4 successive waves of surveys. Diagnosis was by both smear and culture among those with chest radiograph abnormalities. This study reports on: i) prevalence of tuberculosis at each survey, stratified by smear status; ii) the incidence between surveys, i.e. new cases at each survey among those free of tuberculosis at previous surveys, outcome (dead, alive and excreting bacilli, or not excreting bacilli) of prevalent cases at each survey during the subsequent survey; iii) the outcome of prevalent cases at the first survey during all subsequent surveys; iv) the outcome of prevalent cases at each survey during the subsequent survey; v) the outcome of incident cases at each survey at the subsequent survey, i.e. 1.5 years later; vi) the relapse ‘rate’ (which was actually a proportion). The presentation of some of the data in the paper is misleading. Notably, the reported (approximately) 50% 5-year mortality, which is also reported in the abstract of the paper, is incorrect. The reason for this is that loss-to-follow up is inadequately accounted for, and disproportionately affects surviving patients. Once a patient is observed to have died he can no longer become lost to follow-up. A simple comparison of data on the cohort of patients identified at survey 1 (Their Fig. 2. Fate of cases discovered at the first survey and of patients still excreting bacilli when examined at subsequent surveys) with data on the fate of patients present at each survey (Their Fig. 3. Fate of prevalence cases discovered at survey I, II, and III over a period of 1.5 years) shows this. In Fig. 2 mortality of those discovered at survey I, after 1.5 years is 30.2%, while in Fig. 3 it is 24.7%. Another shortcoming of the paper is that patients without abnormalities on chest radiograph were not examined in this survey and thus not identified. The percentage of pulmonary tuberculosis patients without chest radiograph abnormalities varies between 3 [138] and 50% [139].

There is a better approach to estimating the CF from the NTI data. Ultimately, all tuberculosis patients will either die or get cured. If the ratio of the mortality rate to the cure rate is independent of disease duration, then one can simply look at the ratio of the number of deaths to number of patients cured over a fixed period of follow-up. This assumption seems to be supported by their data (their Fig. 2), as the cured-to-death ratio among the cohort of tuberculosis patients discovered at survey 1 seems to remain about equal at 27.8/30.2, to 23.6/20.0 to 17.2/15.0 in the intervals between survey 1 and 2, between survey 2 and 3, and between survey 3 and 4 respectively. Thus, the prognosis (outcome) of the participants' disease (death or cure) did not seem to depend on the time they had already suffered from tuberculosis. Nevertheless, an exception may have to be made for incident tuberculosis patients who appear to fare somewhat better than prevalent cases, with a cured-to-death ratio of 44/24.

The study reports a total of 428 (often overlapping) individuals alive with tuberculosis at the beginning of any of the 1.5-year intervals. During the subsequent 1.5 years, a total of 89 died and 132 were cured, suggesting an (ultimate) tuberculosis mortality of 40.2%. However, this is not entirely correct as the paper reports 7% mortality among “cured cases” (most presumably dying from tuberculosis) and a “relapse rate” of 10%. We thus subtract 17% from 132 giving 109.5 and add 7% of 132 to 89 giving 98. Thus if the fate of prevalent cases would equal that of incident cases, 47% would ultimately die.

The assumption, as stated above, that there is a constant death-to-cure ratio may not be entirely true, as among follow-up incident cases there were almost twice as many cured cases (44) as deaths (24). This ignores relapses. However, as the proportion dying (35%) among those who either die or get cured in these incident cases differs only marginally (and statistically not significantly) from the uncorrected (for relapse) mortality of prevalent cases (40.2% of those who either die or get cured), we seem to be justified assuming a constant death-to-cure rate. Thus our ‘best’ estimate of tuberculosis CF from this study is 47%.

Unfortunately, it is not possible to estimate the CF for smear-positive and smear-negative tuberculosis separately from the data provided. If we accept an ultimate mortality of smear-positive tuberculosis of 70% (based on the studies presented elsewhere in this paper) then assuming that 50% of cases are smear-positive (of all prevalent cases, 51% were smear-positive [29], but what counts is incident cases which are unidentifiable from their data, so this assumption is questionable) then (ultimate) mortality among smear-negative pulmonary patients would be 24%. Thus the 20% mortality for smear-negative pulmonary tuberculosis, as assumed by WHO and others in their estimates of the burden of tuberculosis (Table 4) seems a reasonable figure.

[Figure omitted. See PDF.]

Table 4. Case fatality rates used by the WHO to provide estimates of burden of disease*.

https://doi.org/10.1371/journal.pone.0017601.t004

Analysis of Duration of Disease

The duration of disease is the time from onset of disease till cure or death. For tuberculosis, it is not possible to measure exactly when it started, as patients may remain asymptomatic or have very mild symptoms shortly after getting the disease. Moreover, of the two possible end points, cure is hard to measure, as relapses are common [140] and establishing cure in untreated tuberculosis patients requires extensive medical investigations. No single study reports on the duration of disease by systematic follow-up of incident cases so we had to estimate duration indirectly.

Prevalence and mortality studies.

Duration of disease can be estimated indirectly from the ratio of prevalence to mortality. The Framingham Community Health and Tuberculosis Demonstration [20], [135]–[137] reported a presence of approximately 9 active (presumably a combination of smear-positive, smear-negative culture-positive, and other forms tuberculosis) living cases to every death, and 3 smear-positive cases for every death. Assuming a long term mortality of 70% among smear-positive and 16% mortality among all others (i.e. assuming that active smear-negative cases are similar to Krebs' closed tuberculosis [121], as both presumably included cases with only chest radiograph abnormalities in addition to culture-positives) one obtains a CF of 0.34, and an average duration of 3 years. On the basis of this study it is impossible to stratify by smear and culture status.

Prevalence and incidence studies.

The duration of disease in the pre-chemotherapy era was only studied prospectively in one other study, viz. the NTI study [29]. As follow-up of prevalent cases does not provide reliable data about duration of disease, the best approach to estimate this parameter would be the prevalence-to-incidence ratio which is (almost) 4. This is very close to the ratio found for bacillary (i.e., sputum and/or culture positive) pulmonary tuberculosis in New Delhi, India over the period 1962–1970 [113] using similar methodology as the NTI study. Unfortunately, availability of treatment, affecting the duration of disease, was not reported on; therefore, we cannot include the study to estimate the duration of untreated tuberculosis.

As waves of surveys in the NTI study were 1.5 years apart (even 2 years for the interval between wave 3 and 4) [29], one has to adjust for missed incident cases, i.e. for the incident cases who recovered, migrated out or died before being detected in one of the surveys. If we would assume an exponential duration of disease with parameter δ (the inverse of the duration of disease), then in an interval of length T (1.5 years) we would observe a fraction (1-exp(-δT))/(δT) of the intervening incident cases at the following survey. Under these assumptions an average duration of 3.33 years (i.e. δ = 0.3) would fit the NTI data almost perfectly. Perhaps, the number missed between surveys may be slightly larger due to non-exponential survival (specifically, incident cases recovering or dying on average faster than prevalent cases). If so, 3.3 years would slightly overestimate the duration of disease. We infer that an average duration of approximately 3 years of smear-positive and smear-negative cases combined would seem the most plausible estimate.

There is almost no reliable information regarding the relative duration of smear-positive and smear-negative tuberculosis disease. A study from South India [141] provides some insight in the natural duration of smear-positive tuberculosis as the authors give the ratio between incidence and prevalence for these patients. They estimated a ratio of 0.46 corresponding to an average duration of 2.2 years. This is considerably shorter than the mean duration estimated in the NTI study in Bangalore for the mix of smear-positive and smear-negative patients, suggesting a much shorter duration for smear-positive than for smear-negative patients. However, as the study was carried out in the 1980s it seems likely that the average duration must have been shortened by available chemotherapy (INH plus thiacetazone), as was also suggested by the authors of the paper. This is also supported by another study carried out in South India [142] where the incidence of culture-positive tuberculosis was 1,578 and that of smear-positive culture-positive tuberculosis 726/100,000 (V. Kumaraswami, personal communication), supporting the assumption that approximately 50% of both incident and prevalent cases of culture confirmed tuberculosis are smear-positive. Overall this seems to support the notion that the natural duration of smear-positive and smear-negative disease are roughly similar.

Discussion

Main findings

In our study we combined available information on untreated tuberculosis to estimate its case fatality and duration of disease. We found only few studies from the pre-chemotherapy era that allow for estimation of CFs and duration of disease of smear-positive tuberculosis. Given the limited information available and assuming that a 10-year CF will closely approximate lifetime CF, we conclude that (lifetime) CF in untreated smear-positive tuberculosis among HIV negative individuals is approximately 70% and about the same for both sexes. Mortality seems to be approximately independent of age until the age of 50 years after which it increases, perhaps due to concomitant complicating diseases such as diabetes or cancer and a greater mortality from other causes. However, this age effect would only be important in (patient) populations with a dramatically different age structure than the ones used in this review. For most high burden countries this is not the case.

For culture-positive smear-negative tuberculosis, lifetime CF is probably slightly over 20%, although this could only be estimated indirectly and with uncertain precision.

The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be grossly similar for smear-positive and smear-negative tuberculosis.

Because of the expected heterogeneity between studies with respect to study design and population, study period, duration and intensity of follow-up, definition of pulmonary tuberculosis (‘open’/‘closed’, bacillary/abacillary, smear-positive/smear-negative), etc., we did not do a formal meta-analysis. Additional heterogeneity among studies may also exist in patient selection and diagnostic procedures, for example the number of sputum samples analyzed and how these were obtained (e.g. induced or spontaneous). However, these data were hardly ever reported in the included studies.

Limitations of our systematic review

Despite the fact that (HIV negative) tuberculosis has for centuries been a major cause of mortality, the number of studies on its natural history is surprisingly low.

This contrasts sharply with, for example, HIV for which detailed information on its natural history became available within decades of the discovery of the virus. Long term follow-up studies of HIV patients in carefully monitored cohorts have generated this information. In contrast, follow-up of most tuberculosis patients is nowadays usually limited to the duration of their treatment.

Another limitation is our serious lack of knowledge on the prognosis of extra-pulmonary and smear-negative pulmonary tuberculosis as most data on the natural history are available for patients who tested sputum smear-positive. No reliable prospective data on smear-negative culture-positive pulmonary patients are available and their long term survival can only be estimated indirectly and thus with great uncertainty. These patients form currently the group most likely to receive no or inadequate treatment, and may well account for large proportion of tuberculosis deaths. The prognosis of untreated extra-pulmonary patients - a very heterogeneous group that also includes most tuberculosis in children - is even more uncertain, and insufficient data were identified to include it in our review.

An important limitation of using electronic databases going back in time is that these do not include abstracts and searches therefore may miss potentially eligible papers. We have tried to obviate this by including quite general search terms (see Table 1). However, this way of searching yielded many references (n = 1560), 43 of which were selected for reading and available in full-text, but none of which was eligible for inclusion into our review.

We therefore supplemented our search strategy with snowball sampling. A limitation of this approach is that it depends, perhaps heavily so, on its starting point. We choose dr. Rieder's book [18] as the starting point since it is known for its thoroughness with respect to discussing all important aspects of tuberculosis and inclusion of (older) literature. Although this approach may have lead to some underrepresentation of e.g. American and francophone literature, this latter strategy yielded 22 eligible papers whereas the electronic searches did not yield any useful references.

Quite some of the identified potentially eligible papers were not available to us. In theory, this may have influenced the outcome of our review. However, we were able to identify papers appearing in a variety of journals, text books and published as reports (‘grey literature’) and did not find any evidence for a correlation between the type of source and the quality of the data. Therefore, we expect no important ‘availability bias’ correlated with prognosis of untreated tuberculosis.

Another limitation of our review is that most of the included studies on CF were on predominantly Caucasian populations whereas most untreated patients currently are of different ethnicity. This is probably mainly due to the fact that evaluating the natural history of tuberculosis requires long term follow-up which has proven to be difficult, especially in resource constrained settings.

A key limitation is that we had to restrict our review to HIV-negative patients, as explained in the introduction. This does not imply that no information on the prognosis of tuberculosis in HIV-positive patients is available. For example, two relevant systematic reviews have been carried out recently: one on any form of tuberculosis in people with HIV infection [143], and one on HIV and MDR-tuberculosis [144]. The prognosis of the latter type of patients likely resembles that of untreated patients. If we exclude data on patients receiving ART, because of the heterogeneity in ART regimes and ART resistance patterns - both between and within countries, then we can at least explore the prognosis of HIV co-infected tuberculosis patients. As regards CF, the review of Payne and Bellamy [143] provided no information on the prognosis of HIV positive MDR-tuberculosis patients. However, it identified several sources on tuberculosis in HIV patients from the pre-ART era. One from the USA found a median survival of tuberculosis patients, including patients with drug susceptible tuberculosis, of 16 months [145]. However, only 13% of patients died from tuberculosis, the others from other AIDS related diseases. Development of tuberculosis may thus be a marker for being severely immunocompromised. Another study, from Malawi, found a mortality of 47% among patients followed-up for 32 months [146]. Thus, HIV infected patients with tuberculosis not treated with ART, have a poor prognosis. The other review [144] identified 8 sources of HIV associated MDR-tuberculosis outbreaks. Five of these were from the USA where second line tuberculosis treatment is presumably available and adequate, and these studies thus did not represent “untreated” tuberculosis. This also appeared from case fatality rates which were lower than those from outside the USA. The other three studies were from Italy (N = 116) [147], Spain (N = 48) [148], and Argentina (N = 124) [149]. The studies from Italy and Argentina both reported that second line treatment was not adequate, while the use of second line drugs was not reported in the study from Spain. Reported mortality was between 93% (Argentina) and 98% (Spain), and time to death was short. In the Spanish study the mean time from diagnosis to death of the 47 who died was 77.6 days [148]. In the Italian study the median time to death was reported as 93 and 79 days for the two participating hospitals [147]. The Argentinean study only reported that half of the patients survived less than 5 weeks and that 1-year survival was as low as 5% [149].

As regards the duration of disease, findings from these studies [143], [144], [146]–[149] suggest that untreated tuberculosis in HIV infected patients must be rapidly fatal, with a mean survival of less than 6 months. However, a limitation of the use of these patients is that all suitable reports were on nosocomial outbreaks among hospitalized HIV patients. Such patients may be more immunocompromised than the “average” HIV patient who develops tuberculosis, and alternative approaches to estimate the prognosis of tuberculosis in various types of HIV infected patients should be developed.

Conclusions

While pre-chemotherapy data appeared to be a useful source of data for the prognosis of untreated tuberculosis, inevitably questions remain. Particularly, the impact of risk factors other than (variably defined) smear status was hard to explore systematically. Perhaps, long-term follow-up of patients with inadequately treated MDR or XDR tuberculosis may fill some of the gaps in our knowledge. Such follow-up may also fill other gaps in our knowledge such as the frequency of transitions between smear-positive and smear-negative tuberculosis and the prognosis and duration of HIV-positive tuberculosis.

Acknowledgments

We thank dr. Ana Bierrenbach, dr. Philippe Glaziou and dr. Ikushi Onozaki from the World Health Organization, and dr. Masja Straetemans from KNCV Tuberculosis Foundation as well as participants to workshops on the revision of the tuberculosis estimates for their useful comments on our data analysis and on the manuscript.

Author Contributions

Statistical/mathematical analysis after discussion with all authors (in particular BW and MW): NN. Conceived and designed the experiments: EWT MJvdW MB BW NN. Performed the experiments: EWT NN. Analyzed the data: EWT NN. Wrote the paper: NN EWT.

Citation: Tiemersma EW, van der Werf MJ, Borgdorff MW, Williams BG, Nagelkerke NJD (2011) Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review. PLoS ONE6(4): e17601. https://doi.org/10.1371/journal.pone.0017601

References

1. Dubos RJ (1987) The white plague: Tuberculosis, man, and society. New Brunswick: Rutgers University Press. 320 p.RJ Dubos1987The white plague: Tuberculosis, man, and society.New BrunswickRutgers University Press320

2. Johnston W (1995) The modern epidemic: A history of tuberculosis in Japan. Harvard East Asian Monographs 162. Cambridge, MA: Harvard University Asia Center. 432 p.W. Johnston1995The modern epidemic: A history of tuberculosis in Japan.Harvard East Asian Monographs 162. Cambridge, MAHarvard University Asia Center432

3. Ryan F (1992) Tuberculosis: The greatest story never told. Bromsgrove: Swift Publishers. 446 p.F. Ryan1992Tuberculosis: The greatest story never told.BromsgroveSwift Publishers446

4. Anonymous (2005) National TB prevalence survey, 2002. Pnom Penh, Cambodia: National Tuberculosis Program. 77 p.Anonymous2005National TB prevalence survey, 2002.Pnom Penh, CambodiaNational Tuberculosis Program77

5. Hoa NB, Sy DN, Nhung NV, Tiemersma EW, Borgdorff MW, Cobelens FG (2010) A national survey of tuberculosis prevalence in Vietnam. Bull World Health Organ 88: 273–280.NB HoaDN SyNV NhungEW TiemersmaMW BorgdorffFG Cobelens2010A national survey of tuberculosis prevalence in Vietnam.Bull World Health Organ88273280

6. Steingart KR, Henry M, Ng V, Hopewell PC, Ramsay A, et al. (2006) Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review. Lancet Infect Dis 6: 570–581.KR SteingartM. HenryV. NgPC HopewellA. Ramsay2006Fluorescence versus conventional sputum smear microscopy for tuberculosis: a systematic review.Lancet Infect Dis6570581

7. Dye C, Watt CJ, Bleed DM, Hosseini SM, Raviglione MC (2005) Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally. JAMA 293: 2767–2775.C. DyeCJ WattDM BleedSM HosseiniMC Raviglione2005Evolution of tuberculosis control and prospects for reducing tuberculosis incidence, prevalence, and deaths globally.JAMA29327672775

8. Chan ED, Iseman MD (2008) Multidrug-resistant and extensively drug-resistant tuberculosis: a review. Curr Opin Infect Dis 21: 587–595.ED ChanMD Iseman2008Multidrug-resistant and extensively drug-resistant tuberculosis: a review.Curr Opin Infect Dis21587595

9. Dye C, Bassili A, Bierrenbach AL, Broekmans JF, Chadha VK, et al. (2008) Measuring tuberculosis burden, trends, and the impact of control programmes. Lancet Infect Dis 8: 233–243.C. DyeA. BassiliAL BierrenbachJF BroekmansVK Chadha2008Measuring tuberculosis burden, trends, and the impact of control programmes.Lancet Infect Dis8233243

10. Korenromp EL, Bierrenbach AL, Williams BG, Dye C (2009) The measurement and estimation of tuberculosis mortality. Int J Tuberc Lung Dis 13: 283–303.EL KorenrompAL BierrenbachBG WilliamsC. Dye2009The measurement and estimation of tuberculosis mortality.Int J Tuberc Lung Dis13283303

11. Espinal MA, Kim SJ, Suarez PG, Kam KM, Khomenko AG, et al. (2000) Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries. JAMA 283: 2537–2545.MA EspinalSJ KimPG SuarezKM KamAG Khomenko2000Standard short-course chemotherapy for drug-resistant tuberculosis: treatment outcomes in 6 countries.JAMA28325372545

12. Cox H, Kebede Y, Allamuratova S, Ismailov G, Davletmuratova Z, et al. (2006) Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance. PLoS Med 3: e384.H. CoxY. KebedeS. AllamuratovaG. IsmailovZ. Davletmuratova2006Tuberculosis recurrence and mortality after successful treatment: impact of drug resistance.PLoS Med3e384

13. Quy HT, Cobelens FG, Lan NT, Buu TN, Lambregts CS, et al. (2006) Treatment outcomes by drug resistance and HIV status among tuberculosis patients in Ho Chi Minh City, Vietnam. Int J Tuberc Lung Dis 10: 45–51.HT QuyFG CobelensNT LanTN BuuCS Lambregts2006Treatment outcomes by drug resistance and HIV status among tuberculosis patients in Ho Chi Minh City, Vietnam.Int J Tuberc Lung Dis104551

14. Bonnet M, Ramsay A, Gagnidze L, Githui W, Guerin PJ, et al. (2007) Reducing the number of sputum samples examined and thresholds for positivity: an opportunity to optimise smear microscopy. Int J Tuberc Lung Dis 11: 953–958.M. BonnetA. RamsayL. GagnidzeW. GithuiPJ Guerin2007Reducing the number of sputum samples examined and thresholds for positivity: an opportunity to optimise smear microscopy.Int J Tuberc Lung Dis11953958

15. Gagneux S, Long CD, Small PM, Van T, Schoolnik GK, et al. (2006) The competitive cost of antibiotic resistance in Mycobacterium tuberculosis. Science 312: 1944–1946.S. GagneuxCD LongPM SmallT. VanGK Schoolnik2006The competitive cost of antibiotic resistance in Mycobacterium tuberculosis.Science31219441946

16. Akksilp S, Karnkawinpong O, Wattanaamornkiat W, Viriyakitja D, Monkongdee P, et al. (2007) Antiretroviral therapy during tuberculosis treatment and marked reduction in death rate of HIV-infected patients, Thailand. Emerg Infect Dis 13: 1001–1007.S. AkksilpO. KarnkawinpongW. WattanaamornkiatD. ViriyakitjaP. Monkongdee2007Antiretroviral therapy during tuberculosis treatment and marked reduction in death rate of HIV-infected patients, Thailand.Emerg Infect Dis1310011007

17. WHO (2008) Global tuberculosis control: Surveillance, planning, financing. WHO report 2008. Geneva: World Health Organization.WHO2008Global tuberculosis control: Surveillance, planning, financing. WHO report 2008. Geneva: World Health Organization.WHO/HTM/TB/2008.393.294 p. WHO/HTM/TB/2008.393.294 p.

18. Rieder HL (1999) Epidemiological basis of tuberculosis control. Paris: International Union against Tuberculosis and Lung Disease . 162 p.HL Rieder1999Epidemiological basis of tuberculosis control.ParisInternational Union against Tuberculosis and Lung Disease 162

19. Rutledge JA, Crouch JB (1919) The ultimate results in 1654 cases of tuberculosis treated at the modern Woodmen of America sanatorium. Am Rev Tuberc 2: 755–763.JA RutledgeJB Crouch1919The ultimate results in 1654 cases of tuberculosis treated at the modern Woodmen of America sanatorium.Am Rev Tuberc2755763

20. Armstrong DB (1921) Four years of the Framingham Demonstration. Am Rev Tuberc 4: 908–919.DB Armstrong1921Four years of the Framingham Demonstration.Am Rev Tuberc4908919

21. Hilleboe HE (1940) Survivorship rate on collapse therapy patients discharged from sanatoria. Chest 6: 104–110.HE Hilleboe1940Survivorship rate on collapse therapy patients discharged from sanatoria.Chest6104110

22. Hilleboe HE (1941) Post-sanatorium tuberculosis survival rates in Minnesota. Public Health Reports 56: 895–907.HE Hilleboe1941Post-sanatorium tuberculosis survival rates in Minnesota.Public Health Reports56895907

23. Gauld RL, Halliday CH, Cullen VF, Fales WT (1941) A five year follow-up of discharges from Maryland tuberculosis sanatoria. Am J Public Health Nations Health 31: 568–576.RL GauldCH HallidayVF CullenWT Fales1941A five year follow-up of discharges from Maryland tuberculosis sanatoria.Am J Public Health Nations Health31568576

24. Loewenstein E (1931) Die Zuchtung der Tuberkelbazillen aus dem stroemenden Blute. Zentralbl Bakteriol Parasitenkd Infektionskr Hyg 1: 127.E. Loewenstein1931Die Zuchtung der Tuberkelbazillen aus dem stroemenden Blute.Zentralbl Bakteriol Parasitenkd Infektionskr Hyg1127

25. Jensen KA (1932) Reinzuchtung und Typenbestimmung von Tuberkelbazillenstammen. Zentralb Bakteriol Parasitenkd Infektionskr Hyg Abt 1: 222.KA Jensen1932Reinzuchtung und Typenbestimmung von Tuberkelbazillenstammen.Zentralb Bakteriol Parasitenkd Infektionskr Hyg Abt1222

26. van Cleeff MR, Kivihya-Ndugga LE, Meme H, Odhiambo JA, Klatser PR (2005) The role and performance of chest X-ray for the diagnosis of tuberculosis: a cost-effectiveness analysis in Nairobi, Kenya. BMC Infect Dis 5: 111.MR van CleeffLE Kivihya-NduggaH. MemeJA OdhiamboPR Klatser2005The role and performance of chest X-ray for the diagnosis of tuberculosis: a cost-effectiveness analysis in Nairobi, Kenya.BMC Infect Dis5111

27. Corbett EL, Watt CJ, Walker N, Maher D, Williams BG, et al. (2003) The growing burden of tuberculosis: global trends and interactions with the HIV epidemic. Arch Intern Med 163: 1009–1021.EL CorbettCJ WattN. WalkerD. MaherBG Williams2003The growing burden of tuberculosis: global trends and interactions with the HIV epidemic.Arch Intern Med16310091021

28. Dooley KE, Chaisson RE (2009) Tuberculosis and diabetes mellitus: convergence of two epidemics. Lancet Infect Dis 9: 737–746.KE DooleyRE Chaisson2009Tuberculosis and diabetes mellitus: convergence of two epidemics.Lancet Infect Dis9737746

29. National Tuberculosis Institute (1974) Tuberculosis in a rural population of South India: a five-year epidemiological study. Bull World Health Organ 51: 473–488.National Tuberculosis Institute1974Tuberculosis in a rural population of South India: a five-year epidemiological study.Bull World Health Organ51473488

30. Hamel GH (1928) Jahresversammlung des Deutschen Zentral-komitees zur Bekämpfung der Tuberkulose. Erster Verhandlungstag. (discussions during annual meeting of the German Tuberculosis Control Committee). Zeitschr Tuberk 51: 497–531.GH Hamel1928Jahresversammlung des Deutschen Zentral-komitees zur Bekämpfung der Tuberkulose. Erster Verhandlungstag. (discussions during annual meeting of the German Tuberculosis Control Committee).Zeitschr Tuberk51497531

31. Meidell B (1931) Die wahrscheinliche Lebensdauer und die Sterblichkeitsmessung. Skandinavisk aktuarietidskrift 14: 217–230.B. Meidell1931Die wahrscheinliche Lebensdauer und die Sterblichkeitsmessung.Skandinavisk aktuarietidskrift14217230

32. Anonymous (1936) The expectation of life of the tuberculous. Tubercle 17: 171–172.Anonymous1936The expectation of life of the tuberculous.Tubercle17171172

33. Westergaard H (1901) Die Lehre von der Mortalität und Morbidität. Antropologisch-statistische Untersuchungen. Jena, Germany: Gustav Fischer Verlag. 703 p.H. Westergaard1901Die Lehre von der Mortalität und Morbidität. Antropologisch-statistische Untersuchungen.Jena, GermanyGustav Fischer Verlag703

34. Anonymous (1953) Tuberculosis mortality. Lancet 1: 178–179.Anonymous1953Tuberculosis mortality.Lancet1178179

35. Fraser R (1948) Chances of survival in pulmonary tuberculosis. Br Med J 2: 106.R. Fraser1948Chances of survival in pulmonary tuberculosis.Br Med J2106

36. Maguire R (1900) The Harveian Lectures on Prognosis and Treatment in Pulmonary Tuberculosis: Delivered before the Harveian Society of London, November, 1900. Br Med J 2: 1637–1639.R. Maguire1900The Harveian Lectures on Prognosis and Treatment in Pulmonary Tuberculosis: Delivered before the Harveian Society of London, November, 1900.Br Med J216371639

37. Maguire R (1900) The Harveian Lectures on Prognosis and Treatment in Pulmonary Tuberculosis: Delivered before the Harveian Society of London, November, 1900. Br Med J 2: 1695–1697.R. Maguire1900The Harveian Lectures on Prognosis and Treatment in Pulmonary Tuberculosis: Delivered before the Harveian Society of London, November, 1900.Br Med J216951697

38. Maguire R (1900) The Harveian Lectures on Prognosis and Treatment in Pulmonary Tuberculosis: Delivered before the Harveian Society of London, November, 1900. Br Med J 2: 1566–1567.R. Maguire1900The Harveian Lectures on Prognosis and Treatment in Pulmonary Tuberculosis: Delivered before the Harveian Society of London, November, 1900.Br Med J215661567

39. Braeuning H (1924) Typische Formen der Lungentuberkulose. Beitr Klin Tuberk 58: 429–450.H. Braeuning1924Typische Formen der Lungentuberkulose.Beitr Klin Tuberk58429450

40. Cummins SL (1935) The problem of the acute pulmonary phthisis of young females. Brit J Tuberc 29: 4–11.SL Cummins1935The problem of the acute pulmonary phthisis of young females.Brit J Tuberc29411

41. Gottstein A (1931) Allgemeine Epidemiologie der Tuberkulose. Berlin, Germany: Springer Verlag . 123 p.A. Gottstein1931Allgemeine Epidemiologie der Tuberkulose.Berlin, GermanySpringer Verlag 123

42. Oldenburg F, Seïsoff C (1931) Gedanken über das Schicksal offentuberkulöser Eisenbahner auf Grund statistischer Erhebungen. Zeitschr Tuberk 61: 334–349.F. OldenburgC. Seïsoff1931Gedanken über das Schicksal offentuberkulöser Eisenbahner auf Grund statistischer Erhebungen.Zeitschr Tuberk61334349

43. Hillerdal O (1963) The mortality from tuberculosis in a Swedish county. Acta Tuberc Pneumonol Scand 42: 251–262.O. Hillerdal1963The mortality from tuberculosis in a Swedish county.Acta Tuberc Pneumonol Scand42251262

44. Paine AL, Matwichuk Z (1964) Five- to seventeen-year end-results in 402 patients with pulmonary resection for tuberculosis. Am Rev Respir Dis 90: 760–770.AL PaineZ. Matwichuk1964Five- to seventeen-year end-results in 402 patients with pulmonary resection for tuberculosis.Am Rev Respir Dis90760770

45. Phillips S (1964) Relapse in treated cases of pulmonary tuberculosis. I. Three-year follow-up of 312 patients discharged from the hospital with medical approval, 1947-1954. Am Rev Respir Dis 90: 120–122.S. Phillips1964Relapse in treated cases of pulmonary tuberculosis. I. Three-year follow-up of 312 patients discharged from the hospital with medical approval, 1947-1954.Am Rev Respir Dis90120122

46. Phillips S (1964) Relapse in treated cases of pulmonary tuberculosis. II. Six-year follow-up of 109 patients discharged from the hospital with medical approval, 1955-1956. Am Rev Respir Dis 90: 61–66.S. Phillips1964Relapse in treated cases of pulmonary tuberculosis. II. Six-year follow-up of 109 patients discharged from the hospital with medical approval, 1955-1956.Am Rev Respir Dis906166

47. Elderton WP, Perry SJ (1910) A third study of the statistics of pulmonary tuberculosis. The mortality of the tuberculous and sanatorium treatment. Draper's Company Research Memoirs. Studies in natural deterioration VI. London: Department of applied mathematics, University College, University of London. 36 p.WP EldertonSJ Perry1910A third study of the statistics of pulmonary tuberculosis. The mortality of the tuberculous and sanatorium treatment. Draper's Company Research Memoirs. Studies in natural deterioration VI.LondonDepartment of applied mathematics, University College, University of London36

48. Elderton WP, Perry SJ (1913) A fourth study of the statistics of pulmonary tuberculosis. The mortality of the tuberculous: sanatorium and tuberculin treatment. Draper's Company Research Memoirs. Studies in natural deterioration VIII. London: Department of applied statistics, University College, University of London. 55 p.WP EldertonSJ Perry1913A fourth study of the statistics of pulmonary tuberculosis. The mortality of the tuberculous: sanatorium and tuberculin treatment. Draper's Company Research Memoirs. Studies in natural deterioration VIII.LondonDepartment of applied statistics, University College, University of London55

49. Frimødt-Moller J (1960) A community-wide tuberculosis study in a South Indian rural population, 1950-1955. Bull World Health Organ 22: 61–170.J. Frimødt-Moller1960A community-wide tuberculosis study in a South Indian rural population, 1950-1955.Bull World Health Organ2261170

50. Geissler D (1923) Das Schiksal offen tuberkulöser Kinder. Beitr Klin Tuberk 55: 155–156.D. Geissler1923Das Schiksal offen tuberkulöser Kinder.Beitr Klin Tuberk55155156

51. Hilleboe HE (1936) The comparative mortality of patients discharged from tuberculosis sanatoria. Am Rev Tuberc 34: 713–724.HE Hilleboe1936The comparative mortality of patients discharged from tuberculosis sanatoria.Am Rev Tuberc34713724

52. Bardswell ND, Thompson JHR (1919) Pulmonary tuberculosis. Mortality after sanatorium treatment. A report on the experience of the King Edward VII Sanatorium, Midhurst. pp. 5–39.ND BardswellJHR Thompson1919Pulmonary tuberculosis. Mortality after sanatorium treatment. A report on the experience of the King Edward VII Sanatorium, Midhurst.539London, UK. London, UK.

53. Lowe CR (1954) Recent trends in survival of patients with respiratory tuberculosis. Br J Prev Soc Med 8: 91–98.CR Lowe1954Recent trends in survival of patients with respiratory tuberculosis.Br J Prev Soc Med89198

54. May W (1928) Welche Konsequenzen ergeben sich aus der Dauerstatistik der Heilverfahren bei Offentuberkulösen? Zeitschr Tuberk 51: 177–184.W. May1928Welche Konsequenzen ergeben sich aus der Dauerstatistik der Heilverfahren bei Offentuberkulösen?Zeitschr Tuberk51177184

55. Ruge H (1909) Dauererfolge nach 10 Jahren bei Lungetuberkulose im Hochgebirge. Zeitsch Tuberk 15: 146–168.H. Ruge1909Dauererfolge nach 10 Jahren bei Lungetuberkulose im Hochgebirge.Zeitsch Tuberk15146168

56. Saegler E (1934) Beitrag zur Frage der Beziehungen zwischen Tuberkulose und Lebensalter. Zeitschr Tuberk 71: 285–288.E. Saegler1934Beitrag zur Frage der Beziehungen zwischen Tuberkulose und Lebensalter.Zeitschr Tuberk71285288

57. Stadler E (1903) Der Einfluss der Lungetuberkulose of Lebensdauer und Erwerbsfähigkeit und der Werth der Volksheilstättenbehandlung. Deutsch Arch Klin Med 95: 412–440.E. Stadler1903Der Einfluss der Lungetuberkulose of Lebensdauer und Erwerbsfähigkeit und der Werth der Volksheilstättenbehandlung.Deutsch Arch Klin Med95412440

58. Stephens MG (1941) Follow-up of 1041 tuberculous patients. Am Rev Tuberc 44: 451–462.MG Stephens1941Follow-up of 1041 tuberculous patients.Am Rev Tuberc44451462

59. Von Düring K (1927) Zur Frage der Prognose und Therapie der tuberkulösen Lungenkavernen. Beitr Klin Tuberk 65: 694–712.K. Von Düring1927Zur Frage der Prognose und Therapie der tuberkulösen Lungenkavernen.Beitr Klin Tuberk65694712

60. Williams CT (1871) On the duration of phthisis pulmonalis and on certain conditions which influence it. Roy Med Chir Trans 54: 95–127.CT Williams1871On the duration of phthisis pulmonalis and on certain conditions which influence it.Roy Med Chir Trans5495127

61. Ames WR, Schuck MH (1953) General population roentgenographic surveys: subsequent course of persons considered to have tuberculosis. Am Rev Tuberc 68: 9–23.WR AmesMH Schuck1953General population roentgenographic surveys: subsequent course of persons considered to have tuberculosis.Am Rev Tuberc68923

62. Katz J (1952) Survival of tuberculous patients. Am Rev Tuberc 66: 651–665.J. Katz1952Survival of tuberculous patients.Am Rev Tuberc66651665

63. Katz J, Kunofsky S, Locke BZ (1954) Tuberculosis morbidity and mortality among mental patients as compared with the general population. Am Rev Tuberc 70: 32–48.J. KatzS. KunofskyBZ Locke1954Tuberculosis morbidity and mortality among mental patients as compared with the general population.Am Rev Tuberc703248

64. Brewster AW, Fletcher RC (1949) Studies of patients discharged from tuberculosis sanatoria; mortality rates associated with selected characteristics of the patient population. Public Health Rep 64: 687–706.AW BrewsterRC Fletcher1949Studies of patients discharged from tuberculosis sanatoria; mortality rates associated with selected characteristics of the patient population.Public Health Rep64687706

65. Puffer RR, Stewart HC, Gass RS (1939) Analysis of the subsequent course of diagnosed cases of tuberculosis. Am J Public Health Nations Health 29: 894–899.RR PufferHC StewartRS Gass1939Analysis of the subsequent course of diagnosed cases of tuberculosis.Am J Public Health Nations Health29894899

66. Stobie W (1933) Prognosis in pulmonary tuberculosis. Br Med J 1: 507–509.W. Stobie1933Prognosis in pulmonary tuberculosis.Br Med J1507509

67. Gillespie JR (1928) Prognosis in pulmonary tuberculosis. Br Med J 1: 436–437.JR Gillespie1928Prognosis in pulmonary tuberculosis.Br Med J1436437

68. Clark WR (1914) The prognosis in pulmonary tuberculosis. Cal State J Med 12: 319–322.WR Clark1914The prognosis in pulmonary tuberculosis.Cal State J Med12319322

69. Cohen D (1954) Rorschach scores, prognosis, and course of illness in pulmonary tuberculosis. J Consult Psychol 18: 405–408.D. Cohen1954Rorschach scores, prognosis, and course of illness in pulmonary tuberculosis.J Consult Psychol18405408

70. Wittkower ED, Durost HB, Laing WA (1955) A psychosomatic study of the course of pulmonary tuberculosis. Am Rev Tuberc 71: 201–219.ED WittkowerHB DurostWA Laing1955A psychosomatic study of the course of pulmonary tuberculosis.Am Rev Tuberc71201219

71. Simpson DG, Lowell AM (1964) Tuberculosis first registered at death. Am Rev Respir Dis 89: 165–174.DG SimpsonAM Lowell1964Tuberculosis first registered at death.Am Rev Respir Dis89165174

72. Holst PF, Nicolaysen L, Ustvedt Y (1906) Untersuchungen über die Lebensdauer der Schwindsüchtigen in Norwegen. Deutsch Arch Klin Med 88: 325–350.PF HolstL. NicolaysenY. Ustvedt1906Untersuchungen über die Lebensdauer der Schwindsüchtigen in Norwegen.Deutsch Arch Klin Med88325350

73. Horwitz O, Knudsen J (1960) Comparison between attenders and non-attenders at the Danish mass tuberculosis campaign, 1950-52. Tuberculosis morbidity and general mortality in two groups during the first four years of follow-up. Bull World Health Organ 23: 669–681.O. HorwitzJ. Knudsen1960Comparison between attenders and non-attenders at the Danish mass tuberculosis campaign, 1950-52. Tuberculosis morbidity and general mortality in two groups during the first four years of follow-up.Bull World Health Organ23669681

74. Braeuning H (1920) Tuberkulöse Erkrankungen bei Schwestern infolge von Ansteckung im Dienst und ihre Verhütung. Zeitschr Tuberk 33: 129–136.H. Braeuning1920Tuberkulöse Erkrankungen bei Schwestern infolge von Ansteckung im Dienst und ihre Verhütung.Zeitschr Tuberk33129136

75. Cochrane E (1935) Course, complications and prognosis of open pulmonary tuberculosis in children. Tubercle 16: 529–538.E. Cochrane1935Course, complications and prognosis of open pulmonary tuberculosis in children.Tubercle16529538

76. De Besche AD, Jørgenson JO (1925) Dødeligheten av Lungentuberkulose i Oslo blandt til Byen indflyttede og der fødte Individer. Norsk Magazin for Laegevidenskaben 86: 1229–1253.AD De BescheJO Jørgenson1925Dødeligheten av Lungentuberkulose i Oslo blandt til Byen indflyttede og der fødte Individer.Norsk Magazin for Laegevidenskaben8612291253

77. Gottstein A (1931) Öffentliches Gesundheitswesen. Beiträge zur Epidemiologie der Tuberkulose. Klin Wochenschrift 10: 796–798.A. Gottstein1931Öffentliches Gesundheitswesen. Beiträge zur Epidemiologie der Tuberkulose.Klin Wochenschrift10796798

78. Hamel GH (1912) Tuberkulosearbeiten aus dem Kaiserlichen Gesundheitsamte. Deutsche Heilstätten für Lungenkranke. Geschichtliche und statistische Mitteilungen V. 13. Heft. Berlin, Germany: Springer Verlag. 124 p.GH Hamel1912Tuberkulosearbeiten aus dem Kaiserlichen Gesundheitsamte. Deutsche Heilstätten für Lungenkranke. Geschichtliche und statistische Mitteilungen V. 13. Heft.Berlin, GermanySpringer Verlag124

79. Kayser-Petersen JE (1926) Offene und geschlossene Lungentuberkulose. Beitr Klin Tuberk 63: 503–514.JE Kayser-Petersen1926Offene und geschlossene Lungentuberkulose.Beitr Klin Tuberk63503514

80. Kayser-Petersen JE, Räder M (1934) Über Veränderungen in der Tuberkulosemorbidität und –mortalität mit besonderer Berücksichtigung der aus bereits bekannten geschlossenen Tuberkulosen entstehenden offenen Tuberkulosen. Beitr Klin Tuberk 84: 492–499.JE Kayser-PetersenM. Räder1934Über Veränderungen in der Tuberkulosemorbidität und –mortalität mit besonderer Berücksichtigung der aus bereits bekannten geschlossenen Tuberkulosen entstehenden offenen Tuberkulosen.Beitr Klin Tuberk84492499

81. Klare K (1922) Zur Prognose der offenen Lungentuberkulose im Kindesalter. Beitr Klin Tuberk 50: 318–321.K. Klare1922Zur Prognose der offenen Lungentuberkulose im Kindesalter.Beitr Klin Tuberk50318321

82. Klare K (1936) Die Prognose der offenen Lungentuberkulose bei Kindern und Jugendlichen. Beitr Klin Tuberk 88: 268–282.K. Klare1936Die Prognose der offenen Lungentuberkulose bei Kindern und Jugendlichen.Beitr Klin Tuberk88268282

83. Krause K (1927) Über das Schicksal Offentuberkulöser in 25 Jahren. Beitr Klin Tuberk 67: 386–388.K. Krause1927Über das Schicksal Offentuberkulöser in 25 Jahren.Beitr Klin Tuberk67386388

84. Lewis-Faning E (1943) Respiratory tuberculosis: effect of the war on the length of the interval between notification and death. BMJ 2: 684–685.E. Lewis-Faning1943Respiratory tuberculosis: effect of the war on the length of the interval between notification and death.BMJ2684685

85. Lissant Cox G (1923) Sanatorium treatment contrasted with home treatment. After-histories of 4067 cases. Brit J Tuberc 1: 27–30.G. Lissant Cox1923Sanatorium treatment contrasted with home treatment. After-histories of 4067 cases.Brit J Tuberc12730

86. Palmer CE, Jablon S, Edwards PQ (1957) Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build. Am Rev Tuberc 76: 517–539.CE PalmerS. JablonPQ Edwards1957Tuberculosis morbidity of young men in relation to tuberculin sensitivity and body build.Am Rev Tuberc76517539

87. Narain R, Geser A, Jambunathan MV, Subramanian M (1963) Tuberculosis prevalence survey in Tumkur district. Ind J Tuberc 10: 85–116.R. NarainA. GeserMV JambunathanM. Subramanian1963Tuberculosis prevalence survey in Tumkur district.Ind J Tuberc1085116

88. Roloff W (1931) Dauererfolge der Lungenkollapsbehandlung. Statistischer Bericht über 1128 Fälle aus den Jahren 1918-1928. Beitr Klin Tuberk 78: 495–516.W. Roloff1931Dauererfolge der Lungenkollapsbehandlung. Statistischer Bericht über 1128 Fälle aus den Jahren 1918-1928.Beitr Klin Tuberk78495516

89. Trauger DA (1963) A note on tuberculosis epidemiology. Am Rev Respir Dis 87: 582–584.DA Trauger1963A note on tuberculosis epidemiology.Am Rev Respir Dis87582584

90. Van Joost CRNF (1935) Opmerkingen naar aanleiding van een 200 tal met kunstmatige pneumothorax- en een 50 tal met middenrifsverlamming (phrenicusexairesis) behandelde gevallen van longtuberculose. Geneeskund Tijdschr v Ned Indië 75: 1223–1235.CRNF Van Joost1935Opmerkingen naar aanleiding van een 200 tal met kunstmatige pneumothorax- en een 50 tal met middenrifsverlamming (phrenicusexairesis) behandelde gevallen van longtuberculose.Geneeskund Tijdschr v Ned Indië7512231235

91. Von Frisch AV (1925) Über Prognostik der Lungentuberkulose. Beitr Klin Tuberk 62: 629–657.AV Von Frisch1925Über Prognostik der Lungentuberkulose.Beitr Klin Tuberk62629657

92. McDonald JC (1952) Factors influencing sex differences in mortality from respiratory tuberculosis in England and Wales. Br J Soc Med 6: 259–264.JC McDonald1952Factors influencing sex differences in mortality from respiratory tuberculosis in England and Wales.Br J Soc Med6259264

93. Comstock GW, Burke MH (1951) Tuberculosis studies in Muscogee County, Georgia. III. Tuberculosis mortality following a community-wide X-ray survey. Public Health Rep 66: 695–711.GW ComstockMH Burke1951Tuberculosis studies in Muscogee County, Georgia. III. Tuberculosis mortality following a community-wide X-ray survey.Public Health Rep66695711

94. Stephani J (1951) Prognosis in pulmonary tuberculosis. Br J Tuberc Dis Chest 45: 1–6.J. Stephani1951Prognosis in pulmonary tuberculosis.Br J Tuberc Dis Chest4516

95. Daw RH (1950) Tuberculosis mortality. Lancet 1: 830.RH Daw1950Tuberculosis mortality.Lancet1830

96. Elliot W (1949) Tuberculosis; certain unexplained mortality figures. Br Med J 2: 297–299.W. Elliot1949Tuberculosis; certain unexplained mortality figures.Br Med J2297299

97. Bentley FJ (1948) Survival in pulmonary tuberculosis. Br Med J 1: 1254.FJ Bentley1948Survival in pulmonary tuberculosis.Br Med J11254

98. Kasius RV, Halpin EH (1947) Deaths from respiratory tuberculosis in institutions in the United States, 1945. Public Health Rep 62: 1296–1315.RV KasiusEH Halpin1947Deaths from respiratory tuberculosis in institutions in the United States, 1945.Public Health Rep6212961315

99. Heise FH (1921) Prognosis of pulmonary tuberculosis. Can Med Assoc J 11: 314–318.FH Heise1921Prognosis of pulmonary tuberculosis.Can Med Assoc J11314318

100. Berg G (1951) Statistik über Tuberkulosemortalität in Kriegszeiten. Beitr Klin Tuberk 106: 1–9.G. Berg1951Statistik über Tuberkulosemortalität in Kriegszeiten.Beitr Klin Tuberk10619

101. McDonald JC, Springett VH (1954) The decline of tuberculosis mortality in Western Europe. Br Med Bull 10: 77–81.JC McDonaldVH Springett1954The decline of tuberculosis mortality in Western Europe.Br Med Bull107781

102. Wegelius C, Bauer HJ (1957) Einwirkung des Schirmbildverfahrens auf Tuberkulose-Morbidität und Prognose. Beitr Klin Tuberk 117: 101.C. WegeliusHJ Bauer1957Einwirkung des Schirmbildverfahrens auf Tuberkulose-Morbidität und Prognose.Beitr Klin Tuberk117101

103. Muntendam P (1959) The influence of the social milieu on the manifestation and course of tuberculosis. Acta Tuberc Scand 37: 63–88.P. Muntendam1959The influence of the social milieu on the manifestation and course of tuberculosis.Acta Tuberc Scand376388

104. Benjamin B (1963) Actuarial methods of mortality analysis; adaptation to changes in the age and cause pattern. Proc R Soc Lond Series B 159: 38–65.B. Benjamin1963Actuarial methods of mortality analysis; adaptation to changes in the age and cause pattern.Proc R Soc Lond Series B1593865

105. Van Vliet B (1963) Analyse van de sterfte aan longtuberculose te Amsterdam in de jaren 1960 en 1961. Ned Tijdschr Geneesk 107: 2180–2181.B. Van Vliet1963Analyse van de sterfte aan longtuberculose te Amsterdam in de jaren 1960 en 1961.Ned Tijdschr Geneesk10721802181

106. Horwitz O, Palmer CE (1964) Epidemiological basis of tuberculosis eradication. II. Dynamics of tuberculosis morbidity and mortality. Bull World Health Organ 30: 609–621.O. HorwitzCE Palmer1964Epidemiological basis of tuberculosis eradication. II. Dynamics of tuberculosis morbidity and mortality.Bull World Health Organ30609621

107. Doege TC (1965) Tuberculosis mortality in the United States, 1900 to 1960. JAMA 192: 1045–1048.TC Doege1965Tuberculosis mortality in the United States, 1900 to 1960.JAMA19210451048

108. Kerntke G (1965) Tuberculosis mortality in Stuttgart, 1957-1961. Beitr Klinik Erforschung Tuberk Lungenkrankh 131: 382–406.G. Kerntke1965Tuberculosis mortality in Stuttgart, 1957-1961.Beitr Klinik Erforschung Tuberk Lungenkrankh131382406

109. Hillerdal O (1963) The altered prognosis in tuberculosis. Svenska Läkartidningen 60: 1059–1071.O. Hillerdal1963The altered prognosis in tuberculosis.Svenska Läkartidningen6010591071

110. Jones DS (2002) The health care experiments at Many Farms: the Navajo, tuberculosis, and the limits of modern medicine, 1952-1962. Bull Hist Med 76: 749–790.DS Jones2002The health care experiments at Many Farms: the Navajo, tuberculosis, and the limits of modern medicine, 1952-1962.Bull Hist Med76749790

111. Frieden TR (2002) Can tuberculosis be controlled? Int J Epidemiol 31: 894–899.TR Frieden2002Can tuberculosis be controlled?Int J Epidemiol31894899

112. Corbett EL, Churchyard GJ, Charalambos S, Samb B, Moloi V, et al. (2002) Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus. Clin Infect Dis 34: 1251–1258.EL CorbettGJ ChurchyardS. CharalambosB. SambV. Moloi2002Morbidity and mortality in South African gold miners: impact of untreated disease due to human immunodeficiency virus.Clin Infect Dis3412511258

113. Pamra SP, Goyal SS, Mathur GP (1973) Changes in prevalence and incidence of pulmonary tuberculosis in Delhi in recent years. Ind J Tuberc 20: 57–64.SP PamraSS GoyalGP Mathur1973Changes in prevalence and incidence of pulmonary tuberculosis in Delhi in recent years.Ind J Tuberc205764

114. Raviglione MC, editor. (2006) Reichman and Hershfield's Tuberculosis. A comprehensive international approach. Part A. 3rd ed. New York: Informa Health Care. 715 p.MC Raviglione2006Reichman and Hershfield's Tuberculosis.A comprehensive international approach. Part A. 3rd edNew YorkInforma Health Care715

115. Berg G (1939) The prognosis of open pulmonaty tuberculosis. A clinical-statistical study. Acta Tuberc Scand suppl IV: 1–206.G. Berg1939The prognosis of open pulmonaty tuberculosis. A clinical-statistical study.Acta Tuberc Scand supplIV1206

116. Drolet GJ (1938) Present trend of case fatality rates in tuberculosis. Amer Rev Tuberc 37: 125–151.GJ Drolet1938Present trend of case fatality rates in tuberculosis.Amer Rev Tuberc37125151

117. Trail RR, Stockman GD (1931) A report upon the experience of the patients of the King Edward VII Sanatorium, Midhurst, with particular reference to their mortality after treatment. RR TrailGD Stockman1931A report upon the experience of the patients of the King Edward VII Sanatorium, Midhurst, with particular reference to their mortality after treatment.Pulmonary Tuberculosis: Sept. Pulmonary Tuberculosis: Sept.

118. Hartley PHS, Wingfield RC, Burrows VA (1935) The expectation of survival in pulmonary tuberculosis. Brompton Hospital Reports IV. Frimley, UK: Brompton Hospital Sanatorium. PHS HartleyRC WingfieldVA Burrows1935The expectation of survival in pulmonary tuberculosis. Brompton Hospital Reports IV.Frimley, UKBrompton Hospital Sanatorium

119. Sinding-Larsen CMF (1937) On the collapse treatment of pulmonary tuberculosis. A clinical adaption and follow-up examination of the material from Vejlefjord Sanatorium, 1906-1932. Acta Med Scand 91: 39–132.CMF Sinding-Larsen1937On the collapse treatment of pulmonary tuberculosis. A clinical adaption and follow-up examination of the material from Vejlefjord Sanatorium, 1906-1932.Acta Med Scand9139132

120. Backer JE (1937) Dodeligheten blandt lungetuberkulose. En statistik undersokelse vedkommende patienter anmeldt til Oslo Helserad i 1911 - 1930 op patienter behandlet pa Vardasen Sanatorium i 1923 - 1934. Oslo: Norske Videnskaps-Akademi . 131 p.JE Backer1937Dodeligheten blandt lungetuberkulose. En statistik undersokelse vedkommende patienter anmeldt til Oslo Helserad i 1911 - 1930 op patienter behandlet pa Vardasen Sanatorium i 1923 - 1934.OsloNorske Videnskaps-Akademi 131

121. Krebs W (1930) Die Fälle von Lungentuberkulose in der aargauischen Heilstätte Barmelweid aus den Jahren 1912–1927. Beitr Klin Tuberk 74: 345–379.W. Krebs1930Die Fälle von Lungentuberkulose in der aargauischen Heilstätte Barmelweid aus den Jahren 1912–1927.Beitr Klin Tuberk74345379

122. Fürth E (1931) Zur Frage der Lebensdauer bei Aktiver Tuberkulose. Beitr Klin Tuberk 76: 573–587.E. Fürth1931Zur Frage der Lebensdauer bei Aktiver Tuberkulose.Beitr Klin Tuberk76573587

123. Tattersall WH (1947) The survival of sputum-positive consumptives. A study of 1192 cases in a county borough between 1914 and 1940. Tubercle 28: 85–96.WH Tattersall1947The survival of sputum-positive consumptives. A study of 1192 cases in a county borough between 1914 and 1940.Tubercle288596

124. Tattersall WH (1947) The survival of sputum-positive consumptives. A study of 1192 cases in a county borough between 1914 and 1940. Tubercle 28: 107–114.WH Tattersall1947The survival of sputum-positive consumptives. A study of 1192 cases in a county borough between 1914 and 1940.Tubercle28107114

125. Magnusson S (1938) Über den Verlauf und die Letalität der Tuberkulose in den verschiedenen Altersperioden. Acta Tuberc Scand 12: 201–263.S. Magnusson1938Über den Verlauf und die Letalität der Tuberkulose in den verschiedenen Altersperioden.Acta Tuberc Scand12201263

126. Münchbach W (1933) Das Schicksal des lungentuberkulösen Erwachsenen. Ergibnisse der Heilstattenbehandlung von annähernd 10000 Männern und Frauen. Tuberkulose-Bibliothek 49: 64.W. Münchbach1933Das Schicksal des lungentuberkulösen Erwachsenen. Ergibnisse der Heilstattenbehandlung von annähernd 10000 Männern und Frauen.Tuberkulose-Bibliothek4964

127. Braeuning H, Neissen A (1936) Prognose der offenen Tuberkulose, Technik der Prognose-stellung und Rentabilität des Heilverfahrens. Zeitschr Tuberk 75: 305–323.H. BraeuningA. Neissen1936Prognose der offenen Tuberkulose, Technik der Prognose-stellung und Rentabilität des Heilverfahrens.Zeitschr Tuberk75305323

128. Braeuning H, Neissen A (1933) Die Prognose der offenen Lungentuberkulose. Tuberkulose-Bibliothek 52: 40.H. BraeuningA. Neissen1933Die Prognose der offenen Lungentuberkulose.Tuberkulose-Bibliothek5240

129. Griep WA (1939) De prognose van de open longtuberculose. [Thesis] Amsterdam: University of Amsterdam. 87 p.WA Griep1939De prognose van de open longtuberculose.[Thesis] AmsterdamUniversity of Amsterdam87

130. Baart de la Faille RL (1939) Onderzoek naar de resultaten der tuberculosebehandeling in het sanatorium “Berg en Bosch”. [Thesis] Utrecht: University of Utrecht. 143 p.RL Baart de la Faille1939Onderzoek naar de resultaten der tuberculosebehandeling in het sanatorium “Berg en Bosch”.[Thesis] UtrechtUniversity of Utrecht143

131. Buhl K, Nyboe J (1967) Epidemiological basis of tuberculosis eradication. 9. Changes in the mortality of Danish tuberculosis patients since 1925. Bull World Health Organ 37: 907–925.K. BuhlJ. Nyboe1967Epidemiological basis of tuberculosis eradication. 9. Changes in the mortality of Danish tuberculosis patients since 1925.Bull World Health Organ37907925

132. Lindhardt M (1939) The statistics of pulmonary tuberculosis in Denmark 1925-1934. A statistical investigation on the occurrence of pulmonary tuberculosis in the period 1925-1934, worked out on the basis of the Danish National Health Service file of notified cases and of deaths. Copenhagen: Ejnaar Munksgaard. 179 p.M. Lindhardt1939The statistics of pulmonary tuberculosis in Denmark 1925-1934. A statistical investigation on the occurrence of pulmonary tuberculosis in the period 1925-1934, worked out on the basis of the Danish National Health Service file of notified cases and of deaths.CopenhagenEjnaar Munksgaard179

133. Thompson BC (1943) Survival rates in pulmonary tuberculosis. BMJ 2: 721.BC Thompson1943Survival rates in pulmonary tuberculosis.BMJ2721

134. Braeuning H (1930) Über die Letalität, Morbidität und Infektionsdauer der offenen Lungentuberkulose. Zeitschr Tuberk 59: 109–111.H. Braeuning1930Über die Letalität, Morbidität und Infektionsdauer der offenen Lungentuberkulose.Zeitschr Tuberk59109111

135. Armstrong DB (2005) The medical aspects of the Framingham Community Health and Tuberculosis Demonstration. Int J Epidemiol 34: 1183–1187.DB Armstrong2005The medical aspects of the Framingham Community Health and Tuberculosis Demonstration.Int J Epidemiol3411831187

136. Comstock GW (2005) Commentary: the first Framingham Study—a pioneer in community-based participatory research. Int J Epidemiol 34: 1188–1190.GW Comstock2005Commentary: the first Framingham Study—a pioneer in community-based participatory research.Int J Epidemiol3411881190

137. Kannel WB, Levy D (2005) Commentary: Medical aspects of the Framingham Community Health and Tuberculosis Demonstration. Int J Epidemiol 34: 1187–1188.WB KannelD. Levy2005Commentary: Medical aspects of the Framingham Community Health and Tuberculosis Demonstration.Int J Epidemiol3411871188

138. Den Boon S, White NW, van Lill SW, Borgdorff MW, Verver S, et al. (2006) An evaluation of symptom and chest radiographic screening in tuberculosis prevalence surveys. Int J Tuberc Lung Dis 10: 876–882.S. Den BoonNW WhiteSW van LillMW BorgdorffS. Verver2006An evaluation of symptom and chest radiographic screening in tuberculosis prevalence surveys.Int J Tuberc Lung Dis10876882

139. Van der Werf MJ, Borgdorff MW (2007) How to measure the prevalence of tuberculosis in a population. Trop Med Int Health 12: 475–484.MJ Van der WerfMW Borgdorff2007How to measure the prevalence of tuberculosis in a population.Trop Med Int Health12475484

140. Lambert ML, Hasker E, Van Deun A, Roberfroid D, Boelaert M, et al. (2003) Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 3: 282–287.ML LambertE. HaskerA. Van DeunD. RoberfroidM. Boelaert2003Recurrence in tuberculosis: relapse or reinfection?Lancet Infect Dis3282287

141. Ray D, Abel R (1995) Incidence of smear-positive pulmonary tuberculosis from 1981-83 in a rural area under an active health care programme in south India. Tuberc Lung Dis 76: 190–195.D. RayR. Abel1995Incidence of smear-positive pulmonary tuberculosis from 1981-83 in a rural area under an active health care programme in south India.Tuberc Lung Dis76190195

142. Radhakrishna S, Frieden TR, Subramani R, Santha T, Narayanan PR (2007) Additional risk of developing TB for household members with a TB case at home at intake: A 15-year study. Int J Tuberc Lung Dis 11: 282–288.S. RadhakrishnaTR FriedenR. SubramaniT. SanthaPR Narayanan2007Additional risk of developing TB for household members with a TB case at home at intake: A 15-year study.Int J Tuberc Lung Dis11282288

143. Payne B, Bellamy R (2007) Tuberculosis in people with HIV. BMJ Clin Evid 12: 920.B. PayneR. Bellamy2007Tuberculosis in people with HIV.BMJ Clin Evid12920Available: http://clinicalevidence.bmj.com/ceweb/pmc/2007/06/0920. Accessed 16 August 2009. Available: http://clinicalevidence.bmj.com/ceweb/pmc/2007/06/0920. Accessed 16 August 2009.

144. Wells CD, Cegielski JP, Nelson LJ, Laserson KF, Holtz TH, et al. (2007) HIV infection and multidrug-resistant tuberculosis: the perfect storm. J Infect Dis 196: S86–107.CD WellsJP CegielskiLJ NelsonKF LasersonTH Holtz2007HIV infection and multidrug-resistant tuberculosis: the perfect storm.J Infect Dis196S86107

145. Small PM, Schecter GF, Goodman PC, Sande MA, Chaisson RE, et al. (1991) Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection. N Engl J Med 324: 289–294.PM SmallGF SchecterPC GoodmanMA SandeRE Chaisson1991Treatment of tuberculosis in patients with advanced human immunodeficiency virus infection.N Engl J Med324289294

146. Kang'ombe C, Harries AD, Banda H, Nyangulu DS, Whitty CJ, et al. (2000) High mortality rates in tuberculosis patients in Zomba Hospital, Malawi, during 32 months of follow-up. Trans R Soc Trop Med Hyg 94: 305–309.C. Kang'ombeAD HarriesH. BandaDS NyanguluCJ Whitty2000High mortality rates in tuberculosis patients in Zomba Hospital, Malawi, during 32 months of follow-up.Trans R Soc Trop Med Hyg94305309

147. Moro ML, Gori A, Errante I, Infuso A, Franzetti F, et al. (1998) An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group. Aids 12: 1095–1102.ML MoroA. GoriI. ErranteA. InfusoF. Franzetti1998An outbreak of multidrug-resistant tuberculosis involving HIV-infected patients of two hospitals in Milan, Italy. Italian Multidrug-Resistant Tuberculosis Outbreak Study Group.Aids1210951102

148. Rullan JV, Herrera D, Cano R, Moreno V, Godoy P, et al. (1996) Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain. Emerg Infect Dis 2: 125–129.JV RullanD. HerreraR. CanoV. MorenoP. Godoy1996Nosocomial transmission of multidrug-resistant Mycobacterium tuberculosis in Spain.Emerg Infect Dis2125129

149. Ritacco V, Di Lonardo M, Reniero A, Ambroggi M, Barrera L, et al. (1997) Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires. J Infect Dis 176: 637–642.V. RitaccoM. Di LonardoA. RenieroM. AmbroggiL. Barrera1997Nosocomial spread of human immunodeficiency virus-related multidrug-resistant tuberculosis in Buenos Aires.J Infect Dis176637642