Tuberculosis: From an incurable scourge to a curable disease - journey over a millennium.

Globally, tuberculosis (TB) still remains a major public health problem. India is a high TB burden country contributing to 26 per cent of global TB burden. During 1944-1980, TB became treatable and short-course chemotherapy emerged as the standard of care. When TB elimination seemed possible in the early 1980s, global human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) pandemic resulted in a resurgence of TB. Widespread occurrence of multidrug-resistant and extensively drug-resistant TB (M/XDR-TB) is threatening to destabilize TB control globally. Atypical clinical presentation still poses a challenge. Disseminated, miliary and cryptic TB are being increasingly recognized. Availability of newer imaging modalities has allowed more efficient localization of lesions and use of image guided procedures has facilitated definitive diagnosis of extrapulmonary TB. Introduction of liquid culture, rapid drug-susceptibility testing (DST), molecular diagnostic methods has helped in rapid detection, speciation and DST profiling of Mycobacterium tuberculosis isolates. While treatment of TB and HIV-TB co-infection has become simpler, efforts are on to shorten the treatment duration. However, drug toxicities and drug-drug interactions still constitute a significant challenge. Recently, there has been better understanding of anti-TB drug-induced hepatotoxicity and its frequent confounding by viral hepatitis, especially, in resource-constrained settings; and immune reconstitution inflammatory syndrome (IRIS) in HIV-TB. Quest for newer biomarkers for predicting a durable cure, relapse, discovery/repurposing of newer anti-TB drugs, development of newer vaccines continues to achieve the goal of eliminating TB altogether by 2050.

Introduction

The “captain of all these men of death”, tuberculosis (TB) has been a scourge of the humankind from time immemorial. Till date, no other disease in history matches the sheer magnitude of the misery inflicted by TB on the human race in terms of morbidity and mortality. The social and economic consequences of TB have had a profound effect on human existence. Historically, even though several other diseases like smallpox and plague have killed millions of people, their reign has been relatively short-lived; TB has been ever present. The inexorable march of time has witnessed the changing face of TB: from an incurable disease to the hype and hope of being an eminently curable one. However, even today TB remains as a formidable foe threatening to annihilate the human race. This review attempts to provide an overview of our understanding of TB, availability of rapid diagnostic tests including imaging modalities and anti-TB drugs and to outline the challenges that lie ahead in TB control.

Historical Background

Since ancient times, there have been references to TB or illnesses resembling TB from several parts of the world from many civilizations. The earliest references to TB can be found in the language Samskritam (Sanskrit). In the ancient Indian scriptures, The Vedas, TB was referred to as Yakshma (meaning wasting disease). Description of a TB-like disease has been documented in ancient Chinese and Arabic literature123. In English literature, the word “consumption” (derived from the Latin word consumer) has also been used to describe TB. The word “tuberculosis” appears to have been derived from the Latin word tubercula (meaning “a small lump”)45.

Fracastorius (1443-1553) believed that TB was contagious. Thomas Willis (1621-1675) had documented the clinical presentation of consumption in detail in his treatise Pthisiologica. Richard Morton (1637-1698) had described several pathological appearances of TB246. John Jacob Manget gave the description of classical miliary TB in 17007. In 1720, Benjamin Marten conjectured that TB could be caused by “certain species of animalcula or wonderfully minute living creatures”. In 1865 Jean Antoine Villemin presented his results suggesting that TB was a contagious disease12. However, it was Robert Koch who announced the discovery of the tubercle bacillus during the monthly evening meeting of the Berlin Physiological Society on 24th March 18828. On this day, after thousands of years, Mycobacterium tuberculosis, the organism causing TB finally revealed itself to humans. Commemorating the centenary of this event, since 1982, 24th March is being celebrated as “World TB Day” world over. Wilhelm Conrad Roentgen's discovery of X-rays, facilitated radiographic visualization of changes caused by TB in a living person. Thus, it was in the early years of 20th century that basic concepts related to aetiological agent of TB, consequent pathological changes in humans and detection of the organism became established.

Discovery of streptomycin, para-amino salicylic acid (PAS) and the availability of isoniazid ushered in modern era of effective treatment of TB in the mid-1940s. With the emergence of ‘short-course’ treatment cure for TB has become a reality. In the late 1970s, though TB continued to ravage developing countries like India, there was an optimism in the developed world that TB may cease to be a public health problem1.

The emergence of the human immunodeficiency virus (HIV) infection and the acquired immuno-deficiency syndrome (AIDS) ended this optimism and fuelled the resurgence of TB worldwide. Recognizing the importance of the impact of TB globally, the World Health Organization (WHO) took an unprecedented step and declared TB to be a “global emergency” in April 19938. The late 1990s also witnessed the resurgence of drug-resistant TB (DR-TB) with multidrug-resistant TB (MDR-TB) emerging as a major threat91011. The first decade of the 21st century has been ravaged by extensively drug-resistant TB (XDR-TB)12. Recently, concern has been expressed regarding the occurrence of extremely drug-resistant TB (XXDR-TB)1314, super XDR-TB15, totally drug-resistant TB (TDR-TB)1516 from some parts of the world. The report on the occurrence of TDR-TB from India17 has raised concern and consternation18. Over the millennia, TB never respected anyone and had treated the rich and poor alike with equal disdain.

Definitions

Certain key definitions concerning clinically important forms of TB, drug-resistant TB are listed in TablesIA19202122232425262728293031323334353637 and IB91011121314151631323334353637 respectively.

Table IA

TB: key clinical definitions

Table IB

Drug-resistant TB: key definitions

Epidemiology

Global burden of TB

The global burden of TB as described in the 16th global report on TB published by WHO in 201237 is shown in Table IIA; most of the cases occurred in Asia (59%) and Africa (26%).

Table IIA

Estimates of global burden of TB 2011

Indian scenario

The current estimated TB burden in India is listed in Table IIB30373839. India has featured among the 22 high TB burden countries; and has accounted for an estimated one quarter (26%) of all TB cases worldwide30

Table IIB

Provisional estimates of TB burden in India 2010

M/XDR-TB

The results of surveillance data on MDR-TB should be interpreted carefully keeping in mind the fact that globally, less than 4 per cent of new bacteriologically-positive cases and 6 per cent of previously treated cases were tested for MDR-TB in 2011 in accredited laboratories, with particularly low levels of testing in the South-East Asia (where India is located) and Western Pacific regions37. The recent global epidemiological data on M/XDR-TB are shown in Table IIIA, Figs 1A and 1B. XDR-TB has been documented from many parts of the world (Fig. 1C)4041.

Table IIIA

Global epidemiology of MDR-TB and XDR-TB

Fig. 1

(A). Distribution of percentage of new tuberculosis cases with MDR-TB 1994-2011. (B). Distribution of percentage of previously treated tuberculosis cases with MDR-TB 1994-2011. (C). Countries that had reported at least one XDR-TB case 1994-2011. MDR-TB, multidrug-resistant tuberculosis; XDR-TB, extensively drug-resistant tuberculosis.

Reproduced with permission from World Health Organization (reference 41)

Indian scenario

Observations from reliable accredited mycobacteriology laboratories from India suggest that the prevalence of MDR-TB is quite low in new TB cases (<3%) compared with previously treated patients (15-30%)42434445 (Table IIIB). The prevalence of XDR-TB in studies published from India where drug-susceptibility testing (DST) was carried out in quality-assured, accredited laboratories is shown in Table IIIC4647484950515253.

Table IIIB

Epidemiology of MDR-TB in India 2011

Table IIIC

Prevalence of XDR-TB in studies published from accredited laboratories for mycobacteriology from India

Risk factors

Conventionally several genetic, social, environmental and biological determinants of health have been intuitively recognized by clinicians as risk factors for TB (Table IV)5455565758596061626364656667686970717273. Some of these risk factors are discussed below.

Table IV

Social, environmental and biological determinants of health considered to be risk factors for TB

Genetic factors

Certain key issues should be considered while evaluating genetic susceptibility to TB disease. Susceptibility to TB does not follow a Mendelian pattern and is polygenic and multifactorial. Presence of two different genomes, (of the TB bacillus and the host) and their interaction can have influence on the disease58. Several reports have implicated a long list of genes with risk of developing TB (Table IV)58596061.

HIV infection

HIV infection and AIDS stand out as the most significant among all the risk-factors for TB and has consistently and significantly altered the incidence rate of TB over the last three decades626364656667686970717273. The impact of HIV/AIDS has been most profound in HIV prevalence sub-Saharan Africa where a dramatic increase in TB notification rates have been documented concurrent with increasing HIV prevalence. Among persons living with HIV (PLWH) TB can develop at any stage of HIV infection and there is a strong evidence suggesting that a declining CD4+ T-lymphocyte count and high viral load are risk factors for disease, while treatment with highly active antiretroviral therapy (HAART) reduces risk626364.

HIV infection and MDR-TB: Even though several institutional outbreaks of MDR-TB among HIV-infected patients drew attention to the problem two decades ago7475767778 as per currently available evidence798081, HIV infection per se does not appear to be a risk-factor for MDR-TB.

Diabetes mellitus

The lethal interaction between diabetes mellitus (DM) and TB is being increasingly recognized world over828384. Epidemiological modelling data suggest that in India, 14.8 per cent of all pulmonary TB cases and 20 per cent of sputum smear-positive cases have DM84 suggesting that DM substantially contributes to the burden of TB, especially sputum smear-positive pulmonary TB in India.

Use of immunomodulator biologicals

Use of immunomodulator drugs (biologicals) has been associated with the development of fatal TB in rheumatoid arthritis8586.

Tobacco smoking

Data from recent systematic reviews on tobacco smoking and TB suggest that tobacco smokers have about three-fold higher risk of TB than non-smokers; even after adjustment for other factors8788899091.

Changing clinical presentation of TB

Natural history of TB

The natural history of TB (Fig. 2)2327629293949596 is influenced by several factors, the course being determined by the balance between the host immunity and the virulence of the TB bacillus. This understanding also facilitates identification of areas where interventional strategies can be identified for control of TB.

Fig. 2

Natural history of Mycobacterium tuberculosis infection and scope for intervention. TB, tuberculosis; BCG, bacille Calmette-Guerin; HIV, human immunodeficiency virus; AIDS, acquired immunodeficiency syndrome; TNF, tumour necrosis factor; LTBI, latent TB infection; SS, sputum smear.

Adapted and updated from references 23, 62, 92.

Atypical clinical presentations

Cryptic miliary TB: Miliary TB that was earlier seen primarily as a disease of children, is being increasingly encountered in adults since the 1970s23272897. Apyrexial presentation with progressive wasting strongly mimicking a metastatic carcinoma (cryptic miliary TB) that has been described especially among older people2327289899 often used to be diagnosed only at autopsy. This entity is being increasingly diagnosed during life in young immunosuppressed persons presently. This has been possible by the advances in imaging studies and increasing use of interventional procedures to procure tissue for confirming the diagnosis.

Acute lung injury and acute respiratory distress syndrome: TB as a primary cause of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) is also being reported in the recent years especially in areas where TB is highly endemic100101102103. Increased awareness regarding this entity among intensivists, invasivists and internists, has resulted in a focused search for TB as the treatable cause in patients presenting with ARDS of obscure aetiology.

TB in patients receiving immunomodulator biologicals: Data regarding the clinical presentation of TB in patients receiving immunomodulator biological, such as, anti-tumour necrosis factor (anti-TNF) antibodies infliximab, adalimumab, golimumab and certolizumab pegol; and the soluble TNF receptor etanercept are emerging. The rate of TB was three to four-fold higher in patients receiving infliximab and adalimumab than in those receiving etanercept86.

Presentation as ‘pyrexia of unknown origin’: In areas where the disease is endemic, TB tops the list of aetiological causes of pyrexia of unknown origin (PUO)104105. Till about two decades ago, clinicians either empirically administered anti-TB treatment or had to resort to invasive surgical procedures such as scalene node biopsy, laparotomy to ascertain the diagnosis. Often, the TB was diagnosed only on post-mortem examination. In patients presenting with PUO, miliary TB2728, intrathoracic (e.g., paratracheal, mediastinal, hilar) and intraabdominal (e.g., retroperitoneal, porta hepatis) lymph node TB94106, intestinal, omental and mesenteric, hepatic, splenic TB107, vertebral TB (often with paraspinal cold abscess)108, pelvic ascites109110 are important occult locations that are identified as the focus of fever by imaging methods facilitating ante-mortem diagnosis. Many times, bone marrow aspirate and biopsy smear, mycobacterial culture and molecular test evidence could be the only discernible cause of TB in these patients6294.

Sudden cardiac death: Sudden cardiac death due to TB myocarditis, especially in young persons is increasingly being recognized. This condition is often diagnosed at autopsy and extensive TB infiltration of the myocardium with minimal systemic involvement has been described; occult miliary TB has been implicated as the possible cause of myocarditis111112. Ante-mortem diagnosis of this condition is now possible with echocardiography, and cardiac magnetic resonance imaging (MRI)113114.

TB among healthcare workers

Health-care workers (HCWs), who are often in close proximity to patients with TB are at an increased risk of developing TB. It has been estimated that in areas of high TB incidence (>100/100,000 population), the stratified pooled estimates for LTBI and TB incidence rate ratios were 8.4 (95% CI 2.7-14.0%) and 3.7 per cent (95% CI 2.9-4.5), respectively; median estimated population-attributable fraction for TB was as high as 0.4% (115). These figures serve as warning bells, especially with regard to HCWs caring for patients with X/MDR-TB116 and highlight the need for institution of preventive measures. Further, it has been shown that institution of basic administrative and engineering controls and personal protection measures can be effective in reducing the annual tuberculin skin test (TST) conversion rates in HCWs117.

Diagnosis

Latent TB infection

Diagnosis of LTBI has been considered important as a tool for assessing the burden of TB for epidemiological purposes. Because LTBI contributes significantly to the pool of active TB cases later on, its recognition is assuming importance in high-risk groups where there is a potential for instituting treatment for this condition92. The tuberculin skin test (TST) and interferon-gamma release assays (IGRAs) have been used as diagnostic tests for the detection of LTBI (Table VA)118119120121.

Table VA

Diagnostic methods for latent TB infection

In high burden TB countries, neither IGRAs nor TST have been found to be adequate in accurately identifying persons who will benefit from treatment of LTBI with false positivity rates greater than 50 per cent being reported for both122123124125. In this connection, a recent policy statement issued by the WHO125 and the European Centre for Disease Prevention and Control guidelines124 discourage the use of IGRAs in preference to TST, in areas where TB is highly endemic.

Diagnosis of active TB disease

The current diagnostic and genotyping methods for TB are listed in Table VB125126127128129130131132133134135136137138139140141. Innovations such as use of fluorescent staining, light-emitting diode (LED) based microscopes have helped optimizing the yield of sputum smear examination126. Sputum mycobacterial culture is considered to be the ‘gold standard’ for the diagnosis of TB and it also facilitates DST. However, reliable, periodically accredited facilities for mycobacterial culture and DST are not widely available in TB high burden countries limiting their usefulness. Conventional sputum mycobacterial culture takes 6-8 weeks time and valuable time is lost in establishing the definitive diagnosis. In the 1980s, new semi-automated and automated culture systems based on liquid culture medium became available, such as the BACTEC-TB460 radiometric system (Becton Dickinson, Sparks, MD, USA) and facilitated rapid culture and detection of M. tuberculosis with a turn-around time of about 10 days127129. For nearly a two decades, this was used for rapid culture and DST. The non-radiometric rapid liquid culture methods like Mycobacteria Growth Indicator Tube (MGIT) and BacT/ALERT (BioMe´rieux) then emerged. In 2007 the WHO endorsed the use of liquid culture assays, DST129 and rapid speciation (strip speciation) tests that detect a TB-specific antigen from positive liquid or solid cultures to confirm the presence of TB bacillus [Capilia TB; Tauns Laboratories Inc., Shizuoka, Japan]130 for faster diagnosis of TB and MDR-TB37.

Table VB

Some of the current diagnostic, genotypic methods for TB125126127128129130131132133134135136137138139140141

The nucleic acid amplification based TB diagnostic tests (NAAT) are based on the amplification of short specific sequences of DNA or RNA of M. tuberculosis complex by PCR and the amplified products are then detected by agarose/acrylamide gel electrophoresis, or by various hybridization methods142. Several in-house PCR assays and commercial kits have been used for rapid diagnosis of TB.

Integrated automated NAAT, the GeneXpert (Cepheid Inc., Sunnyvale, CA, USA) platform combines automated sample preparation, real-time PCR amplification, identification of M. tuberculosis and detection of rifampicin resistance in less than 120 minutes142. GeneXpert has the advantage of being simple to use even in field conditions and appears promising technology for rapid diagnosis of TB. However, this test requires uninterrupted electric power supply and is expensive. This test is being evaluated by Revised National Tuberculosis Control Programme (RNTCP) in field conditions.

Promising results from studies carried out in low-resource countries suggest that loop mediated isothermal amplification (LAMP) has the potential to be a candidate as a molecular test for the rapid diagnosis of TB in clinical samples143144. M. tuberculosis produces volatile organic compound (VOC) metabolites in-vitro, and their presence in the breath has been considered to be apparent biomarkers of infection145146.

Serodiagnostic Tests

A broad range of serodiagnostic tests with a varying degree of reliability, repeatability and concordance have been used for the diagnosis of TB. Since no commercial serological assay could consistently result in an improved outcome, the WHO recently recommended that commercial serological tests should not be used for the diagnosis of pulmonary and extrapulmonary TB147. This view has been endorsed by the RNTCP of Government of India also148.

Diagnosis of extrapulmonary TB (EPTB)

The yield of conventional AFB smear and mycobacterial culture and some commonly used non-conventional tests in the diagnosis of EPTB is shown in Table VI149150151152153154155156157158159160161162163. A focused diagnostic approach, procurement of appropriate body fluid and tissue specimens and subjecting these to a battery of diagnostic tests including culture (and DST where feasible) will enhance the diagnostic yield in EPTB. There is a need to systematically evaluate and establish the utility of recently available newer tests such as GeneXpert to facilitate an early diagnosis and increase the diagnostic yield.

Table VI

Diagnostic yield of commonly used tests in the diagnosis of certain forms of extrapulmonary TB

Development of accreditation system, quality assured laboratory network expansion

The eventual goal of controlling and probably eliminating TB hinges on rapidly and correctly identifying all TB cases and ensure that all diagnosed patients receive individualized treatment with anti-TB drugs tailored to the DST profile of the isolates obtained164. The ongoing struggle to meet the global target for case detection of diagnosing at least 70 per cent of new smear-positive cases, reflects the yawning gap between the need and the availability of quality assured laboratory infrastructure, especially in developing countries like India. Strengthening the capacity of public-sector laboratory networks, ensuring their accreditation initially and periodically thereafter so that a network of reliable quality assured accredited laboratories is eventually available to take TB control forwards are initial steps in this direction. The Expanding Access to New Diagnostics for TB (EXPAND-TB) project165, a collaboration among WHO, the Global Laboratory Initiative (GLI), Foundation for Innovative New Diagnostics (FIND) and the Global Drug Facility (GDF), and funded by UNITAID and other partners aims to improve capacity to diagnose MDR-TB in upgraded laboratory services in 27 countries.

In India, The RNTCP has also adopted a rigorous procedure for granting accreditation to culture and DST laboratories both in public and private sectors and medical colleges to provide accurate and reliable services for MDR-TB diagnosis and treatment follow-up. By 2015, it is expected that universal access to MDR-TB diagnosis and treatment will be made available for all smear positive TB cases under the RNTCP30.

Imaging Studies

Imaging modalities such as conventional radiography, ultrasonography, computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography CT (PET-CT) have been used to localize the disease, assess the extent of organ involvement and evaluate response to treatment. The chest radiograph is the mainstay of imaging pulmonary TB (Fig. 3A–3E). However, the chest radiograph can be normal in HIV-infected patients with late HIV disease with active TB disease and in some patients with miliary TB166167. Ultrasonography helps in detecting pleural effusion and ascites (which may sometimes be loculated), focal lesions in the liver and spleen, cold abscesses, intra-abdominal lymphadenopathy, involvement of other abdominal organs. High resolution CT (HRCT), thin-section multidetector row CT (MDCT) have been helpful in identifying pulmonary and miliary lesions, even in those in whom the chest radiograph is normal and has facilitated more frequent antemortem diagnosis of ‘cryptic miliary TB’ that was earlier diagnosed only at autopsy. CT of the thorax also allows detection of intrathoracic lymphadenopathy, calcification, pleural, pericardial and vascular lesions (Figs. 3F–3I, 4). CT and MRI of the brain and CT of the abdomen have also been extensively used to study CNS TB and abdominal TB, respectively (Fig. 5). Magnetic resonance spectroscopy (MRS) has been found to be useful in patients with intracranial tuberculomas where a characteristic large lipid peak with reduced n-acetyl aspartate peak can be seen. PET-CT using 18F labelled 2-deoxy-D-glucose (FDG) is helpful in locating, defining the extent of activity of TB at various organ sites (that may sometimes not be clinically discernible) (Fig. 6) especially in patients with disseminated TB and assessing the activity of lesions that might persist following anti-TB treatment on follow-up. 11C-choline PET scans can help differentiate between lung cancer and tuberculoma. The standard uptake value of tuberculoma is low in 11C-choline PET scans168.

Fig. 3

(A) Chest radiograph (postero-anterior view) showing a cavity in the right upper zone (arrow), and (B) lower zone (arrow). (C). Chest radiograph (postero-anterior view) in a patient presenting to the emergency room with severe breathlessness showing right-sided pneumothorax (asterisk). Sputum smear was positive for acid-fast bacilli. (D). Chest radiograph (poster-anterior view) showing left-sided massive pleural effusion. (E). Chest radiograph (poster-anterior view) in another patient showing left-sided loculated pleural effusion. (F). CECT (chest) of the same patient showing left-sided loculated pleural effusion (asterisks). (G) Clinical photograph of a patient with disseminated TB showing right-sided cervical lymphadenopathy with cold abscess. (H) CECT chest of the same patient showing left-sided pleural effusion (asterisk), left hilar lymphadenopathy [arrow (mediastinal window)]; and (I) and bilateral parenchymal infiltrates and left sided pleural effusion (asterisk) (lung window).

Fig. 4

Nonspecific aortoarteritis. (A) Axial contrast enhanced CT showing an enlarged mediastinal lymph node (thick arrow) and diffuse wall thickening of left subclavian artery (Thin arrow) (B). Volume rendered CT angiography image showing diffuse long segment narrowing of left subclavian artery (thick arrow) and abdominal aorta at the renal artery origin level as well as infrarenal segment (thin arrow) (C). Axial contrast enhanced CT showing diffuse wall thickening of abdominal aorta (long arrow) with luminal narrowing of the origin of superior mesenteric artery (arrow head) (D). Axial contrast enhanced CT showing an enlarged subcarinal mediastinal lymph node (thick arrow) and diffuse wall thickening of descending thoracic aorta (arrow head). Bilateral pleural effusions [left more than right (thin arrows)] can also be seen (E). Digital substraction angiography (DSA) showing diffuse long segment narrowing of abdominal aorta at the renal artery origin level and infrarenal segment (white arrow). There is a marked narrowing of the bilateral renal arteries (black arrows)

Fig. 5

(A) T1-weighted pre-contrast and (B) contrast-enhanced MRI images showing ring enhancing lesion with perileional oedema in the left parietal lobe (arrows). (C) T1-weighted axial MRI image showing conglomerate ring enhancing lesions in the right frontoparietal regions (arrow) (D). FLAIR sequence showing hypointense lesions with perilesional oedema (arrow) (E). T1-weighted contrast enhanced MRI showing collapse of L2 vertebral body with abnormal enhancement in L1-L3 vertebrae, prevertebral regions (arrow-head) and epidural abscess (arrow) at L2 (F). Coronal image of the same patient showing collapse of L2 vertebral body (arrow-head) and left-sided psoas abscess (arrow). (G) Pre-Contrast T1-weighted sagittal MRI showing hypointense signal in L1-L3 vertebral bodies (arrow). T2-weighted sagittal image showing hyperintensities in the end-plates of L1-L2 and L2-L3 vertebral bodies and intervening discs (arrows).

Fig. 6

Intrathoracic lymph node TB. (A) CT of the chest (mediastinal window), FDG-PET (B) showing left-sided hilar lymphadenopathy (arrow). (C) PET-CT image of the same patient showing increased uptake in the lesion (arrow). (D,E,F, upper panel). Nonspecific aortoarteritis. PET-CT images showing increased uptake (arrows) at the time of initial presentation. (G,H,I lower panel) The post-treatment images of the same patient shows significant decrease in the uptake suggestive of resolution of lesions with treatment.

Kind courtesy: Dr TC Kalawat, Department of Nuclear Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati (Figures 6 A-C and Drs. Arun Malhotra, Rakesh Kumar, Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi (Figures 6D-I)

In patients presenting with PUO with no focal localizing clue, nuclear medicine techniques using gallium-67 citrate, technetium-99m methylene diphosphonte (Fig. 7), radiolabelled white blood cells, and human immune globulin imaging have been used to identify occult foci of infection especially in the bones. However, these techniques have been relatively non-specific and have not been able to distinguish bacterial mediated infection from non-bacterial inflammation due to other causes169. Recently, the radiopharmaceutical technetium-99m labelled ciprofloxacin (99mTc-CPF) has been developed and shown to localize in high concentrations in bacterial abscesses, and not in areas of sterile inflammation170171. Though not specific for TB, this technique has been used to localize foci of TB osteomyelitis as well172 and also assess the adequacy of short-course treatment of TB osteomyelitis173.

Fig. 7

(A) 99mTc-methylene diphosphonte (MDP) whole body anterior and (B) posterior sweep views in a patient presenting with backache and low-grade fever showing diffuse increased radiotracer localization in the body of L4 and 5 vertebrae (arrows) suggestive of spinal TB.

(Kind courtesy: Dr TC Kalawat, Department of Nuclear Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati)

Procurement of body fluids/tissues for diagnostic testing

Radiographic image guided interventional procedures, biopsy of peripherally accessible lesions (e.g., lymph nodes), endoscopic procedures like laparoscopy, colonoscopy, thoracoscopy, can be used in appropriate settings to procure material for diagnostic testing for TB. Endoscopic interventions, such as, endobronchial ultrasound bronchoscopy (EBUS) and endoscopic oesophageal ultrasound, FNACs, biopsies are useful in situations where patients are sputum smear-negative, are unable to produce sputum, present with intrathoracic (e.g., mediastinal, sub-carinal, hilar) lymphadenopathy to procure tissue. Material thus obtained should be subjected to cytopathological, histopathological, microbiological (including DST) and molecular methods for confirmation of TB diagnosis.

Treatment

Evolution of modern multiple drug treatment

The humankind had to wait for more than 60 years following Robert Koch's momentous announcement of the discovery Mycobacterium tuberculosis for drug(s) that could cure TB to become available (Fig. 8)174175176177178179180181182183184185186187188189190191192193194. The first controlled clinical trial in the history of medicine conducted by the British Medical Research Council (BMRC)179 demonstrated the activity of streptomycin. The BMRC assessed the addition of PAS to streptomycin in a controlled clinical trial181 which showed a lower rate of clinical deterioration, higher rate of culture conversion, and a lower rate of streptomycin resistance in patients receiving streptomycin plus PAS, suggesting that combination treatment with PAS was helpful in preventing the emergence of drug resistance to streptomycin. The first clinical trial with isoniazid was initiated in 1951182. Subsequent studies by BMRC183184 further assessed the utility of using two of the three drugs, namely, streptomycin, isoniazid and PAS in various combinations to treat TB. A later clinical trial by BMRC185 established the duration of anti-TB treatment that would effectively prevent relapse, to be 18-24 months.

Fig. 8

A brief history of development of antituberculosis drugs.

Ethambutol, discovered in 1961 got added to the armamentarium of anti-TB drugs186 and soon replaced PAS in the standard regimens. In the 1960s seminal research conducted by Wallace Fox and co-workers at the National Institute for Research in Tuberculosis (NIRT), Chennai [then called as Tuberculosis Chemotherapy Centre, Madras; later renamed as Tuberculosis Research Centre (TRC), Madras in 1978] showed that home or ambulatory treatment was almost as effective as sanatorium treatment “provided the regular use of anti-TB medication was well organized and supervised”, a fact that is often neglected even today187. The classic NIRT studies187188 also established the efficacy of intermittent administration of anti-TB medications. These fundamental principles have since then remained the pillars on which modern treatment of TB is based.

Subsequently, with the introduction of rifampicin189 based on the data from studies conducted in the 1970s190 the standard treatment duration of anti-TB treatment could be shortened to 9 months. By then the 9-month rifampicin containing regimens replaced the then prevailing standard treatment of 18-months. In 1972, the therapeutic role of pyrazinamide used in a reduced dosage was rediscovered in the studies conducted by East Africa Medical Council and BMRC193. Combining pyrazinamide to rifampicin containing regimens then ensued. The 6-month regimens containing rifampicin and pyrazinamide were as effective as either rifampicin or pyrazinamide containing regimens in the clinical trials by the British Thoracic Society194 heralding the modern 6-month short-course chemotherapy endorsed by the WHO that has become the standard of care worldover. Since then, most countries have been using the WHO endorsed standardized daily or thrice-weekly intermittent treatment regimens in National TB Control Programmes.

National Tuberculosis Programme (NTP)

In 1962, the NTP was started in India, the first time ever a ‘national programme’ was conceived to tackle the menace of TB in the world. Short-course chemotherapy was introduced in the NTP by 1985. However, uninterrupted drug supply and treatment adherence continued to plague the NTP and the programme did not make a significant epidemiological impact on the prevalence of TB in the country195. This led to introspection and a comprehensive joint review of the TB programme in India by members of several organizations including the Government of India, WHO and Swedish International Development Agency (SIDA) in 1992 identified many issues that were affecting the programme performance196.

Revised National Tuberculosis Control Programme

To revamp TB control in India, in 1993, the RNTCP, based on the WHO-recommended DOTS strategy, began operations in five pilot sites. Following pilot testing, large scale expansion of RNTCP in India began in 1997 in a phased manner and by March 24, 2006, the whole country was covered by the RNTCP. The Programme aims at achieving and maintaining a cure rate of at least 85 per cent among new sputum positive (NSP) patients, and to achieve and maintain case detection of at least 70 per cent of the estimated NSP cases in the community196197.

Treatment of active TB disease: issues concerning dosing frequency and duration of treatment

The current treatment regimens listed in the recent WHO guidelines for national programmes29 and the RNTCP of Government of India30 are shown in Tables VIIA, VIIB and VIIC. The WHO guidelines29 suggest that HIV patients co-infected with TB should be treated with daily regimens. This recommendation has been based on evidence from meta-analyses198199 that showed that HIV co-infected patients with pulmonary TB were at a higher risk of acquired rifampicin resistance, when failing a three times weekly short-course intermittent regimen. In the meta-analysis199 of treatment of active TB in HIV co-infected patients, data from six randomized trials and 21 cohort studies showed that compared with daily therapy in the initial phase (n=3352 patients from 35 study arms), thrice-weekly therapy (n=211 patients from 5 study arms) was associated with higher rates of treatment failure (adjusted risk ratio, 4.0; 95% CI 1.5-10.4) and relapse (adjusted risk ratio 4.8; 95% CI 1.8-12.8) and a trend toward higher relapse rates if rifamycins were used for only 6 months, compared with 8 months or more, or if antiretroviral therapy was not used. In a study from India200 the outcome of fully intermittent thrice-weekly antituberculosis treatment regimens of 6-month isoniazid, rifampicin, pyrazinamide and ethambutol, followed by 4 months of isoniazid and rifampicin; and a 9-month regimen where the intensive phase was same but continuation phase was 7 months, were assessed in HIV-TB co-infected patients. In the ‘intent-to-treat analysis’, among patients who had a favourable outcome at the end of treatment, bacteriologically confirmed recurrence rate was significantly higher with the 6-month regimen compared with the 9-month regimen.

Table VIIA

WHO standard treatment regimens for new TB patients

Table VIIB

WHO standard treatment regimens for previously treated TB patients

Table VIIC

Categorization and treatment regimens under RNTCP

Daily vs thrice-weekly treatment: Under the RNTCP, in India, 15,852,745 patients have been treated with thrice-weekly intermittent treatment and 2,853,494 lives have been saved201 reflecting the huge success achieved by the RNTCP programme over the last 15 years. While thrice-weekly intermittent treatment seems adequate in HIV-seronegative patients, use of daily therapy is an important issue to contend with in HIV-seropositive persons. The prospect of considering the implementation of a daily treatment regimen and the logistics of direct observation of treatment are being actively considered and a clear-cut government policy on the same is expected to be available soon. However, head-on comparisons of adequately powered, fully daily, partial daily (daily intensive phase and thrice-weekly intermittent continuation phase) and fully thrice-weekly intermittent regimens are not available in the literature and studies of this nature will help in arriving at optimal dosing frequency issue so that policy can be modified.

There is also a lack of consensus regarding the optimal duration of therapy in patients with EPTB, especially bone and joint TB, neurological TB; disseminated and miliary TB. While 6-months of treatment may be adequate in HIV-seronegative new patients with pulmonary TB and focal extrapulmonary TB, individual patients may require 9 to 12 months of treatment when TB meningitis is present given the serious risk of disability and mortality; and 9 months of treatment when bone and joint TB is also present. The efficacy and safety of erstwhile Category III (intermittent thrice-weekly rifampicin, isoniazid and pyrazinamide for 2 months, followed by rifampicin and isoniazid for 4 months) DOTS has been documented in the patients with uncomplicated small (<1500 ml) unilateral pleural effusion202, and peripheral lymph node TB203.

Treatment of HIV-TB co-infection and X/MDR-TB

Treatment of active TB in patients co-infected with HIV requires careful consideration of drug-drug interactions between anti-TB and anti-retroviral drugs (Fig. 9)204205. Treatment of X/MDR-TB is expensive and time-consuming, and requires special facilities with adequate infrastructure, reliable, access to periodically accredited mycobacterial culture and sensitivity laboratories, medical, nursing and para-medical personnel trained in the management of X/MDR-TB206. In India, the RNTCP started treatment of X/MDR-TB through the DOTS-Plus services in 2007 in a phased manner and at present all Indian states have been covered30.

Fig. 9

Guidelines on timing of antiretroviral treatment in patients with HIV-TB co-infection

ART, antiretroviral treatment; BHIVA, British HIV Association; EFV, efavirenz; HAART, highly active antiretroviral treatment; HIV, human immunodeficiency virus; NNRTI, non-nucleoside reverse transcriptase inhibitors;

Source: References 204, 205

Key issues in TB treatment monitoring

Drug-drug interactions

Clinically significant interactions during anti-TB treatment should be carefully monitored as these may sometimes result in therapeutic failure or drug toxicity207208. This is particularly important in HIV-co-infected persons, the elderly and those with significant co-morbidities receiving treatment for the same (Box I)207208209210211212213214215216217218219220221222223224225226227228.

Box 1

Key issues in monitoring treatment of TB

Drug induced hepatotoxicity (DIH)

Principles underlying evaluation of patients with DIH are listed in Box I207208209210211212213214215216217218219220221222223224225226227228.

Immune reconstitution inflammatory syndrome (IRIS)

Paradoxical deterioration of lesions of TB in patients receiving anti-TB treatment has been known for a long time (218). Key developments in the understanding of IRIS are listed in Box I219220221222223224225226227228. Minor manifestations of IRIS can be managed with non-steroidal anti-inflammatory drugs (NSAIDS). Moderate-to-high dose corticosteroid treatment, sometimes for prolonged periods may be required for the treatment of paradoxical TB-IRIS and may be beneficial in TB-IRIS with CNS manifestations, tracheal compression due to lymphadenopathy, acute kidney injury and acute respiratory distress syndrome (ARDS)218219.

Treatment of LTBI

The WHO has stressed on the importance of interventions like ART provision and the three Is for HIV-TB coinfection, namely intensified TB case finding, infection control, and isoniazid preventive therapy (IPT), as part of prevention, care and treatment services229. The diagnosis and treatment of LTBI have been extensively reviewed recently92. It is necessary to rule out active TB disease before initiating treatment for LTBI. Important issues concerning LTBI and its treatment92230231232233234 are listed in Box 2

Box 2

Latent TB infection: key issues

Control of TB

Global measures: India conceived the NTP and set an example to the world in the programmatic approach to TB control in 1962197. Since then several efforts have been undertaken globally to achieve control of TB and are summarized in Box III235236237238. These developments reflect the efforts towards achieving universal access to preventive, diagnostic and treatment services for all forms of TB.

Box 3

Global efforts at TB control (1991-2013): a journey

As a result of the implementation of RNTCP, prevalence of all forms of TB has been brought down (from 338/100,000 population in 1990 to 249/100,000 population in 2009); TB mortality has also reduced (from >42/100,000 population in 1990 to 23/100,000 population in 2009) in India. The Phase II (2006-2012) of the RNTCP has achieved the set goals, the country is coursing towards achieving “universal access” for control of TB197 and appears to be on track to achieve the TB related United Nations Millenium development Goals (UNMDG). Jointly with National AIDS Control Programme (NACP), RNTCP has developed “National framework of joint TB/HIV collaborative activities” that are being implemented in the country197.

Involvement of Medical Colleges in TB control

For the first time in the global history of TB control, Indian Medical Colleges were involved in the RNTCP. This unique experiment in the history of TB control has resulted in medical colleges providing diagnostic services (Designated Microscopy Centres), treatment (DOT Centres), referral for treatment, recording and reporting data, carrying out advocacy for RNTCP and conducting operational research on the RNTCP238.

Prevention

Even though the declining trends observed in the global burden of TB currently37239240241242, this trend seems insufficient to achieve the global target of elimination of TB in 2050164. Therefore, the need for other measures including infection control measures, newer or repurposed anti-TB drugs, newer and better vaccines for TB is pressing.

Airborne infection control measures

Recognizing the importance of airborne infection control and in view of the association of TB with HIV and the emergence of X/MDR-TB, guidelines have been issued for implementing the same by the WHO239 and the RNTCP240 as well. However, there is a wide gap between the needs and the actual implementation of these guidelines presently especially in the overcrowded government hospitals in India and other developing countries.

TB Vaccine

Till date the bacille Calmette-Guerin (BCG) vaccine is the only vaccine available for TB241242243244. Though BCG confers consistent protection against severe forms of TB, such as TB meningitis, disseminated and miliary TB in children in areas where TB is endemic its ability to protect against pulmonary TB has been found to be variable245246. New candidate vaccines for TB are in various stages of development and are listed in Table VIII241242247.

Table VIII

Some of the potential TB vaccines in various stages of development

The summary of important changes in TB during the last 130 years since the time of Robert Koch in 1882 are listed in Table IX.

Table IX

Summary of important changes in TB

The Future

The search for newer and more efficient biomarkers for predicating a durable (non-relapsing) cure, indication of reactivation risk, prediction of eradication of LTBI; and prediction of vaccine efficacy248249, discovery of newer anti-TB drugs250251252253 and development of newer additional candidate vaccines254255256257 is required to achieve the WHO and UNMDG goal of halting the incidence, prevalence and death rates associated with TB by 2015 and eliminating the disease altogether by 2050197. Translation of newer innovative diagnostics for TB, such as, use of a ‘hand-held’ nuclear magnetic resonance (NMR) apparatus capable of offering a 30-minute diagnosis of TB258, applications of nanotechnology259260 to point-of-care diagnostic tests needs to be pursued.

Newer, repurposed drugs in pipeline

Presently, several newer or repurposed drugs are in pipeline in various stages of development as anti-TB drugs252261. Among the newer drugs, delamanid (OPC67683), bedaquiline (TMC207) and the nitroimidazole-oxazine PA-824 have been found to be active against both drug-sensitive and drug-resistant strains. Bedaquiline (TMC207) has been approved for use by the United States-Food and Drug Administration (US-FDA). Their efficacy and safety have been demonstrated in MDR-TB patients in double-blind, placebo controlled phase II clinical trials262263264. The Government of India is planning to regulate the introduction of these newer drugs in a systematic fashion by streamlining the conduct of clinical trials in India. Evidence is available that isoniazid-resistant clinical isolates of M. tuberculosis remain fully susceptible to the drug pyridomycin, a compound produced by Dactylosporangium fulvum with specific bactericidal activity against mycobacteria265. Pyridomycin merits further evaluation as an anti-TB drug.

Initiatives like the Critical Path to New TB Regimens (CPTR) involving several pharmaceutical companies and non-governmental organizations have been attempting to develop the newer drugs concomitantly in combination trials so that the best regimen and the shortest duration of time can be evolved266. Additional vaccine candidates are likely to enter clinical trials in future254255256257.

The last 70 years have witnessed an initial euphoria of emergence of drug treatment of TB that raised hopes and even signalled a likely ‘elimination’ of TB. Inspite of political commitment, global and national programmatic strategy to contain and control TB, eventual elimination of TB in near future appears to be a mirage as of now. The widespread occurrence of X/MDR-TB threatens to take us back to the era of untreatable TB. TB has come a long way, from despair and the status of an incurable malady, through a brief interlude of a curable disease to a scourge that is menacingly threatening the return to dark ages. The fall in the absolute number of TB cases globally observed since 2006 is heartening. With newer and repurposed anti-TB drugs emerging and becoming available for use, the march of the humankind towards the goal of TB elimination, i.e., reducing the annual incidence to less than 1 case/1,000,000 population by 2050267 appears to be on course in the right direction.