Prevalence and history of tuberculosis:

THE EXISTENCE of tuberculosis dates back to antiquity. The earliest unambiguous detection of Mycobacterium tuberculosis is in the remains of Pleistocene bison animal dated 18,000 years ago. However, whether tuberculosis originated in cattle and then transferred to humans or diverged from a common ancestor is unclear. Skeletal remains show prehistoric humans (4000 BC) had tuberculosis and tubercular decay has been found in the spines of mummies from 3000-2400 BC. Genetic studies suggest that tuberculosis was present in South America for 2000 years. In ancient Hindu texts tuberculosis has been referred to as Rogaraj, The king of disease and Rajayakshma, the disease of kings.

In 1901, John Bunyan illustrated that tuberculosis is ’Captain of all these men of death’. Many countries are still under the clutches of tuberculosis resulting in a morbidity and mortality. Tuberculosis is caused by members of the genus of Mycobacterium. In 1874, Armaeur Hansen discovered the tubercle bacillus from infected sputum. In 1882, Koch cultured the Mycobacterium tuberculosis. The name Mycobacterium meaning ’Fungus-bacterium’ is an allusion to the characteristic fungus-like pellicle produced by the tubercle bacillus when grown on liquid media. In 1898 Theobold Smith divided Koch’s tubercle bacilli into human and bovine types according to small but constant cultural differences. Wells (1946) separated three types of species named Mycobacterium tuberculosis, Mycobacterium bovis and Mycobacterium microti.

The approved lists of bacterial names included 41 Mycobacterial species and over 20 have been published or reintroduced subsequently. The currently recognised species are listed in Table . The Mycobacterial species fall in two main clusters- the slow growers and the rapid growers. From the purely clinical point of view, Mycobacteria are divisible in three groups :

1.The obligate pathogens – The Mycobacterium tuberculosis complex and Mycobacterium leprae.

2.Species that normally live freely in the environment but also cause ‘opportunist’ infections in humans.

3.Species that never cause or with extreme rarity cause disease.

Mark Spigelman, 2008 examined the DNA sequences of six thousand years excavated human and animal bones in Jericho (Jerusalem), which is the one of the earliest towns on earth, dating back to 9,000 BC. According to Spigelman that tuberculosis would have prevailed 6,000 years ago.

Classification of tuberculosis:

Tuberculosis is broadly classified into two categories – pulmonary tuberculosis and extra pulmonary tuberculosis. Nearly 75 per cent of the cases are pulmonary tuberculosis. On the other hand among 25 per cent of active cases, the infection moves from lungs to pleura, central nervous system, the lymphatic system in scrofula of the neck, the genitourinary system and bones and joints in Pott’s disease of the spine. Even though extra pulmonary tuberculosis is not contagious, it may co-exist with pulmonary tuberculosis which is contagious .

Epidemiology of tuberculosis:

According to the reports of World Health Organisation, about one third of the world’s population has been infected by the tubercle bacillus. Every year between eight and ten million cases of active tuberculosis develop from the infected pool and infect a further 100 million people. The annual mortality is around three million (two million adults and one million children). The impacts of the Human Immuno Virus (HIV) and Tuberculosis (TB) have been termed ‘the cursed duet’. Although tuberculosis is associated with Human Immuno Virus (HIV) people responds to chemotherapy, the mortality over the following two years is high, possibly because of a synergy between the immunosuppressive properties of the two pathogens. It was estimated that around half a million AIDS infected persons have develop tuberculosis during 1990-1991. The developing countries like India, saddled with problems of overcrowding, insanitation, malnutrition, etc are much more a vulnerable.

Evolution of tuberculosis:

During its evolution, Mycobacterium tuberculosis has lost numerous coding and non-coding regions in its genome, losses that can be used to distinguish between strains of the bacteria. The implication is that Mycobacterium tuberculosis strains differ geographically, so their genetic differences can be used to track the origins and movement of each strain. Lymphocytes, β-lymphocytes and fibroblasts are among the cells that aggregate to form a granuloma with lymphocytes surrounding the infected macrophages. The granuloma functions not only to prevent dissemination of the Mycobacteria, but also provides a local environment for communication of cells of the immune system. Within the granuloma, T-lymphocytes (CD4 +) secrete cytokines such as interferon gamma, which activates macrophages to destroy the bacteria with which they are infected. T-lymphocytes (CD8+) can also directly kill infected cells. Importantly, bacteria are not always eliminated within the granuloma, but can become dormant resulting in a latent infection. Another feature of the granulomas of human tuberculosis is the development of cell death. To the naked eye this has the texture of soft white cheese and was termed Caseous necrosis.

If tuberculosis bacteria gain entry to the blood stream from an area of damaged tissue they spread through the body and set up many foci of infection, all appearing as tiny white tubercles in the tissues. This severe form of tuberculosis disease is most common in both infants and the elderly. It is termed as Miliary tuberculosis. Patients with this disseminated tuberculosis have a fatality rate of approximately 20 per cent even with intensive treatment. In many patients the infection waxes and wanes. Tissue destruction and necrosis are balanced by healing and fibrosis. During active disease, some of these cavities are joined to the air passages bronchi and this material elute as a sputum while cough up. It contains living bacteria and can therefore pass on infection. Treatment with appropriate antibiotic can cause lethal to bacteria and allows healing to take place. Tuberculosis healed areas are eventually replaced by scar tissue.

Diagnosis of tuberculosis:

Tuberculosis is diagnosed by finding Mycobacterium tuberculosis bacteria in clinical specimen taken from the patient. A complete medical evaluation for tuberculosis must include a medical history, a physical examination, a chest X-ray and microbiological examination. It may also include a tuberculin skin test, lung scans and surgical biopsy. The medical history includes obtaining the symptoms of pulmonary tuberculosis: that include prolonged cough for three or more weeks, chest pain and hemoptysis. Systemic symptoms include fever, chills, night sweats, appetite loss, weight loss and easy fatigability. Other parts of the medical history include prior tuberculosis exposure that HIV infection increases the risk for tuberculosis disease. Physical examination is done to assess the patient’s general health and find other factors which may affect the tuberculosis treatment plan.

Microbiological studies:

A definitive diagnosis of tuberculosis can only be made my culturing Mycobacterium tuberculosis organisms from a specimen taken from the patient (Most often sputum, but may also include pus, cerebero spinal fluid (CSF)), biopsied tissue, etc. Sputum smears and cultures should be done for acid-fast bacilli. The preferred method for the identification is fluorescence microscopy which is more sensitive than conventional Ziehl- Neelson staining.

If sputum is not produced, specimens can be obtained by inducing sputum, gastric washings, an laryngeal swab, bronchoscopy with broncho alveolar lavage or fine needle aspiration of a collection. A comparative study found that inducing three sputum samples is more sensitive than three gastric washings (Brown et.al., 2007). Many types of culture medias are available. Traditionally Lowenstein –Jensen (LJ), Kirchner or Middle Brook media (7H9, 7H10, 7H11 and 7H12) are used for cultivating of Mycobacterial species. A culture of the acid-fast bacilli distinguishes the various forms of Mycobacteria. New automated systems that are faster include BACTEC 460 TB, BACTEC 9000 and the Mycobacterial growth Indicator tube (MGIT). The microscopic observation drug susceptibility assay (MODS) culture may be faster and more accurate method (Moore et.al., 2006).

Radio diagnosis of tuberculosis:

In active pulmonary tuberculosis, infiltrates or consolidations and cavities are often seen in the upper lungs with or without mediastinal or hilar lymphadenopathy or pleural effusions. However, lesions may appear any where in lungs. In disseminated tuberculosis a pattern of many tiny nodules through out the lung fields is quite common, so called Miliary tuberculosis. Chest radiographs may be suggestive, but are never diagnostic of tuberculosis. However, chest radiographs may be used to rule out the possibility of pulmonary tuberculosis in a person who has a positive reaction to the tuberculin skin test and symptoms of disease. A variant of the chest X-ray, abreugraphy was a small radiographic image also called Miniature Mass Radiography (MMR). Though its resolution is limited, it is sufficiently accurate for diagnosis of tuberculosis.

Tuberculin skin test:

Two tests are available: The Mantoux and Heaf test. The equivalent Mantoux test positive levels done with 10 Tu (0.1mL in 100TU/mL, 1:1000) are

0-4mm induration ( Heaf 0-1)

5-14mm induration ( Heaf 2)

Greater than 15mm induration (Heaf 3-5).

An induration of more than 5-15mm to 10 Mantoux units is considered a positive result indicating tuberculosis infection.

Laboratory diagnosis:

Since tuberculin skin test shows certain difficulties, many laboratory methods of diagnosis were adopted. These tests have been reviewed in detail.

Adenosine Deaminase (ADA) test:

In 2007, a systematic review of adenosine deaminase by the National Health Sciences Technology Assessment Programme reported that there is considerable evidence to support their use in pleural fluid samples for diagnosis of pleural tuberculosis. In both peural tuberculosis and tuberculosis meningitis, ADA tests had higher sensitivity than any other tests.

Nucleic Acid Amplification Tests (NAAT):

This is a heterogeneous group of tests that uses the polymerase chain reaction (PCR) technique to detect Mycobacterial nucleic acid. These tests vary in which nucleic acid sequence they detect may vary in their accuracy. The two most common commercially available tests are the amplified Mycobacterium tuberculosis direct test (MTD).

In 2007, a systematic review of NAAT by the NHS Technology Assessment Programme states, "NAAT test accuracy is far superior when applied to respiratory samples as opposed to other specimens". In a more recent before –after observational study, it was found that use of MTD test reduce inappropriate tuberculosis therapy. The study found the accuracy of the MTD test as follows. Overall sensitivity is 99 per cent and specificity is 92 per cent. In the case of tuberculosis positive patients sensitivity is 99 per cent and specificity 98 per cent. Alternatively, smear negative patients sensitivity is 62 per cent and specificity 99 per cent.

Modern drugs used in tuberculosis:

Active tuberculosis will kill about two of every three people affected if left untreated. Treated tuberculosis if taken up early has a mortality rate of less than 5%.The standard short course treatment for tuberculosis comprises of Isoniazid, Rifampicin, Pyrazinamide and Ethambutol for two months, then Isoniazid and Rifampicin alone for a further four months. For latent tuberculosis, the standard treatment is six to nine months of Isoniazid alone. Drug regimens are abbreviated in a standardized manner.

a) Streptomycin is STM or S

b) Isoniazid is INH or H

c) Rifampicin is RMP or R

d) Ethambutol is EMB or E

e) Pyrazinamide is PZA or Z.

According to WHO norms, there are six classes of second line drugs that are used for the treatment of tuberculosis. A drug may be classified as second line instead of first line for one of two possible reasons; it may be less effective than the first line drugs or it may produce toxic side –effects. They are classified based on their chemical nucleus:

a) Aminoglycosides – Amikacin and Kanamycin

b) Polypeptides – Capreomycin

c) Fluoroquinolones – Ciprofloxacin

d)Thioamides – Ethionamide, Prothionamide and Cycloserine.

e) Para-amino Salicylic acid.

Tuberculosis has been treated with combination therapy over fifty years. Drug are not used singly and regimens that use only single drugs result in the rapid development of resistance and thus treatment results in failure. The rationale for using multiple drugs to treat tuberculosis are based on simple probability. The frequency of spontaneous mutations that confer resistance to an individual drug are well known: 1 in 10 7 for Ethambutol (EMB); 1 in 108 for streptomycin (STM) and Isoniazid (INH); 1 in 10 10 for Rifampicin (RMP). A patient with extensive pulmonary tuberculosis has approximately 10 12 bacteria in his body and therefore will probably be harboring approximately 10 5 Ethambutol- resistant bacteria, 10 4 Streptomycin – resistant bacteria, 10 4 Isoniazid –resistant bacteria and 10 2 Rifampicin –resistant bacteria respectively. DOTS stands for ‘Directly Observed Therapy, Short - course’ and is a major plank in the WHO global tuberculosis eradication programme. The WHO advises that all tuberculosis patients should have at least the first two months of their drug therapy should be observed with the aid of observer within that society. DOTS is used with intermittent dosing – Thrice weekly (Rifampicin, Isoniazid, Ethambutol and Pyrazinamide) or twice weekly. The relative incidence of major adverse effects has been carefully described:

a)Isoniazid – Hepatitis, Neuropathy – 0.49 per hundred patient.

b)Rifampicin – Skin rash, Thrombocytopenia and Hepatitis – 0.43 per hundred patient.

c)Pyrazinamide – Skin rash and Hepatitis - 1.48 per hundred.

d)Streptomycin – Vertigo - 0.43 per hundred patient.

Human Immuno Virus (HIV) and tuberculosis:

In patients with Human Immuno Virus, treatment for the HIV should be delayed until tuberculosis treatment is completed. According to British Human Immuno Virus Association

a)CD4 count over 200 - delay treatment until the six months of tuberculosis treatment is complete.

b)CD4 count 100 to 200 - delay treatment until the initial two month intensive phase of therapy is complete.

c)CD4 count less than 100 - the situation is unclear and patients should be enrolled in clinical trials.

Drug resistant tuberculosis ( MDR AND XDR – TB):

Multi Drug Resistant Tuberculosis (MDR-TB) is defined as tuberculosis that is resistant at least to Isoniazid and Rifampicin isolates. In the year 2006 "Extensively Drug Resistant Tuberculosis" (XDR-TB) is emerged and defined as multi drug resistant tuberculosis that is resistant to quinolones and also to any one of kanamycin, capreomycin or amikacin (WHO, 2006).

Epidemiology of drug –resistant tuberculosis:

A 1997 survey of 35 countries found that 2 per cent of the tuberculosis populations are infected by drug – resistant tuberculosis. The highest rates were in USSR, the Baltic states, Argentina, India and China. In 2006, MDR –TB in New York city has been increased to 20-30 per cent. Annual risk of mortality rates increases by 10-15 per cent. There is currently an epidemic of XDR-TB in South Africa. The outbreak was first reported as a cluster of 53 patients in a rural hospital in Kwazulu –Natal of whom 52 died . The treatment and prognosis of MDR-TB are much more akin to that of cancer than to that for infection.

Tuberculosis and secondary infections:

The prevalence of secondary infection in the pathogenesis and symptomatology of pulmonary tuberculosis is evidenced by the extensive literature which has accumulated since Koch’s discovery of the primary and essential cause of tuberculous infection. Subsequent invasion of the secondary bacteria and fungi such as Beta – hemolytic streptococci, Klebsiella pneumoniae, Pseudomonas aeruginosa,Candida albicans, Aspergillus niger and Aspergillus flavus resulting in the secondary infection which causes tissue destruction and ulceration which had already occurred as a result of primary infection.

The initial focus offers a ready portal of entry and a suitable nidus for secondary invaders, since local resistance is already diminished and the natural protective forces of the body are exhausted by the original infection. In such instances the primary lesion may remain localized and the secondary bacteria become disseminated in metastatic foci. In pulmonary tuberculosis it is this latter form of secondary infection which plays a vital role in blocking the direct access of air in to the alveoli and produce tissue symbiosis producing a passive mixed infection leading to chronic obstructive lung disease resulting in a fatal death. The mortality rate is 50-60 per cent in pulmonary tuberculosis is due to the invaders of secondary bacteria and fungi. Hence more attention is to be focused for the simultaneous treatment for secondary infections along with the tuberculosis.