Clinical manifestations , diagnostic and pharmacotherapy of Tuberculosis

1. Tuberculosis
RVS Chaitanya Koppala

2. Introduction
Tuberculosis (TB) is a bacterial infection, treatable by anti- TB drugs.
The burden of TB in many countries is compounded in those who have co-
infection with the human immunodeficiency virus (HIV).
Additional concern has been the increase in multidrug- resistant tuberculosis
(MDR-TB), with outbreaks in different parts of the world.
 In 2006, the emergence of extensively drug-resistant tuberculosis (XDR-TB)
was first reported.

3. Aetiology
TB is caused by tubercle bacilli, which belong to the genus Mycobacterium.
These form a large group but only three relatives (Mycobacterium tuberculosis
complex) are obligate parasites that can cause TB disease.
M. tuberculosis complex: M. tuberculosis, M. bovis, M. africanum
Mycobacteria other than tuberculosis: Around 15 are recognised as pathogenic to
humans and some cause pulmonary disease resembling TB.
They have been found in soil, milk and water (atypical mycobacteria)
Mycobacterium leprae: The cause of leprosy.

4. Clinical aspects
Infection with tubercle bacilli occurs in the vast majority of cases by the
respiratory route.
The lung lesions caused by infection commonly heal, leaving no residual
changes except occasional pulmonary or tracheobronchial lymph node
calcification
About 5% of those initially infected will develop active primary disease
lungs, lymphatic, haematogenous spread of bacilli to pulmonary, meningeal
or other extra pulmonary

5. In the other 95%, the primary lesion heals without intervention but in at least one-
half of patients, the bacilli survive in a latent form.
which may then reactivate later in life. Infants, adolescents and immunosuppressed
people are more susceptible to the more serious forms of TB such as miliary or
meningeal TB.
Sites of extra pulmonary disease include the pleura, lymph nodes, pericardium,
kidneys, meninges, bones and joints, larynx, skin, intestines, peritoneum and eyes.

6. In 2008, 55% of cases were pulmonary and 21% involved the extrathoracic lymph
nodes.
Pulmonary TB may arise from exogenous reinfection or endogenous reactivation
of a latent focus remaining from the initial infection.
If untreated, about 65% of patients will die within 5 years, the majority of these
within 2 years.
Completion of chemotherapy using drugs to which the tubercle bacilli are
sensitive almost always results in a cure, even with HIV infection.

7. Incubation period
The incubation period from infection to demonstrable primary lesion
or significant tuberculin reaction ranges from 2 to 10 weeks.
Latent infection may persist for a lifetime.
HIV infection appears to shorten the interval for the development of
clinically apparent TB.

8. Transmission
Air-borne exposure to droplet nuclei of tubercle bacilli by coughing or sneezing.
In general, only the respiratory forms of TB (tuberculosis of the larynx is highly
contagious but rarely seen ) are infectious.
Most infections are acquired from adults with post-primary pulmonary TB.
The greatest risk of infection is to close, prolonged contacts, mainly household
contacts.
Between 90% and 95% of cases of TB in children are non-infectious.
 TB cannot be acquired from individuals with LTBI.

9. Smear negative/positive:
Patients should be considered infectious if they have sputum smear-positive
pulmonary disease or laryngeal TB.
Patients with smear-negative pulmonary disease (three sputum samples) are less
infectious than those who are smear positive.
The relative transmission rate from smear-negative compared with smear-positive
patients has been estimated to be 0.22

10. Risk groups
 Certain groups are at increased risk of LTBI and possibly TB disease if
exposed. These include:
Close contacts of patients with TB (sputum smear-positive pulmonary)
Casual contacts (e.g. work colleagues) if they are immunosuppressed
People from countries with a high incidence of TB (40/100,000 population or greater).
 People with certain medical conditions are at increased risk of developing
active TB if they have LTBI.

11. Examples of factors that increase risk of
developing TB
HIV positive
Injecting drug users
Solid organ transplantation, jejunoileal bypass or gastrectomy
Haematological malignancy, for example leukaemia and lymphomas
Chronic renal failure or receiving haemodialysis
Receiving anti-TNFα treatment
Silicosis

12. Drug-resistant TB
MDR-TB is caused by bacteria that are resistant to at least isoniazid and rifampicin,the
most effective anti-TB drugs.
MDR-TB results from either primary infection with resistant bacteria.
XDR-TB is a form of TB caused by bacteria that are resistant to isoniazid and
rifampicin, fluoroquinolone and any of the second-line anti-TB injectable drugs
including amikacin, kanamycin or capreomycin

13. Epidemiology
The key measures for TB are the number of new cases in a specified period of time,
usually 1 year, and the incidence rates, that is, new cases per 100,000 of the population.
Globally, it is estimated that TB causes about 2 million deaths worldwide each year.
One-third of the world's population is infected with the tubercle bacillus.
It is becoming the leading cause of death among HIV-positive people.
Over 4 million cases of TB disease are notified annually although the estimated number
of new cases is put at 9 million.

14. The majority of cases occur in poor countries in the southern
hemisphere
In 2008, it was estimated that 440,000 people had MDR-TB
worldwide, and one-third of these died.
The brunt of the MDR-TB epidemic is borne by Asia, with almost
50% of cases worldwide estimated to occur in China and India.

15. Symptoms
The symptoms and signs of TB include:
Cough for 3 weeks or more/productive cough
Sputum usually mucopurulent or purulent
Haemoptysis not always a feature
Fever may be associated with night sweats
Tiredness
Weight loss variable
Anorexia variable
Malaise.

16. Clinical diagnosis
The clinical diagnosis of TB disease is based on the symptoms and signs in
the patient together with chest radiography, microscopy of sputum
followed by culture and tuberculin skin testing.
Blood-based immunological tests, introduced in the last few years, will
play an increasingly important role in TB diagnosis.
These tests can distinguish between TB infection and previous BCG
vaccination.

17. Microbiological
Microbiological investigations are undertaken to assess the infectious state (mycobacteria causing
TB and other mycobacteria).
Determine the drug-susceptibility patterns of the infecting organisms, to ensure that the drugs .
Investigations comprise microscopy, culture, drug-susceptibility testing and strain typing.
Direct microscopy of sputum is the simplest and quickest method of detecting the infectious
patient, by looking for acid-fast bacilli.
A minimum of three sputum samples, one of which should be early morning, should be collected
from patients with suspected respiratory TB.

18. Cultures
Direct microscopy is not as useful in non-pulmonary disease, any specimens taken should
be sent for culture.
Lowenstein–Jensen medium, growth may take up to 6 weeks.
Polymerase chain reaction (PCR)-based tests can also detect M. tuberculosis complex in
clinical specimens.
A rapid test is available for assessing rifampicin resistance in individuals thought to have
drug-resistant TB.
A positive result indicates the need to assess susceptibility to other first line anti-TB drugs.
DNA fingerprinting, or strain typing, is useful in the public health management of TB.
New method, mycobacterial (MIRU/VNTR) 24-loci strain typing, became available in
UK

19. Tuberculin testing
 Tuberculin testing is used to detect LTBI.
 The standard Mantoux test consists of an intradermal injection of 2 TU of Statens Serum Institute (SSI)
tuberculin RT23 in 0.1 mL solution for injection.
 In this test, 0.1 mL of the appropriate solution is injected intradermally, usually on the forearm, so that a bleb
of around 7 mm is produced.
 The results are read 48–72 h later, although a valid reading can be obtained up to 96 h later.
 The transverse diameter of the area of induration is measured with a ruler and the result recorded in
millimetres.
 The interpretation of the test will depend on the clinical circumstances, including a past history of TB or
exposure to TB.

20. Chest radiography
The chest radiograph is a non-specific diagnostic tool, as TB may present as
virtually any abnormality on chest radiography.
This is why microbiological evidence of confirmation should be sought.
Pulmonary TB may appear as bronchopneumonia with confluent shadowing,
without cavitation.
Cavitation may be seen, the incidence can vary between 10% and 30%.
Uncharacteristic radiological patterns may occur in the presence of HIV infection .

21. Diagnosis in people with HIV
TB can occur early in the course of HIV infection and may therefore be diagnosed before
the patient is known to be HIV positive.
The possibility of HIV infection in people with TB should therefore be considered, and
testing for the virus is appropriate in those with risk factors for HIV.
Early in the course of HIV infection, before serious immunodeficiency occurs, TB is more
likely to present with typical clinical features, and a positive tuberculin skin test, with
cavitation and/or pleural disease on chest radiography.
In the late stages of HIV infection show chest findings and extra pulmonary disease.

22. Treatment
In treating TB, a number of factors are important:
• Choice of drugs
• Length of treatment
• Co-morbidity especially HIV infection, liver and renal diseases
• Adherence to treatment by the patient.
It is important to tailor the management of the patient according to his
or her situation, rather than just focus on the drug treatment of TB, as
other factors in the patient's life may affect adherence.

23. Drug treatment
 Treatment with anti-TB drugs has two main purposes:
• to cure people with TB, provided the bacilli are drug sensitive
• to control TB, by either preventing the development of infectious forms
 With the advent of effective anti-TB chemotherapy, patients no longer needed treatment in a sanatorium.
 Results with regimens containing isoniazid together with p-aminosalicylate (PAS) or ethambutol, and sometimes
streptomycin, gave excellent results.
 Treatment was required for 18–24 months if relapse was to be prevented.
 The availability of pyrazinamide and, more importantly, rifampicin made shorter courses of treatment a possibility.
 Most regimens in the developed world now contain isoniazid and rifampicin, which are the two most important drugs
together with pyrazinamide and possibly with another agent, such as ethambutol.

24. Bacterial characteristics
There are three populations of the M. tuberculosis (MTB) organism.
The first population is that of the actively growing extracellular bacilli (pulmonary cavities
within liquefied caseous debris)
The second population consists of slow growing or intermittently growing bacilli, which are
inside macrophages (intracellular environment )
The third population is made up of slower growing bacilli, which grow in solid caseous
material (neutral pH)
Rifampicin is the only drug that is bactericidal against all three populations.
 Isoniazid, streptomycin and the other aminoglycosides are bactericidal against extracellular bacilli

25. Treatment
The recommended standard treatment regimen for respiratory and most other forms
of TB
• rifampicin, isoniazid, pyrazinamide and ethambutol for the initial 2 months
(initial phase)
• a further 4 months of rifampicin and isoniazid (continuation phase).
A longer period of treatment than the standard 6 months is needed for meningeal TB
and where there is direct spinal cord involvement.
Patients should be started on the standard treatment Regimen on clinical diagnosis.

27. The purpose of the concurrent use of four drugs in the initial phase is to reduce
the bacterial population as rapidly as possible and prevent the emergence of
drug-resistant bacteria.
It is important, however, to ensure the combination product contains the required
dose of the constituent drugs.
Patients with suspected drug reactions or drug-resistant TB should always be
referred back to the specialist physician and the healthcare team supervising their
treatment.

28. Respiratory TB
Respiratory TB is defined as active TB affecting any of the following:
• lungs
• pleural cavity
• mediastinal lymph nodes
• larynx.
The standard 6-month regimen, as set out earlier, is recommended for the
treatment of active respiratory TB in:
• adults not known to be HIV positive
• adults who are HIV positive
• children.

29. TB of peripheral lymph nodes
Trials have shown that 6 months of treatment are just as effective as 9
months for fully susceptible bacilli.
The standard 6-month treatment regimen is recommended.
Meningeal TB Patients with active meningeal TB (tuberculous meningitis)
should be treated with rifampicin and isoniazid for 12 months together
with pyrazinamide, and normally ethambutol, for the first 2 months.

30. Bone and joint TB
The spine is the most common site for bone TB.
Bone and joint TB are treated effectively with standard agents such as isoniazid
and rifampicin for 6 months, together with pyrazinamide and a fourth drug,
usually ethambutol in the initial phase (for 2 months).
This recommendation covers active spinal TB and active TB at other bone and
joint sites.
Occasionally, surgery may be needed to either relieve spinal cord compression or
correct spinal deformities.

31. Pericardial TB
The standard 6-month treatment regimen is recommended for patients with
active pericardial disease.
Glucocorticoids should also be prescribed at the following doses
• Adults: a glucocorticoid equivalent to prednisolone at 60 mg/day
• Children: a glucocorticoid equivalent to prednisolone 1 mg/kg/day
(maximum 40 mg/day), with gradual withdrawal of the glucocorticoid,
starting within 2–3 weeks of initiation.

32. Adverse effects associated with FIRST LINE