TUBERCULOSIS

 Tuberculosis (TB) is a global

problem, with varying incidence across
the world.
 In 1993, the World Health
Organization (WHO) declared TB a
global emergency due to an increase in
reported cases worldwide.
 Co-infection with HIV
compounds the burden of TB in many
countries.
 Multidrug-resistant
tuberculosis (MDR-TB) and extensively
drug-resistant tuberculosis (XDR-TB)
are major concerns, with outbreaks
occurring in different parts of the
world.
 Treating drug-resistant TB is complex, costlier, and longer in duration compared to drug-
susceptible cases.
 Adequate and effective treatment is crucial for both patient care and TB control since the BCG
vaccine does not prevent infection.
 Successful TB control requires collaboration between clinical, microbiological, pharmacy,
infection control, and public health teams, along with a shared understanding among primary
care teams.
 In the UK, clinical and public health practice for TB control is guided by the National Institute
for Health and Clinical Excellence and the Joint Committee on Vaccination and Immunisation

AETIOLOGY
 Tuberculosis (TB) is caused by tubercle bacilli, specifically the ones belonging to the genus
Mycobacterium.
 Only three relatives of Mycobacterium are obligate parasites that can cause TB disease, and
they are part of the Mycobacterium tuberculosis complex.
 In the UK, the majority of confirmed TB cases in 2008 were caused by M. tuberculosis (99%),
with M. bovis accounting for 0.4% and M. africanum for 0.5% (Health Protection Agency,
2009).
 Mycobacterium species include those within the M. tuberculosis complex (M. tuberculosis,
M. bovis, M. africanum), as well as other mycobacteria that can cause pulmonary disease
resembling TB. These atypical mycobacteria are found in soil, milk, water, and are referred
to as "Mycobacteria other than tuberculosis."
 Leprosy, a separate disease, is caused by Mycobacterium leprae.

Clinical Aspects of Tuberculosis (TB)

1. Infection and Disease Progression:
 Tuberculosis is primarily
transmitted through the
respiratory route.
 Most cases of infection result in
healing lung lesions without
residual changes.
 Approximately 5% of initially infected individuals develop active primary disease, which can
manifest as pulmonary disease or spread to other organs (extrapulmonary involvement)
through lymphatic or hematogenous routes.
 The remaining 95% of individuals experience latent infection, where the bacilli remain
dormant but can reactivate later in life.
 Infants, adolescents, and immunosuppressed individuals are more susceptible to severe
forms of TB such as miliary or meningeal TB.
 Pulmonary TB is more common than extrapulmonary TB in the UK, with the most common
extrapulmonary site being lymph nodes.
2. Pulmonary and Extrapulmonary TB:
 Pulmonary TB can arise from reinfection or reactivation of latent infection.
 Extrapulmonary TB can affect various organs, including the pleura, lymph nodes,
pericardium, kidneys, meninges, bones, joints, larynx, skin, intestines, peritoneum, and eyes.
 In 2008, 55% of TB cases in the UK were pulmonary, while 21% involved extrathoracic lymph
nodes.
3. Incubation Period:
 The incubation period from infection to the development of a primary lesion or significant
tuberculin reaction ranges from 2 to 10 weeks.
 Latent infection can persist for a lifetime, but HIV infection may accelerate the development
of clinically apparent TB.
4. Transmission:
 Transmission occurs through exposure to airborne droplet nuclei containing tubercle bacilli,
primarily generated by individuals with pulmonary or respiratory tract TB during coughing
or sneezing.
 Respiratory forms of TB are infectious, while other forms such as laryngeal TB are highly
contagious but rarely seen in the UK.
 Close and prolonged contacts, especially household contacts, face the highest risk of
infection.
 Most infections are acquired from adults with post-primary pulmonary TB.
 TB cannot be acquired from individuals with latent TB infection (LTBI).
5. Risk Groups:
 Close contacts of patients with TB, particularly those with sputum smear-positive
pulmonary disease, are at increased risk of LTBI and TB disease.
 Immunosuppressed casual contacts (e.g., work colleagues) may also be at risk.
 People from countries with a high incidence of TB (≥40/100,000 population) are at increased
risk.
 Certain medical conditions increase the risk of developing active TB if individuals have LTBI.
6. Impact of HIV Infection:
 People with HIV infection have a higher risk of developing TB when exposed to infection.
 The annual risk of TB in those with HIV and TB co-infection is around 10% compared to a
lifetime chance of 10% in individuals infected with TB only.
7. Drug-Resistant TB:
 Multidrug-resistant TB (MDR-TB) is caused by bacteria resistant to isoniazid and rifampicin,
the most effective anti-TB drugs.
 MDR-TB can result from primary infection with resistant bacteria or develop during the
course of treatment.
  Extensively drug-resistant TB (XDR-TB) is a form of TB caused by bacteria resistant to
isoniazid, rifampicin, fluoroquinolones, and second-line injectable drugs.
 Treatment of drug-resistant TB is more complex, costlier, and longer in duration compared
to drug-susceptible TB.

Epidemiology of Tuberculosis (TB)

1. Key Measures:
 Epidemiology measures the occurrence of a disease in different populations.
 Key measures for TB include the number of new cases in a specified time period (usually 1
year) and incidence rates (new cases per 100,000 population).
 Incidence rates are useful for comparing TB occurrence between countries or population
sub-groups, as they consider population size.
2. Global Burden:
 TB causes approximately 2 million deaths worldwide annually.
 One-third of the global population is infected with the tubercle bacillus.
 TB is becoming a leading cause of death among HIV-positive individuals.
 Over 4 million cases of TB disease are reported annually, but the estimated number of new
cases is around 9 million.
 The majority of cases occur in poor countries in the southern hemisphere.
3. Regional Distribution:
 South East Asia has the highest number of TB cases globally, while Africa has the highest
incidence rates.
 In 2008, an estimated 440,000 people had multidrug-resistant TB (MDR-TB) worldwide, with
one-third of them dying from the disease.
 The MDR-TB epidemic is primarily concentrated in Asia, particularly China and India.
 Some regions have a high prevalence of drug-resistant TB, with up to one in four individuals
diagnosed with TB having the multidrug-resistant form

Diagnosis of Tuberculosis (TB)

1. Symptoms of TB:
  Cough lasting 3 weeks or more, often productive.
 Sputum is usually mucopurulent or purulent.
 Haemoptysis (coughing up blood) may or may not be present.
 Fever, especially associated with night sweats.
 Tiredness, weight loss, anorexia, and malaise are variable symptoms.
2. Importance of Awareness:
 Awareness of TB among healthcare professionals and high-risk communities is crucial for
control.
 Early diagnosis, especially of pulmonary TB, and prompt treatment initiation can reduce the
period of infectivity and protect vulnerable contacts.
 Health professionals should be vigilant for TB symptoms in healthcare workers, childcare
workers, and individuals in institutional settings, initiating investigations promptly to
identify cases and protect others.
3. Clinical Diagnosis:
 Clinical diagnosis of TB is based on patient symptoms, signs, chest radiography, and
microscopy of sputum for acid-fast bacilli, culture, and tuberculin skin testing.
 Blood-based immunological tests have emerged in recent years and play an increasing role
in TB diagnosis.
 These tests can differentiate between TB infection and previous BCG vaccination.

Investigations for Tuberculosis (TB)

1. Microbiological Investigations:
 Microbiological tests are crucial for confirming clinically suspected TB and assessing the
infectious state of the patient.
 Direct microscopy of sputum is the simplest and quickest method for detecting acid-fast
bacilli, especially in pulmonary TB.
 Sputum samples should be collected, preferably three samples, including an early morning
sample, from patients with suspected respiratory TB.
 Culture and drug-susceptibility testing are important to determine the specific
mycobacteria causing TB and their drug-susceptibility patterns.
 Polymerase chain reaction (PCR)-based tests can detect M. tuberculosis complex in clinical
specimens.
 DNA fingerprinting or strain typing helps in public health management, establishing links
between cases, disproving apparent clusters, and detecting laboratory cross-
contamination.
2. Tuberculin Testing:
 Tuberculin testing, specifically the Mantoux test, is used to detect latent TB infection (LTBI).
 The Mantoux test involves an intradermal injection of 2 TU of tuberculin.
 The results are read 48-72 hours later, with a valid reading obtainable up to 96 hours later.
 Interpretation of the test depends on clinical circumstances, with an induration diameter of
less than 6mm considered negative, 6-15mm suggesting previous TB infection or BCG
vaccination, and more than 15mm strongly suggestive of TB infection or disease.
3. Chest Radiography:
 Chest radiography is a non-specific diagnostic tool for TB.
 TB can present with various abnormalities on chest radiographs.
 Microbiological confirmation should be sought as radiographic findings alone are
insufficient.
 Pulmonary TB may appear as bronchopneumonia with or without cavitation.
 Atypical radiological patterns may occur in the presence of HIV infection, and the chest
radiograph may be normal in up to 40% of cases.
4. Diagnosis in People with HIV:
 TB can occur early in the course of HIV infection, and testing for HIV is appropriate in
individuals with TB and risk factors.
 In early HIV infection, TB is more likely to present with typical clinical features, positive
tuberculin skin test, and chest radiographic abnormalities.
 In late-stage HIV infection, atypical presentations and extrapulmonary disease are more
common, and the chest radiograph may be normal in some cases.
5. Public Health Action:
 TB is a statutorily notifiable communicable disease in the UK.
 Cases should be notified to the local authority's Proper Officer for communicable disease
control.
  Notification enables public health action, including investigation of close contacts for latent
TB infection or active TB disease.
 Public health action is not taken for infections caused by mycobacteria other than TB

Treatment of Tuberculosis (TB)

Factors in TB Treatment:

 Choice of drugs: Selection of appropriate anti-TB drugs based on drug sensitivity testing.
 Length of treatment: Standard treatment duration is 6 months, but longer periods are
needed for specific cases.
 Co-morbidity: Consideration of comorbidities such as HIV infection, liver disease, and renal
disease in treatment planning.
 Adherence to treatment: Patient adherence to the prescribed treatment regimen is crucial
for successful outcomes.
Drug Treatment:
  Anti-TB drug treatment aims to cure individuals with TB and control the disease.
 Regimens containing isoniazid, rifampicin, pyrazinamide, and possibly ethambutol are
commonly used in the developed world.
 Rifampicin is bactericidal against all three populations of M. tuberculosis (actively growing
extracellular bacilli, slow-growing or intermittently growing bacilli inside macrophages,
and slower-growing bacilli in solid caseous material).
 Isoniazid, streptomycin, and other aminoglycosides are bactericidal against extracellular
bacilli.
 Pyrazinamide is bactericidal against intracellular organisms and works well in an acidic pH.
 Other first-line TB drugs are bacteriostatic, while quinolones have high bactericidal activity
against M. tuberculosis.
Treatment Regimen:
 The standard treatment regimen for respiratory and most other forms of TB in the UK
includes:
 Initial phase (2 months): Rifampicin, isoniazid, pyrazinamide, and ethambutol.
 Continuation phase (4 months): Rifampicin and isoniazid.
 Longer treatment periods are required for meningeal TB and cases with direct spinal cord
involvement.
 Treatment should be initiated on clinical diagnosis, and drug doses should be adjusted
based on drug-susceptibility testing results.
 Combination tablets can be used to ensure proper dosing and prevent inadvertent single-
drug therapy.
Important Considerations:
 Concurrent use of four drugs in the initial phase aims to rapidly reduce the bacterial
population and prevent the emergence of drug-resistant bacteria.
 Daily dosing schedules are generally recommended.
 Suspected drug reactions or drug-resistant TB cases should be referred back to specialist
physicians and the healthcare team supervising treatment.
Respiratory TB:
 Respiratory TB refers to active TB affecting the lungs, pleural cavity, mediastinal lymph
nodes, or larynx.
  The standard 6-month treatment regimen is recommended for active respiratory TB in
adults (both HIV-positive and HIV-negative) and children.
 Trials have shown that 6 months of treatment is as effective as 9 months for fully
susceptible bacilli.
Meningeal TB:
 Meningeal TB (tuberculous meningitis) is a serious disease requiring prompt treatment.
 The recommended treatment for active meningeal TB is:
 Rifampicin and isoniazid for 12 months.
 Pyrazinamide and ethambutol (or streptomycin) for the first 2 months.
 Glucocorticoids (e.g., prednisolone) are used as adjunctive therapy and should be initiated
simultaneously with anti-TB drugs.
 Gradual withdrawal of glucocorticoids within 2-3 weeks of initiation should be considered.
 Recent guidelines recommend the use of adjunctive corticosteroids (dexamethasone) for all
patients with meningeal TB, regardless of disease severity.
Bone and Joint TB:
 The spine is the most common site for bone TB.
 Standard agents such as isoniazid and rifampicin are used for 6 months to treat bone and
joint TB.
 The initial phase includes pyrazinamide and a fourth drug, usually ethambutol (for 2
months).
 Surgery may be required for spinal TB to relieve spinal cord compression or correct
deformities.
Disseminated TB:
 Disseminated or miliary TB requires prompt treatment.
 The standard 6-month regimen with isoniazid, rifampicin, pyrazinamide, and ethambutol in
the initial 2 months is used.
 If there is evidence of central nervous system (CNS) involvement, the treatment is the same
as for meningeal TB.
Pericardial TB:
 Pericardial TB is rare but can lead to cardiac complications.
  The standard 6-month treatment regimen is recommended.
 Glucocorticoids (prednisolone) should be prescribed at specific doses, and gradual
withdrawal is recommended
TB in Children:
 Doses of anti-TB drugs for children are provided in Table 40.3.
 Ethambutol should not be routinely used in young children due to their inability to report
visual disturbances.
 However, it may be considered if there is toxicity or resistance to other agents.
Pregnancy:
 Treatment for TB in pregnant women should be initiated when there is a moderate or high
probability of TB.
 Standard therapy is given, but streptomycin should be avoided due to potential ototoxicity to
the fetus.
 Breastfeeding is considered safe during anti-TB treatment.
 Pyridoxine (vitamin B6) supplementation is recommended for breastfeeding women taking
isoniazid.
 The reduced effectiveness of oral contraceptives in regimens containing rifampicin should
be discussed, and alternative non-hormonal contraceptives should be considered.
Renal Disease:
 Isoniazid, rifampicin, and pyrazinamide can be given in standard doses to patients with
renal disease.
 Ethambutol requires dose reduction due to its extensive renal elimination.
 Streptomycin should be used with caution and is best avoided in renal failure.
 Rifampicin can be given in standard doses to patients on dialysis, while doses of other
agents may need to be modified.
Liver Disease:
 Monitoring of liver enzymes is recommended in patients with liver failure or alcoholism, as
rifampicin, isoniazid, and pyrazinamide can be hepatotoxic.
 Transient increases in transaminases at the start of treatment are common and usually do
not require treatment discontinuation unless accompanied by jaundice or hepatitis.
 Treatment can usually be resumed when transaminases return to pre-treatment levels.
Immunocompromised Patients:
 Immunocompromised patients, including those with HIV infection, should generally be
treated with normal first-line agents unless multidrug-resistant TB is suspected.
 These patients may have a higher risk of relapse and may require longer treatment duration
than the standard 6 months.
TB and HIV Co-infection:
 TB/HIV co-infected patients should be managed by a multidisciplinary team.
 When initiating highly active antiretroviral therapy (HAART) in patients on anti-TB therapy,
antiretrovirals should be chosen to avoid interactions with TB drugs.
 Modification of TB treatment should only be done if drug interactions with antivirals prevent
the optimal TB treatment regimen.
 Chemo-preventive therapy for TB is not recommended in HIV-infected patients, but the
detection and treatment of latent TB infection are important.
Drug-Resistant TB:
 Drug-resistant TB is a global problem, but the proportion of drug-resistant TB isolates in the
UK is relatively low.
 Individualized treatment regimens involving multiple reserve drugs are required for drug-
resistant TB.
 Treatment of drug-resistant TB should be carried out by experienced physicians in hospitals
with appropriate isolation facilities and in close conjunction with specialist centers.
Monitoring Treatment:
 Sputum examination and culture are the most sensitive markers of treatment success in
pulmonary TB.
 Patients taking regimens containing rifampicin and isoniazid should become non-infectious
within 2 weeks.
 Persistent positive cultures may indicate drug resistance or non-adherence, with non-
adherence being more likely.
 Good adherence to treatment is crucial for successful outcomes, but checking adherence
can be challenging, especially when a patient is uncooperative.
Adverse Reactions:
 Major adverse reactions of first-line drugs for TB are summarized in Table 40.5.
 Rifampicin, isoniazid, and pyrazinamide all have the potential for hepatotoxicity, and liver
function should be checked before initiating treatment with these drugs.
 Transient increases in liver enzymes and bilirubin commonly occur at the start of treatment,
but routine monitoring of liver function is not necessary if pre-treatment liver function was
normal.
 Liver function tests should be performed if fever, malaise, vomiting, or jaundice develop,
and all drugs should be stopped.
 Treatment can be recommenced one drug at a time after liver function returns to normal.
 Rifampicin can cause gastrointestinal upsets, fever, rash, and has numerous drug
interactions.
 Hypersensitivity reactions or rashes can occur with any of the drugs, with rifampicin
causing a rare but severe reaction.
 Isoniazid can cause fever, skin rashes, and peripheral neuropathy (more common in certain
patient groups).
 Pyridoxine supplementation (vitamin
B6) is recommended for high-risk
groups taking isoniazid.
 Pyrazinamide can cause hepatitis,
especially in patients with pre-
existing hepatic dysfunction.
 Ethambutol's most important side
effect is ocular toxicity (optic neuritis),
which can lead to vision impairment
or permanent damage.
 Ophthalmological assessment should
be performed before treatment and
monitored during therapy, especially
in patients with pre-existing ocular
problems.
 In children older than 5 years, a safe dose of ethambutol is 15mg/kg, and baseline and
follow-up ophthalmological assessments are recommended.
Chemoprophylaxis:

Chemoprophylaxis is crucial in preventing individuals with latent tuberculosis infection (LTBI) from
progressing to active TB disease.
Without chemoprophylaxis, a significant proportion of individuals with LTBI are at risk of developing
active TB disease.
In infants, approximately 40-50% of those with LTBI will develop active TB disease within 1-2 years
without prophylaxis.
In older children, about 15% of those with LTBI will develop active TB disease within 1-2 years
without prophylaxis.
Prophylaxis for LTBI typically involves the use of isoniazid alone for a duration of 6 months.
Alternatively, a combination of rifampicin and isoniazid can be used for a shorter duration of 3
months.
Detailed guidelines regarding the choice of isoniazid or rifampicin and isoniazid for
chemoprophylaxis are provided by the National Institute for Health and Clinical Excellence (NICE) in
their 2006 guidelines

Patient Care:
1. Importance of Adherence:
 Adequate treatment regimens and patient adherence are essential for curing TB infection or
disease.
 Non-adherence is the leading cause of treatment failure and can result in disease relapse
and the development of drug-resistant organisms.
 Non-adherent patients with infectious TB pose a risk to public health.
2. Factors Affecting Adherence:
 Studies indicate that adherence decreases as the number of tablets per day increases,
especially if doses need to be taken frequently.
 Patients may fail to adhere if they start feeling better and underestimate the importance of
continuing medication.
 Conflicting advice from different healthcare professionals and lack of clear instructions can
compromise adherence.
 Adverse effects or perceived adverse effects may also impact adherence.
3. Strategies to Improve Adherence:
 Prescribe anti-TB therapy once daily with as few tablets as possible.
 Single daily dosing allows patients to incorporate medication into their daily routine.
 Rifampicin and isoniazid should be taken on an empty stomach, preferably 1 hour before
food, to ensure optimal absorption.
 Cueing tablet taking to a regular activity can help improve adherence for some patients.
 Combination preparations that reduce the number of tablets per day may be used, but their
suitability in children may differ from adult regimens.
4. Formulation:
 Except for streptomycin, first-line TB drugs are usually administered orally.
 Liquid formulations of rifampicin are available for patients unable to take tablets or
capsules.
 In severely ill patients unable to take oral medication, rifampicin may be given
intravenously, and isoniazid can be administered via intravenous or intramuscular routes.
5. Information for Patients:
 Provide written instructions and patient information leaflets (PILs) in addition to verbal
counseling to ensure patient understanding.
 Emphasize that TB can be cured but requires months of treatment, and patients should
adhere to the prescribed medication even if they start feeling better.
 Educate patients about potential adverse effects, distinguishing between harmless side
effects and those requiring healthcare professional intervention.
 For patients with limited English proficiency, resources in other languages can be accessed
from organizations such as TB Alert.
6. Non-Licensed Drugs:
 In some cases, drugs not licensed for use in the UK but licensed abroad may be prescribed
for TB.
 Patients receiving these medications require specific counseling and appropriate patient
information to understand the unique circumstances surrounding their use.
7. Directly Observed Therapy (DOT):
 DOT, where a healthcare professional observes the patient taking medication, is not
required for most cases of active TB.
 Risk assessment for treatment adherence should be conducted for all patients, and DOT
regimens considered for individuals with a history of non-adherence or specific
circumstances (e.g., homelessness, alcoholism).
 Intermittent DOT regimens have shown comparable effectiveness to daily regimens, with
specific drug doses adjusted accordingly.
8. Counselling Points:
 Patients should be provided with a PIL for the medication they are taking and advised to
read it.
 Rifampicin users should be informed about harmless discoloration of urine, sweat, tears
(important for soft contact lens users), and the reduced effectiveness of hormonal
contraceptives during and after rifampicin treatment.
 Ethambutol users should be warned about potential ocular side effects and advised to
discontinue the drug and consult a doctor if any changes in vision occur.