Tuberculosis

1. Causative Organism
2. Clinical Signs Symptoms and Complications
3. Method of Transmission
4. Public Health Significance
5. Prevention - Non Immunisation Methods
6. Prevention - Immunisation
7. Vaccine/s and Vaccination
8. Efficacy and Effectiveness
9. Availability
10. Dosage and Administration
11. Indications and Recommendations
12. Adverse Events
13. Contraindications
14. Risks vs Benefits

Causative organism

Several different mycobacterial organisms (gram negative, acid-fast bacilli) known as Mycobacterium tuberculosis complex (M.TB complex), which consists mainly of Mycobacterium tuberculosis, M. bovis, and M.africanum. M. tuberculosis is an important pathogen in the Asia-Pacific region. 

Electron micrograph of Mycobacterium tuberculosis. Courtesy of Wadsworth Center, NY, USA

Signs and Symptoms

Most individuals infected with TB remain asymptomatic, but a few develop clinical disease. TB infection can remain latent in the body and develop active disease many years later. Although TB usually attacks the lungs it can affect other areas of the body. Active disease has two main manifestations: pulmonary (lung) and extra pulmonary (sites include meninges, bone and/or joints, kidneys, terminal ileum, caecum, lymph nodes, testicles, ovaries, eyes, pericardium, skin and spleen).

Pulmonary TB 

• Cough
• Haemoptysis
• Fever
• Sweats
• Weight loss
• Shortness of breath

Extra Pulmonary Disease

• Fever, pain, reduced range of motion in affected joints
• Sweats, rigors, weight loss
• Neck stiffness, headache, photophobia, seizures and evidence of cranial neuropathies if tuberculous meningitis is present.
• Lymphadenopathy (either lymphoedema or hardened palpable nodes)
• Pittinoedema at the peripheries
• Peripheral neuropathies
• Evidence of renal failure (e.g. raised urea and creatinine) and / or palpable kidneys
• Splenomegaly
• Cardiac murmurs and conduction defects on ECG in tuberculous pericarditis
• Pain and swelling on palpation of the scrotum in testicular TB
• Palpable ovaries, flank pain, infertility in ovarian TB or tuberculous salpingitis
• Blindness, pain, photophobia, conjunctivitis and iritis in tuberculous eye disease
• Diarrhoea, nausea, vomiting, abdominal cramps, distension, rebound tenderness, inability to pass faeces in ileocaecal TB. There may also be shifting dullness if ascites is present.
• Maculopapular, encrusting and ulcerating lesions in cutaneous TB

Method of Transmission

Transmission is via airborne droplets during episodes of coughing in a patient with active pulmonary TB. Most individuals infected enter the latent stage. Of these, 5-15% develop active TB.

Public Health Significance

• The principal control measures for TB are case finding of active and latent infections, treatment with appropriate medications (directly observed if necessary), contact tracing and selective screening.
• The frequency of TB in certain population groups (South East Asian, Eastern European, Pacific, African) is increasing worldwide, partly in association with the HIV/AIDS epidemic.
• Re-emergence of the disease and an increase in the prevalence of multi-drug resistant strains (MDRTB) led the World Health Organization (WHO) to declare tuberculosis a global emergency in 1995. A large proportion of MDRTB cases are from South East Asia, where adherence to standard anti-tuberculous regimens is lower.

New Zealand Epidemiology

The overall incidence rate of TB in New Zealand is low compared with most countries, but has not declined over the last 20 years. TB is still one of the most common notifiable infectious diseases. Reasons for the persistence of TB as a public health problem in New Zealand are complex and include immigration from countries where there is a high incidence of TB, social conditions favouring transmission, and the fact that identification and prophylaxis for all infected people is not practicable. High rates of TB exist in New Zealand among population groups from Asia, Africa and the Pacific, particularly recent immigrants from these areas.

In 2000 the incidence rates in New Zealand were 1.7 per 100,000 for Europeans, 13.8 for Maori, 36.4 for Pacific, and 91.8 for other ethnic groups.   The proportion of TB cases born in New Zealand was stable at about 40 percent between 1995 and 2000. In 2004 there were 372 (new and reactivated) cases of TB notified, a rate of 10.0 per 100,000. As in previous years, rates were low in Europeans (1.5 per 100,000) and higher in Maori (13.9 per 100,000) and Pacific peoples (32.9 per 100,000). Rates were highest in those of ‘other’ ethnicity, with a rate of 78.1 per 100,000.In 2004 there were 27 cases of tuberculosis reported, a rate of 3.2 per 100,000, in children aged 0–14 years. The age groups with highest rates of disease were females aged 20–29 years (52 cases, or 20.8 per 100,000) and males over 70 years (21 cases, or 15.7 per 100,000), and a high rate was especially seen in Pacifi c males over 70 years. In general the rates of disease increased with age, although in people of ‘other’ ethnicity there was a bimodal peak, with a high rate in those from 20 to 49 years as well as in older people.

Extrapulmonary TB (particularly miliary and meningeal), which is vaccine preventable in children, continues to occur in New Zealand. Pacific, African and Asian children are disproportionately affected. 

(Immunisation Handbook 2006, Ministry of Health.)

Prevention

i)  Non-immunisation related preventions

• Promotion of improved living conditions, improved nutrition and health care.
• HIV/AIDS awareness and prevention/control.
• Early identification and treatment of affected individuals and contact tracing.

ii) Vaccination

• BCG (Bacille Calmette-Guerin) vaccine – (freeze-dried live vaccine prepared from an attenuated strain of M. bovis). When reconstituted with accompanying buffered saline diluent, BCG vaccines contain a concentration of 1 mg BCG/ml. and monosodium glutamate 1.5% w/v.
• In New Zealand, Mantoux testing is done before immunisation to exclude prior infection. It is not needed if BCG is given before the age of three months unless a history of contact with a known or possible case of TB is obtained. Because the Mantoux test is usually positive following BCG vaccination it has lower utility for diagnosing TB infection in a vaccinated individual (Immunisation Handbook 2006, Ministry of Health.)
• More information about vaccine eligibility and high risk groups can be found here.

Efficacy and Effectiveness

• BCG (Bacille Calmette-Guérin) vaccine is a suspension of live attenuated M. bovis.
• BCG vaccination does not prevent transmission of infection to the individual.
• The benefits of BCG in adolescents and adults are controversial.
• Controlled trials demonstrate a wide range of efficacy estimates (ranging from 0 to 90%). This is poorly understood but may be due to differences in vaccine strains, prevalence of (protective) local environmental mycobacteria (which may confer immunity to M.TB complex organisms) and host factors such as age at vaccination (less effective in individuals over 5 years) and nutritional status.
• However, it should be noted that BCG is highly effective in young children under 5 years, particularly in preventing serious extrapulmonary disease in neonates.
  The protective efficacy of BCG for preventing serious forms of TB (including meningeal and disseminated forms of the disease) in children is over 80%, and the overall protective efficacy about 50%.
• BCG has been found to be also highly protective against leprosy.

Availability

There are many BCG vaccines available worldwide and all are derived from the strain propagated by the Institut Pasteur. It was first tested in humans in 1921.

Dosage and Administration

NB: Guidelines in different countries and states vary, so it is recommended that you check the following information against the recommendations for your local area.

BCG vaccine should only be given by specially trained staff, fully conversant with the following recommended procedures:

• Administer BCG Vaccine (Freeze-Dried) intracutaneously (intradermally); do not inject subcutaneously.  A 1 inch, 26G needle should be used with the bevel facing upwards.
• The freeze-dried vaccine is reconstituted to a concentration of 1 mg BCG/mL by introducing the diluent supplied into the vial of vaccine.  Refer to instructions given on the packaging.
• Dosages are as follows: newborns and infants up to 12 months of age - 0.05 mL; children over 12 months of age and adults - 0.1 mL.
• BCG vaccine must not be combined with other vaccines (for example, diphtheria, typhoid fever and tetanus) in the same syringe; however, it may be administered at the same time as other vaccines provided they are injected SEPARATELY and at different sites. 

Typical Response to BCG vaccination

• A small red papule forms and ulcerates within 2 to 3 weeks of vaccination. The ulcer heals with minimal scarring in several weeks. There may be swelling and tenderness in local lymph nodes for several months following immunisation.
• Subjects who are given BCG despite previous tuberculosis infection will experience an accelerated response characterised by induration within 24 to 48 hours, pustule formation in 5 to 7 days and healing within 10 to 15 days.
  

Indications and Recommendations

Indications and recommendations below are given as a guide only. Check your local area recommendations before administering BCG.

Countries with High Endemnicity

BCG immunisation at birth is a commonly recommended for all children in regions where there is a high incidence of TB.

Countries with Low Endemnicity

BCG immunisation may be recommended in targeted programmes in regions where TB cases are rare in the general community.

• Individuals who during their first 5 years of life will be living for 3 months or longer in a high-incidence country*.
• Those with household contacts or parents who, within the last 5 years, have lived in a high-incidence country* for more than 6 months.
• Household contacts (less than 5 years of age) of an individual with either current or a past history of TB.
• Immigrants less than 5 years of age from a high-incidence country*.
• Individuals with severely limited access to healthcare.
• Those exposed to animals that are likely to be infected with M.TB complex organisms. (e.g. infected cattle, ferrets, stoats and rats.)
• Infants, children and adolescents who are repeatedly exposed to persistently untreated or ineffectively treated patients with sputum-positive pulmonary tuberculosis, or such patients in whom isoniazid therapy is contraindicated.
• Some areas recommend BCG immunisation for Health workers at increased risk of repeated exposure, especially those working in institutions serving major urban population centres in which the endemic prevalence of tuberculosis is relatively high.  Check your local health authority for more detailed recommendations. Some countries recommend infant BCG immunisation for individuals of indigenous ethnicity (e.g. Aborigines and Torres Strait Islanders in Australia).  Consult your local health authority for further details.
• BCG Vaccine should be administered to all infants at risk of early exposure to the disease.
• Revaccination is not recommended by the WHO.

* All countries except Australia, Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Holland, Iceland, Ireland, Israel, Italy, Luxembourg, Malta, Monaco, New Zealand, Norway, Sweden, Slovakia, Switzerland, UK and the USA.

NB: tuberculin skin test

The skin test is used to detect latent infection in contacts of patients with TB and other potentially infected individuals, as an aid to the diagnosis of TB, and to check suitability of vaccination with BCG. Hypersensitivity (induration greater than 10mm) to tuberculin Purified Protein Derivative (PPD) follows either natural infection, with either M. tuberculosis or other mycobacteria that induce cross-reactivity, or BCG vaccination. It is not needed if BCG is given before the age of 3 months unless a history of contact with a known or possible case of TB is found.  Because the skin test is usually positive following BCG immunisation its utility in diagnosing TB in a vaccinated individual is reduced. Most tuberculin testing is performed using the Mantoux technique. The PPD preparation for this test is usually supplied in multidose vials containing either 100 or 1000 units/mL. For routine testing, 0.1 mL of PPD at 100 units/mL (ie. 10 units) is injected intradermally into the skin of the upper third of the flexor surface of the forearm, producing an “orange peel” bleb 7 to 10 mm in diameter.

The reaction is examined 48 to 72 hours later, and the diameter of the palpably indurated skin is measured and recorded. Less than 5mm induration is considered a negative test, and greater than 10mm induration a positive test. In certain circumstances, 2-stage skin testing may be required. It is used to detect individuals previously infected or vaccinated with BCG who may test negative to tuberculin testing initially, but who show a strong reaction to tuberculin if the same procedure is repeated one to two weeks later. The 2-stage test is important to establish the baseline reaction when future tuberculin testing is required as part of contact tracing or monitoring of high-risk groups. Contact your local health authority tuberculosis service for detailed advice.

Erythema without induration should be disregarded. Strongly positive reactions may be accompanied by skin necrosis, lymphangitis and regional adenitis. Patients with a history of such reactions should have their dose reduced to 1 unit or not be tested. The reaction to PPD may be suppressed by viral infections, live vaccines (especially MMR and Varicella, but not OPV, oral typhoid or oral cholera vaccines), recent surgery, sarcoidosis, immunosuppressant drugs and immunosuppressing illnesses such as Hodgkin’s disease, lymphoma and HIV infection. The reaction also wanes with increasing age. Most adults vaccinated with BCG in childhood have negative tuberculin reactions. Individuals over 12 weeks of age with a positive PPD reaction should not receive BCG. There is no correlation between post-BCG PPD and vaccine effectiveness.

Contraindications

NB: Guidelines may vary among industrialised nations and developing countries reflective of the different resources and capabilities within health services.

• Individuals suffering from generalised skin disease or conditions such as measles, eczema, furunculosis, atopic dermatitis or other exudative or inflammatory dermatologic conditions.
• BCG should not be given within 4 weeks of a dose of a live attenuated vaccine (although such a vaccine may be given concurrently with BCG at a separate site).
• Individuals with known natural or acquired immunodeficiency conditions or cell-mediated immune deficiency.
• Individuals receiving immunosuppressant therapy.
• A positive PPD reaction (although pre-vaccination testing is not carried out routinely).
• Keloid and lupoid reactions may occur at the site of injection and such children should not be revaccinated.
• Significant fever.
• Pregnancy (except in exceptional circumstances – see note below).

Guidelines for Human Immunodeficiency Virus (HIV) Infected Persons

National health authorities should balance the risk from the vaccine against the risk from the disease according to their regional incidence of TB. The risk from the vaccine is extremely low in comparison to the risk from the disease in most developing countries, and therefore BCG immunisation may be appropriate for persons infected with HIV in these countries. 

• HIV infected, non-symptomatic persons should be immunised with BCG Vaccine according to standard schedules.
• Persons with clinical (symptomatic) AIDS should not receive BCG Vaccine.
• BCG Vaccination has NO value in the treatment of tuberculosis.

Use in Pregnancy:
Vaccination of women during pregnancy is not recommended unless there is an excessive risk of unavoidable exposure to infective tuberculosis. No harmful effects of BCG on the fetus have been observed.

Adverse Events

• Almost all vaccinees develop an ulcerating papule at the injection site, which develops into a keloid scar.  In some cases an abscess may appear at the site of injection. Spontaneous resortion usually occurs. In a few instances the abscess will soften and may spontaneously ulcerate (especially in children); this usually leaves a superficial scar 2-10 mm in diameter.
• Inadvertent subcutaneous injection produces abscess formation and may lead to ugly retracted scars. Do not administer subcutaneously.
  Enlargement of the regional lymph glands may occasionally develop after vaccination (25-387 per million doses). Spontaneous regression usually occurs after a period of several months. Surgical drainage is not recommended.  Anti-tuberculous therapy should be administered.
• Muskuloskeletal lesions and/or disseminated BCG disease with multiple lymphadenitis rarely develops (0.06 to 0.89 per million doses). Administer anti-tuberculous therapy.
• Fatal disseminated BCG occurs at a rate of 0.02-1.56 per million.
  

Risks vs Benefits

DISEASE	EFFECTS OF DISEASE	SIDE EFFECTS OF VACCINE
TB (Tuberculosis) - Mycobacterium tuberculosis complex, a slow growing, aerobic, acid-fast bacillus	·       Causes chronic lung disease but can affect any part of body (40% chance of children in developing countries developing active infection). ·         Disseminated (miliary TB) and meningeal TB are the most serious forms, particularly in children (2-5% of all active TB cases) ·         Rates of TB can be high among indigenous populations.	Adverse events in 5% of vaccinees ·         injection site abscesses - 2.5% ·         lymphadenitis  - 1% ·         anaphylactic reactions, musculoskeletal lesions, disseminated BCG rarely reported (<0.000001%) ·         keloid formation on scar can occur