20. Tuberculosis

Key information

Mode of transmission

Inhalation of airborne droplets produced by people with pulmonary or laryngeal tuberculosis (TB).

People with latent TB infection and non-pulmonary TB disease are not infectious.

Incubation period

Between 2 and 10 weeks from infection to primary lesion or significant tuberculin skin test (Mantoux) reaction.

Period of communicability

May be years with untreated pulmonary TB.

See the Guidelines for Tuberculosis Control in New Zealand 2019 (or current edition) – see section 20.5.3.

Burden of disease

Disseminated and meningeal TB are more common in very young children.

The immunocompromised individuals, particularly HIV-infected, are more at risk of disease and complications.

In New Zealand, TB incidence is highest in those born in high prevalence countries.

Funded vaccine

Bacillus Calmette-Guérin (BCG) Vaccine SSI.

Dose, presentation and route

Vaccine can only be administered intradermally by an authorised vaccinator with BCG endorsement.

Live attenuated vaccine, which must be reconstituted.

Funded vaccine indications and recommended schedule

Neonatal BCG vaccine should be offered to infants at increased risk of TB, as defined in section 20.5.2.

(See Appendix 8 for a list of countries with a TB rate ≥40 per 100,000.)

Contraindications

Individuals with primary or secondary immunocompromise, including:

  • receiving immunosuppressive treatment
  • malignant conditions of the reticulo-endothelial system (eg, lymphoma, leukaemia)
  • HIV-positive or potentially HIV-positive individuals
  • infants of mothers who received biologic immunosuppressive agents during pregnancy
  • other individuals in whom immunocompromise is known or suspected (see section 20.6.1).

Individuals with generalised infected skin conditions.

Potential responses

A local reaction develops in 90–95% of those vaccinated with BCG, which may scar within 3 months.

A minor degree of adenitis is normal, not a complication.

Suppurative adenitis may take months to resolve; usually no treatment is required.

Public health measures

All cases of active TB must be notified to the local medical officer of health.

20.1. Bacteriology

Human TB is caused by infection with Mycobacterium tuberculosis or Mycobacterium bovis.

20.2. Clinical features

M. tuberculosis or M. bovis infection most commonly causes disease in the lungs, but any part of the body can be affected.

The initial infection with M. tuberculosis usually goes unnoticed. Early infections can be cleared, progress rapidly to primary TB, or be contained in a latent phase (LTBI): see Figure 20.1.

Primary TB occurs most commonly in young children aged under 5 years, individuals with immunocompromise and those infected by particularly transmissible isolates of TB.

Latent TB infection has no symptoms and is diagnosed by a positive tuberculin skin test or interferon gamma release assay after the exclusion of active TB. Latent infection progressing to active TB is also called reactivation TB.

The lifetime risk for infected people progressing from this latent phase to active TB disease may be as high as 20 percent, but this risk is strongly affected by infecting dose, the age of the person, the presence of healed lesions on chest X-ray and immunocompromise.[12]

The time from infection to clinical manifestations of primary TB varies, from one to six months after infection. Reactivation TB can occur at any time thereafter, even decades after infection. The most common site of infection is the lung (pulmonary TB), where TB infection classically causes an asymmetrical pulmonary infiltrate. The ‘classic’ TB pathology of caseation, cavity formation and fibrosis occurs late and in a minority of cases. Young children with active TB disease may be asymptomatic or present with symptoms of fever, lassitude and failure to thrive. Older children and adults with active TB disease may present with symptoms of anorexia, fatigue, weight loss, chills, night sweats, cough, haemoptysis and chest pain.

Any organ can be affected by extrapulmonary TB, causing meningitis, pleurisy, pericarditis, bone or joint infection, renal infection, gastrointestinal tract infection, peritonitis or lymphadenitis, or disseminating via the bloodstream and affecting multiple organs (disseminated TB). Disseminated and meningeal TB are more common in very young children. Immunocompromise, like HIV, is associated with higher rates of disseminated TB and less specific clinical features.[3]

Figure 20.1: Stages in the natural history of tuberculosis

This charge shows the stages of tuberculosis. It begins with M. tuberculosis inhaled. This branches into either immediate killing (TST/IGRA negative) or primary complex (TST/IGRA positive). If so, it is either primary TB or latent TB infection (TST/IGRA Positive), which leads to reactivation TB.

Key: TST = tuberculin skin test; IGRA = interferon gamma release assay; TB = tuberculosis.

20.3. Epidemiology

20.3.1. Global epidemiology

Worldwide, the incidence rate of TB is slowly falling by about 1.5 percent per year, but TB remains a major global health problem. Much of the TB burden exists in 30 high-burden countries, spread mainly in poor, crowded and poorly ventilated settings. Globally, as of 2018, an estimated 1.7 billion people are infected with M. tuberculosis of which 5–15 percent will develop active TB during their lifetime.[4] WHO estimates there were 10.4 million new TB cases in 2016 and TB remained the top cause of infectious disease mortality with 1.7 million deaths.[4] Of those cases, an estimated 1.9 million cases were linked to undernourishment and 1 million to HIV, 0.8 million to smoking and 0.8 million to diabetes. There has been an increasing burden of multidrug-resistant TB (defined as resistance to at least isoniazid and rifampicin) with an estimated 600,000 new cases of multidrug-resistant TB in 2016.[4]

In low-burden countries, such as New Zealand, the peak age for TB is in older adults, reflecting their exposure to TB in the past when incidence was higher. In high-burden countries TB is most common in children and young adults. The risk of TB in people who emigrate from high-burden countries is proportionate to the incidence in their country of origin.[5]

20.3.2. New Zealand epidemiology

For detailed TB information, see the Tuberculosis in New Zealand: Annual Report.

Notification rates and risk factors

TB remains one of the most common notifiable infectious diseases in New Zealand. Cases of TB declined substantially between 1980 and 2007, but they have remained relatively stable since then.[6]

In 2019, there were 323 notifications for TB (notification rate of 6.6 per 100,000; ESR, 8 June 2020 at a similar rate to 2018 (6.4 per 100,00).[67] Notification rates were highest in those aged 20–29 years (12.2 per 100,000) and 30–39 years (10.6 per 100,000), with slightly higher rates in males than females.

Asian ethnic groups had the highest notification rate in 2019 (35.7 per 100,000, 206 cases), followed by Middle Eastern/Latin American/African (30.7 per 100,000, 17 cases) and Pacific peoples (15.5 per 100,000, 49 cases). Of the 306 new TB cases with risk factors recorded in 2019, 251 were born overseas (ESR, 8 June 2020). The highest disease rate was among those born in Southern and Central Asia (129 per 100,000), followed by those born in South-East Asia (57 per 100,000), the Pacific Islands (23 per 100,000). The most reported country of birth in SE Asia was Philippines (64 percent).

The notification rate was considerably lower for Māori (3.8 per 100,000, 29 cases) and European/Other (0.6 per 100,000, 20 cases) groups (ESR, 8 June 2020). There is substantial regional variation in TB notification rates: the highest rates are in the Auckland and Wellington regions; this is associated with immigration.

Of the 81 percent of cases in 2019 with date of arrival recorded, the median interval between arrival and the TB notification ranged from 0 to 65 years (mean 8 years and median 5 years) (ESR, 8 June 2020).

One child under 5 years of age was notified with TB in 2019 (ESR, 8 June 2020). The child was born in New Zealand and not vaccinated.

Multidrug-resistant TB

Multidrug-resistant TB is rare but does occur in New Zealand. Over 10 years (2009–2018), a total of 36 cases were multidrug resistant (annual average rate of 2 percent).[7] All these cases were born and assumed to have acquired the infection overseas; 83 percent were born in an Asian country.

20.4. Vaccine

Note: Depending on world supply, BCG vaccine may not be available in New Zealand.

BCG vaccine types vary widely, with different strains. The incidence of side-effects with BCG vaccination differs between strains that are considered more reactogenic (ie, those that elicit stronger immune responses in animal models) and strains that are considered less reactogenic.[8] The more reactogenic strains have also been associated with a higher rate of lymphadenitis and osteitis, especially among neonates. Reducing the vaccination dosage for the more reactogenic strains also reduces the incidence of lymphadenitis.

20.4.1. Licensed vaccine

BCG Vaccine SSI (Seqirus (NZ) Ltd) is a live attenuated vaccine, containing the less reactogenic Danish 1331 strain of M. bovis. The 0.1 mL dose for adults and children aged 12 months and older contains 2–8 × 105 colony-forming units of M. bovis, and the 0.05 mL dose for infants contains 1–4 × 105 colony-forming units. Other components and residuals include sodium glutamate, magnesium sulphate heptahydrate, dipotassium phosphate, citric acid, L‑asparagine monohydrate, ferric ammonium citrate and glycerol.

20.4.2. Efficacy and effectiveness

The exact immune response elicited by BCG vaccination and the mechanism of action in the host are still not well understood. There is no reliable established laboratory correlate for immunity to M. tuberculosis,[9] though this remains an active area of study.[10]

BCG protection is partial and varies according to the age at which vaccination is administered and the disease phenotype in question. A meta-analysis of randomised controlled trials showed neonatal BCG had 59 percent efficacy against pulmonary TB (95% CI: 0.42–0.71) and 90 percent efficacy against meningeal TB (95% CI: 0.23–0.99).[11] Studies conducted since the advent of interferon gamma release assays suggest BCG may also be effective against M. tuberculosis infection. A meta-analysis has estimated BCG effectiveness against M. tuberculosis infection at 20 percent, though different methods in the included studies each had a wide range of estimates.[12] Thus, the principal role of BCG in New Zealand is to protect young children who are at greatest risk of disease, particularly miliary and meningeal disease.[8] BCG is less effective in adults and older children, particularly if they already have latent infection.

As BCG has been propagated in vitro for over 40 years, there are now several strains being manufactured.[13] Immunological responses vary considerably across vaccine strains, but the data to date cannot differentiate which strains, if any, are overall more effective.[1415]

In low-income countries, a birth dose of BCG significantly reduces overall infant mortality.[1617]

BCG has had little effect in reducing the population rate and transmission of TB,[18] so there are no herd immunity effects. Duration of protection is unknown, possibly 10 to 15 years, but it may be much longer in some populations.[8]

There have been a number of different approaches to using BCG in the control of TB in middle- and high-income countries.[19] For example, the US has not had a BCG programme, whereas New Zealand (see Appendix 1) and the UK had programmes until 1990 and 2005, respectively. The WHO recommends that countries with low rates of active TB, such as New Zealand, target BCG vaccination at children who are at significantly increased risk of TB exposure through household contact.[4] New Zealand (see section 20.5) and the UK now only offer BCG vaccine to high-risk individuals. A study from the Netherlands suggests that around 9,000 children from countries with rates greater than 50 per 100,000 population would have to be given BCG to prevent a severe case.[20]

The current recommendation to use neonatal BCG vaccination in populations with high rates of active TB is part of a control and treatment programme for TB in New Zealand, which includes active contact tracing and treatment of latent TB infection.

There are large international efforts working to improve BCG vaccines and develop new, more effective vaccines.[21]

20.4.3. Transport, storage and handling

Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store in the dark at +2°C to +8°C. Do not freeze.

There are variances in strain potency between brands of BCG vaccine so vaccinators should always follow the instructions in the vaccine data sheet (available on the Medsafe website).

BCG vaccine requires reconstitution before administration. It is presented as freeze-dried vaccine in a multi-dose vial with diluent in a separate vial. The diluent must be added to the freeze-dried vaccine vial and mixed gently (do not shake vigorously). Protect the vial from light. Leave the reconstituted vaccine to stand for one minute until it forms an opalescent liquid. Reconstituted vaccine should be stored at 4°C, protected from sunlight and used within four hours.

20.4.4. Dosage and administration

Only authorised vaccinators with BCG endorsement can administer BCG vaccine (see Appendix 4).

Administer a dose of:

  • 0.05 mL to infants aged under 12 months
  • 0.1 mL to children aged 12 months or older and adults.

The vaccine is administered by intradermal injection over the point of insertion of the left deltoid muscle (see sections 2.2.3 and 2.2.4).

No follow-up tuberculin skin testing is required.

Repeat BCG vaccination is not recommended.

BCG immunisation given in other countries

BCG is one of the vaccines that are part of the WHO Expanded Programme on Immunization. It is given at birth in most low-income countries.

The following Pacific Island countries[22] recommend BCG vaccination at birth: Cook Islands, Fiji, Kiribati, Nauru, Niue, Papua New Guinea, Samoa, Solomon Islands, Tonga, Tuvalu and Vanuatu.

Usually BCG vaccine is administered in the left deltoid area, but other sites of administration have also (although uncommonly) been used, such as the right deltoid. Revaccination with BCG is not recommended by the WHO.[4]

Co-administration with other vaccines

BCG can be given simultaneously with any other vaccine. However, it must be administered into a separate site in a separate syringe. Because of the risk of local lymphadenitis, no further vaccinations should be given into the arm used for BCG for at least three months. If not given concurrently, BCG should be given at least four weeks after MMR or VV. Note that no time interval is required between administration of BCG and rotavirus vaccines.

HBIG (given at birth to babies of mothers with chronic HBV infection) or human normal immunoglobulin is thought not to reduce the effectiveness of BCG immunisation, which principally acts through cell‑mediated immunity.

20.5. Recommended immunisation schedule

20.5.1. Tuberculin skin testing (Mantoux) before BCG vaccination

Tuberculin skin testing is not needed if BCG is given before age 6 months unless a history of contact with a known or possible case of TB is obtained. Although the tuberculin skin test is usually positive in the year following BCG vaccination, at least 50 percent of children will be negative beyond that time, so tuberculin skin testing still has utility for diagnosing TB infection.

Children who have missed vaccination at birth may be vaccinated at any time up to age 5 years. If the child is 6 months or older, they should have a pre-vaccination tuberculin skin test to detect whether they have already been infected: vaccination only to being given if the child is uninfected.

20.5.2. BCG eligibility criteria

TB is more common in migrants or families of migrants from high-incidence countries. However, all pregnant women should have a discussion with their lead maternity carer about the risk of TB for their baby.

Neonatal BCG is recommended and funded for infants at increased risk of TB, as defined in Table 20.1.

Table 20.1: Neonatal BCG eligibility criteria

Neonatal BCG is recommended and funded for infants at increased risk of TB, defined as those who:

  • will be living in a house or family/whānau with a person with either current TB or a history of TB
  • have one or both parents or household members or carers who within the last five years lived for a period of six months or longer in countries with a TB rate ≥40 per 100,000*
  • during their first five years will be living for three months or longer in a country with a TB rate ≥40 per 100,000.*

* A list of high-incidence countries and their TB rates is available in Appendix 8.

As a general indication, the following global areas have TB rates ≥40 per 100,000:

  • most of Africa
  • much of South America
  • Russia and the former Soviet states
  • the Indian subcontinent
  • China (including Hong Kong) and Taiwan
  • South-East Asia
  • some parts of the Pacific (Kiribati and Papua New Guinea have consistently high rates; see Appendix 8 for a list of the high-incidence countries).

Neonates at risk should be identified antenatally by lead maternity care providers and antenatal referral made to the neonatal BCG service. Health care providers can also identify and refer neonates at risk. Immunisation is desirable before infants leave hospital. If this does not happen, immunisation should be arranged through the local medical officer of health.

Infants born before 34 weeks’ gestation should have their BCG vaccination delayed until 34 weeks’ post-conceptual age.[23] Babies born after this or with low birthweight appear to produce an adequate response, based on tuberculin skin test responses.[242526]

If the baby has not been vaccinated before leaving hospital, and if there is a history of current TB in a relative who has had contact with the baby, do not vaccinate immediately. Withhold vaccination, conduct tuberculin skin testing, seek paediatric advice and vaccinate only after the possibility of infection in the baby has been excluded. Vaccination may not protect the baby who is incubating disease and may prevent the tuberculin test from assisting with the diagnosis of disease.

A parent’s/guardian’s request should not be accepted as an indication for immunisation. Parents/guardians seeking vaccination of children who do not meet the above criteria should be referred to the local medical officer of health to discuss the risks and benefits of immunisation before a final decision is made.

BCG vaccine information for parents

Information about the BCG vaccine is available in English and other languages from the HealthEd website. This includes information for parents on why the vaccine is recommended, what to expect and how to care for the vaccination site.

20.5.3. Other high-risk individuals or groups

Repeat BCG vaccination is not recommended.

Funded BCG may be offered to the following at-risk people if they are tuberculin skin test- or interferon gamma-release assay negative:

  • contacts of active TB cases aged under 5 years (note that a contact exposed to TB in the preceding three months will need two negative tuberculin skin tests, 8–12 weeks apart, before vaccination)
  • immigrants aged under 5 years from countries with a rate ≥40 per 100,000
  • health care workers and laboratory staff, depending on their risk of exposure
  • people exposed to animals that are likely to be infected.

Refer to the Guidelines for Tuberculosis Control in New Zealand 2019[27]).

Vaccination for overseas travel is not available in New Zealand.

20.5.4. Pregnancy and breastfeeding

BCG vaccine is not routinely recommended for pregnant or breastfeeding women.

As BCG is a live vaccine, its use in pregnancy is not recommended (see section 20.6.2). If indicated, BCG vaccine may be given to breastfeeding women.[28]

20.6. Contraindications and precautions

See also section 2.1.3 for pre-vaccination screening guidelines and section 2.1.4 for general contraindications for all vaccines.

20.6.1. Contraindications

BCG vaccine should not be given to individuals:

  • known to be hypersensitive to any component of the vaccine
  • receiving corticosteroids or other immunosuppressive treatment, including radiotherapy (see section 4.3)
  • suffering from malignant conditions such as lymphoma, leukaemia, Hodgkin’s disease or other tumours of the reticulo-endothelial system
  • in whom immunocompromise is known or suspected, such as individuals with hypogammaglobulinaemia – primary immune deficiencies in children are often not detected until after the first few weeks of life (ie, after BCG vaccine is given), so a family history of immune deficiency should be sought and, if present, discussed with a paediatrician before vaccination
  • known to be infected with HIV, including neonates where the mother’s HIV status is unknown – maternal HIV infection should be excluded prior to neonatal vaccination; testing should have been offered as part of the National Antenatal HIV Screening Programme, and infants born to HIV-infected mothers should be under the care of a paediatrician
  • with generalised infected skin conditions.

Infants born to mothers who received immunosuppressive biologic agents during pregnancy must not be vaccinated with a BCG vaccine until they are identified as being immunocompetent. See section 4.3.7 and Table 4.2 for a list of the highly immunosuppressive medications with long half-lives that require a prolonged delay before vaccination (for up to one year in those being treated). These include monoclonal antibody (mab) agents that readily cross the placenta. Each case should be assessed with specialist advice.

20.6.2. Precautions

  • BCG vaccine should be avoided in those who are pregnant (this is a counsel of caution, as no harmful effects to the fetus have been observed following accidental immunisation of the mother during pregnancy).
  • In the case of eczema, an immunisation site should be chosen that is free of skin lesions.
  • Infants born before 34 weeks’ gestation should have their BCG vaccination delayed until 34 weeks’ post-conceptual age.[23]
  • Avoid or defer immunisation in a child born with a condition that may require immunosuppressive therapy in future.

20.7. Potential responses and AEFIs

20.7.1. Potential responses

Following the BCG injection, a white weal should appear. This should subside in approximately 30 minutes. The site requires no swabbing or dressing.

A local reaction develops in 90–95 percent of people vaccinated with BCG, which may include shallow ulceration, followed by healing and scar formation within three months. To ensure appropriate healing, encourage parents/caregivers to keep the injection site clean and dry, to allow sore to scab and to avoid ointments and scratching. A minor degree of adenitis developing in the weeks following immunisation should be regarded as normal, not a complication. It may take months to resolve. Suppurative adenitis may also take months to resolve; usually no treatment is required.

20.7.2. AEFIs

AEFIs with BCG vary with age and vaccine strain and are summarised in Table 20.2.

Table 20.2: Age-specific estimated risks for complications after administration of BCG vaccine

Complication

Incidence per 1 million vaccinations

Age <1 year

Age 1–20 years

Local subcutaneous abscess; regional lymphadenopathy

387

25

Musculoskeletal lesions

0.39–0.89

0.06

Multiple lymphadenitis; non-fatal disseminated lesions

0.31–0.39

0.36

Fatal disseminated lesions

0.19–1.56

0.06–0.72

Reprinted with permission of the International Union Against Tuberculosis and Lung Disease. Copyright © The Union. Lotte A, Wasz-Hockert O, Poisson N, et al. 1988. Second IUATLD study on complications induced by intradermal BCG-vaccination. Bulletin of the International Union against Tuberculosis and Lung Disease 63: 47–59.

The risk of BCG adverse reactions depends on many factors, including strain type, route of administration and the underlying immune state of the patient. Severe injection-site reactions, large ulcers and abscesses can occur in individuals who are tuberculin positive. Special care is needed both in interpreting initial tuberculin skin results and in delivering the BCG vaccine.

Rarely, osteitis and osteomyelitis, lupoid and other types of skin disorders, and neurological disorders have been reported following BCG vaccination. Although rare, disseminated BCG disease is the most severe BCG vaccine complication occurring in immunocompromised people, such as children with primary immune deficiency. This needs rapid and aggressive treatment and has a high mortality.

Keloid scars at the injection-site, although not uncommon, are largely avoidable. Some sites are more prone to keloid formation than others and vaccinators should adhere to the site recommended (mid-upper arm). Most experience has been with the upper arm site, and it is known that the risk of keloid formation increases greatly if the injection is given higher than the insertion of the deltoid muscle into the humerus.

Every effort should be made to recover and identify the causative organism from any lesions that constitute a serious complication.

Most local and regional adenopathy resulting from BCG vaccination will resolve spontaneously, and there is rarely a need for medical or surgical intervention. Treatment recommendations for local abscess formation and suppurative lymphadenitis remain controversial.[29] If suppurative adenitis reactions persist for longer than three months, seek specialist opinion. However, anyone presenting with more widespread or distant disease needs referral to a specialist.

Abscesses and more serious complications should be reported to CARM (see ‘AEFI reporting process – notifying CARM’ in section 1.6.3), and also reported to the local medical officer of health in the interests of quality control of the BCG vaccination technique.

20.8. Public health measures

It is a legal requirement that all cases of active TB be notified to the local medical officer of health. While there is no legal requirement to notify cases of latent TB infection that are being treated, for surveillance purposes and with the patient’s consent they should be reported to the local medical officer of health.

Under the Health (Protection) Amendment Act 2016, the medical officer of health is given wide powers to investigate and control all TB cases and their contacts, while DHBs are required to make provision for the treatment and supervision of patients and their contacts.

The primary purpose of neonatal BCG vaccination is to protect child case contacts from TB disease and its most devastating consequences. Screening of certain risk groups and case contact management are other elements of TB control in New Zealand. These programmes do not obviate the need for BCG vaccination, as screening coverage is partial and contact tracing may not occur in time to prevent illness in child contacts. The local medical officer of health can advise on local TB control policies, including issues in BCG immunisation.

Both TB infection and BCG immunisation lead to the development of a cellular immune response, which can be detected by measuring dermal induration after the injection of tuberculin-purified protein derivative (eg, via the tuberculin skin test). A positive response to a tuberculin skin test may be an indication of current infection, previous natural infection or prior BCG immunisation. However, the false positive effect after vaccination will wane, rapidly in all individuals who receive the vaccine in the neonatal period and more slowly in those who are vaccinated at an older age such as during the primary-school years.[30]

In vitro tests have been developed to measure the release of interferon-gamma from host lymphocytes in response to well-defined antigens. The antigens used are not present in BCG strains of M. bovis or most non‑tuberculous mycobacteria. Interferon gamma release assay has the advantage of greater specificity and convenience, but it is more expensive.[31]

For more information, refer to the ‘Tuberculosis’ page of the Ministry of Health website and the ‘Tuberculosis’ chapter of the Communicable Disease Control Manual.

20.9. Variations from the vaccine data sheet

The data sheet states that BCG vaccine should not be given to infants born to HIV‑positive mothers. The Ministry of Health recommends that BCG may be given to HIV‑negative infants born to HIV-positive mothers – providing that the infant is confirmed to be HIV negative by appropriately-timed PCR tests before the vaccine is given.[2832] Seek specialist advice.

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