Childhood Tuberculosis

See also Tuberculosis.

• Tuberculosis (TB) is the most common worldwide cause of infection-related death.¹
• Although perhaps surprising to those in developed countries, TB is a major health problem in particularly the poor population of developing countries.
• TB is a notifiable disease in the United Kingdom (UK) but even in the UK and United States (US) the incidence may be underestimated.^2,3
• Children, because of greater representation in the population of developing countries, are especially at risk of infection and at increased risk of dying once infected.
• TB has been considered by the WHO to be a global public health emergency since 1993.¹
• Disease in children is nearly always a primary infection usually contracted from another adult.
• The clinical course of TB is significantly different in children as compared with adults. The age of the child and his or her immune status are important factors affecting clinical course. For example:
  • Where infection occurs at age <4 years the chances of clinical disease with X-ray changes are very high.
  • With infection occurring in older children the patient often develops a more severe form of adult-type primary disease either immediately or years later.

• Mycobacterium tuberculosis is the most common cause, but other rarer causes include M. bovis and M. africanum. These are aerobic, non-spore bearing, rod shaped bacilli. They are slow-growing and hardy (able to survive in adverse environmental conditions).
• Humans are the only known reservoirs of M. tuberculosis infection.
• Infection is spread by aerosol distribution from infected individuals. Pathogenicity is largely determined by the ability to overcome host defences and several virulence factors have been identified.
• Primary infection of the respiratory tract results from this aerosol inhalation. The bacteria are deposited in largest numbers usually in the alveoli or distal bronchioles. Alveolar macrophages are initially unable to destroy the bacterium and they multiply. Subsequently infected macrophages are transported to regional lymph nodes and beyond (kidney, bones, meninges, apical posterior areas of the lung). A cell-mediated immune response terminates growth of M. tuberculosis some 2 to 3 weeks after first infection. CD8 suppressor T cells destroy the infected macrophages causing caseating granulomas to form. Hence the site of first infection usually heals with caseation and encapsulation but can continue to grow and cause symptoms.
• The initial site of infection and adjacent nodes is the primary complex (or Ghon focus). These can sometimes be seen as calcified areas on X-ray.
• Most people infected with M. tuberculosis do not go on to have active disease. Factors affecting host resistance and the various risk factors will play a part in whether or not disease ensues.
• Disease may result from:
  • Progression of the primary complex with progressive hilar and mediastinal lymph node enlargement and bronchial collapse.
  • Spread by progressive caseation and cavitation through the adjacent bronchi.
  • Spread through the bloodstream and lymphatics occurs more often in children and can progress to miliary TB (when several organs or tissues are infected).
  • Bacteria released into the bloodstream can produce disseminated disease virtually anywhere in the body but meningeal involvement is an early (2-6 months) and serious complication that affects ~0.3% of untreated cases.
    Other forms of the disease include:
    • Skeletal
    • Pleural
    • Cutaneous
    • Oropharyngeal
    • Genitourinary (rare)
    • Gastrointestinal (rare)
  • Reactivation of TB that has remained dormant (usually in the apical posterior areas of lung).

• The WHO report that there are 8 million new cases of TB in the world every year. The incidence in 2005 was 8.8 million.¹
• There are estimated to be between 1.5 to 3 million deaths worldwide every year from TB.¹
• Between 15 and 43.5% of the world's population is infected with TB.
• 75% of the TB occurs in developing countries (including India, China, Pakistan, Philippines, Bangladesh, the Congo).
• Around the world figures for 2005 show:
  • Around 15 million people are infected with tuberculosis in the United States.
  • The incidence of tuberculosis in the United States has increased between the 1980s and early 1990s (probably as a result of HIV). This increase was most marked in children under 15 years (a 33% increase).
  • The incidence in Europe was 50/100,000 population.
  • The incidence in Africa was 343/100,000 population.
  • The incidence in South East Asia was 181/100,000 population.
  • The incidence in the Russian Federation was 133/100,000 population.
  • In contrast, although UK incidence is increasing,² it was only ~4/100,000 in 1999-2002. It was 14.6/100,000 in 2006.⁴

With a large proportion of children in the developing world there are disproportionate numbers of children infected with TB:

• Up to 40% of the total population may be infected with TB as children.
• Up to 40% of all cases of TB may be in children in these areas, with many new cases presenting.
• It has been estimated that in 1991, 450,000 children died from TB.

Risk factors

• The risk of infection is increased by environmental factors which increase the capacity of infective aerosol droplets to be inhaled. Confined spaces and poor ventilation for example, encourage spread from infected patients.
• Country of origin. Rates of TB are higher in people from for example India. However race itself is unlikely to be an independent risk factor and the risk relates to social, economic and medical factors in certain countries.
• Living in a city (and in the UK especially London).
• Visiting areas where TB is endemic.
• The elderly and very young are at higher risk of having the disease. Mortality too is highest in the very young (and the very old).
• Defects in cell mediated immunity, for example:
  • HIV infection (one of the most important risk factors)
  • Malnutrition
  • Chemotherapy
  • Steroids
• Poverty brings with it several risk factors for TB infection.
• Living with adults infected with TB increases risk.
• Genetic predisposition may play a part.

• Symptoms:
  • It is important to to have a high-level of suspicion in high-risk children
  • Often children are asymptomatic and only diagnosed as part of contact tracing (they are tuberculin test positive but have no clinical or radiographic evidence of infection)
  • The most common symptoms are:
    • Non-productive cough
    • Slight dyspnoea
    • Failure to gain weight
  • Systemic symptoms are uncommon
  • Suspect TB if:
    • Fever of unknown origin
    • Unexplained lymphadenopathy
    • Weight loss
• Signs:
  • Occasionally, wheezing and reduced breath sounds with tachypnoea.
  • Infection of superficial lymph nodes (scrofula) with lymphadenopathy, often cervical, is seen.
  • Meningeal involvement presents with typical symptoms of meningitis but can develop rapidly into hydrocephalus with seizures and raised intracranial pressure.
  • With miliary form the child may be severely ill but often there is slow onset with anoxia, weight loss and low-grade pyrexia. Hepatomegaly, splenomegaly and lymph node enlargement are often found.
  • The disseminated form of TB often presents only with PUO.

• Other infections with some similar general features:
  • Actinomycosis
  • Aspergillosis
  • Coccidiomycosis
  • Cysticerosis
  • Brucellosis
  • Legionella infection
• Other infections at similar sites:
  • Meningitis (other causes)
  • Septic arthritis
  • Pneumonias
  • Osteomyelitis
• Non- infectious conditions with similar features:
  • Failure to thrive
  • Bronchopulmonary dysplasia
  • Chronic granulomatous disease
• Other mixed (infectious/non-infectious) conditions with similar features:
  • Bronchiectasis
  • Pyrexia of unknown origin
  • Histoplasmosis
  • Constrictive pericarditis
  • Pleural effusion

It can be especially difficult to make the diagnosis in children. Definitive diagnosis can be made from secretions or biopsy specimens. Although there have been advances in the methods and techniques used for diagnosis, worldwide the long established methods are still useful. The classic combination is:

• Positive Mantoux test
• Typical clinical picture
• Positive radiology
• History of contact with an infected adult

However, unlike adult cavitating TB, where diagnosis with microscopy of stained sputum smear and chest X-ray is normally straightforward, accurate diagnosis of child TB can be difficult. The following can be performed:

• Collection of specimens will depend on where disease is suspected. Consultation with the laboratory is recommended. For example the following can be tested:
  • Sputum (difficult to collect in young children, cough may be stimulated with special aerosol spray)
  • Gastric lavage (useful in under 6 years instead of sputum)
  • Bronchial lavage
  • Lymph node tissue
  • Bone marrow aspirate
  • Blood
  • Urine (early morning)
  • Stool
  • CSF
• Analysis of specimens:
  • Staining for AFB can give initial confirmation and quantitative assessment (but is usually negative in children)
  • 10,000 organisms per ml are required for reliable positive result from staining
  • Culture positive result requires only 10 organisms per ml
  • Culture takes 6-8 weeks conventionally or 3-8 weeks with newer liquid based media
  • Some techniques can culture organisms even more quickly (for example BACTEC- 9 to 16 days)
• Modern detection techniques have been developed but are not normally available outside the developed world. For example:
  • Rapid liquid based media⁵
  • Nucleic acid probes using chemiluminescence
  • Polymerase chain reaction tests (fast but may only detect half of smear-negative cases)
  • Enzyme linked immunoassays
• Imaging techniques:
  • CXR (a classic diagnostic tool typically showing parenchymal changes and enlarged nodes)
  • CT/MRI scanning (if CXR unhelpful and to identify other features such as hilar nodes, pericardial involvement, bronchiectasis)
• Tuberculin skin testing:
  • Another classic test- no better test is so widely available
  • When to use:⁶
    • Immediate: contacts, immigrants from high risk countries, clinically or radiologically suspected
    • Annual: HIV infected children or household, residential homes
    • Routinely (for example at 4-6 years and 11-16 years): high prevalence areas, travel or family travel to high risk countries/areas
  • How to administer:
    • Mantoux test (0.1 ml, 27 gauge needle, raise 6-10 mm wheal)
    • Read at 48 to 72 hours
    • Tine, Heaf no longer recommended (lack of sensitivity and specificity)
  • How to interpret:
    • Care and consultation needed in interpretation
    • Positive at > 5mm in contacts, immunosuppressed, abnormal CXR
    • Positive at >10mm in at risk and under 5 years
    • Positive at 15mm or more in over age 5 and without risk factors
    • Beware false positives and false negatives
    • Previous BCG may affect interpretation but not if TB strongly suspected

• HIV infection
• Cancer
• Childhood infections (measles, varicella) may reactivate TB
• Malnutrition (from whatever cause)

The American Thoracic Society has defined simple stages which can be clinically useful in a disease with an often complex progression and natural history:

See Tuberculosis Management article.
As with adults the aims are to successfully treat the individual, but also to prevent spread of infection and development of resistant strains. Hence important principles are:

• Eradication of active infection in as short a time as possible
• Adherence to treatment regimens
• Multiple drug regimens

The drugs used are as for adults:^7,8,9

• Initially 3 drugs for 2 months - isoniazid, rifampicin, pyrazinamide plus ethambutol if risk of resistance
• Then continuation therapy - isoniazid, rifampicin for 4 months
• Needs to be supervised if any doubts over compliance (directly observed therapy or DOT)¹⁰
• World-wide level of drug resistance is increasing¹¹
• Optimal therapy for HIV co-infection not yet clear
• Regimens for drug resistant strains have been developed
• Monitoring for adverse effects in children is particularly important (although they are rare)

The possible complications depend on site and type of infection. For example:

• Complications of primary TB include:
  • Miliary TB
  • Tubercular meningitis
• Complications of pulmonary TB include:
  • Pneumothorax
  • Pulmonary effusion
  • Pulmonary atelectasis
  • Bronchiectasis
• Complications of intestinal TB:
  • Small bowel obstruction
  • Fistulas
  • Malabsorption
• Cardiac complications:
  • Pericardial effusion
  • Constrictive pericarditis
• Renal complications:
  • Rare in children, but include hydronephrosis
• Spinal complications:
  • Paraplegia
  • Potts disease of the spine

• Prognosis very much depends on the extent and type of infection.
• Miliary TB, disseminated TB and tubercular meningitis are associated with a particularly poor prognosis.
• Early stages of tubercular meningitis have a much better prognosis than stage 3 meningitis which is associated with sequelae. These include deafness, blindness and other neurological problems as well as diabetes insipidus.
• Mortality is highest in the under 5 year olds (20%) and in those who have had infection longest (80% if ill for more than 2 months).

• Contact tracing with pre-emptive antibiotics and screening of high-risk adults is used. The details of this can be complex. Guidelines and a comprehensive strategy are in place.^9,6
• BCG vaccination is used selectively in certain circumstances. This includes for example travellers to endemic areas.
• Neonatal vaccination in high risk groups helps to protect against clinical disease and reduces the severity of bacteraemic spread including tubercular meningitis.
• Chemoprophylaxis with isoniazid for 6-9 months for children who have been contact with infection is essential. Although recommended by the WHO, it is not usually adhered to in the developing world.
• As children usually catch TB from adults, finding and treating adult cases is important. However, effective diagnosis and treatment of children themselves is of paramount importance.