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Tuberculosis 

Tuberculosis
Chapter:
Tuberculosis
Author(s):

Jeremy Hull

, Julian Forton

, and Anne Thomson

DOI:
10.1093/med/9780199687060.003.0022
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Introduction

In most developed countries, TB notifications have fallen steadily over the last 50 years, and, in the UK, there are now approximately ten new cases of TB per 100 000 population per year. In other parts of the world, TB remains a very significant cause of mortality and morbidity in both children and adults. It has been estimated that one-third of the world’s population (2 billion people) has latent TB infection and that around 10 million people per year will develop TB disease. Population migration will make eradication of TB in any one country impossible, and, within many countries, there will be geographical variation in TB incidence, reflecting the origins of immigrant residents. For example, some London boroughs have a TB incidence of over 100 new cases per 100 000 per year.

Pathogenesis

  • The most frequent route of infection by MTB is inhalation, and, in 95% of cases, the primary focus is in the lung.

  • Once in the alveoli, MTB are ingested by alveolar macrophages, and in 80% of infections, the MTB will be killed at this point, without causing further problems. The efficiency with which this occurs depends on the virulence and quantity of MTB present and on the host immune competence. The site of infection is walled off by epithelial cells, and a tubercle forms. In most individuals, this primary focus is undetectable on CXR. In a proportion of people, the lesion may calcify or necrose or caseate. If calcification occurs, the lesion is called a Ghon focus and, in combination with calcified hilar lymph nodes, constitutes the Ghon complex.

  • CMI develops slowly during the first weeks of infection in all individuals. Where there are a relatively large number of MTB organisms or the organisms are particularly virulent, the MTB organisms will divide, and a more prominent primary focus will develop, associated with enlarged mediastinal and paratracheal lymph nodes.

  • During the phase of caseation, before CMI is fully developed, MTB multiplication can lead to local extension (progressive primary TB) and distant haematogenous spread of infection. In some cases, haematogenous spread will result in symptomatic miliary TB. In the majority, however, the bacilli are contained in tubercles within the tissues in which they lodge and where most of the bacilli are killed by effector cells of the CMI response.

  • A small number of MTB organisms can lie dormant in the lung and other tissues (e.g. bone, brain, kidney), with a risk of reactivating later in life.

Progressive primary tuberculosis

Although the tendency is for primary pulmonary TB to heal, the primary focus can continue to enlarge. There may be local spread, which can include the pleura. The caseous centre can liquefy and empty into the bronchi and produce a cavity and cause cavitating primary TB. This is unusual and more likely to occur in young children. Most complications of TB occur during the first few years after infection.

Reactivation of tuberculosis disease

Adolescence is a time when reactivation can occur with ‘adult-type’ disease. This occurs twice as often in girls as in boys. Reactivation usually occurs in the apical portion of the lung. Cavities form more readily, and liquefied material disseminates through the airways. If untreated, large areas of the lung can be destroyed. Reactivation can also occur in any organ in which TB organisms were deposited during the primary infection. Reactivation of multiple sites of infection can result in miliary TB.

Important concepts

There are a few important concepts that will help in understanding the management of children with TB.

  • TB is infectious. Thirty to 50% of children who are household contacts of adults with untreated pulmonary TB will become infected. The risk of infection is highest if the index case is smear-positive. The presence of infection is detected by either a delayed hypersensitivity response, in the form of the tuberculin skin test (TST), or by interferon-gamma tests (IGTs).

  • TB infection is different from TB disease. A positive TST/IGT indicates that infection with TB has occurred and an immune response has been made. A positive TST/IGT, plus clinical, radiological, or microbiological abnormalities, indicates TB disease.

  • After TB infection, small numbers of viable organisms may reside in several tissues for many years, without causing symptoms. Reactivation of the disease can occur, given the right conditions, e.g. a waning of host immunity.

  • The risk of TB disease after TB infection varies with age (Table 22.1). In children under 2 years, it is as high as 50%, with most disease occurring within 6 months of the infection. Disease at this age group is also more likely to include miliary disease and tuberculous meningitis (TBM). Because of the high risk in this age group, children under 2 years of age who have not had BCG and are in close contact with smear-positive TB should be protected with chemoprophylaxis as soon as possible after exposure, whilst awaiting a TST/IGT test.

  • In healthy adults, the disease risk after infection is thought to be about 10% and can occur at any time, sometimes many years after the primary infection. The risk is dependent on the health of the individual involved.

  • There are no good data indicating the amount by which the risk of TB infection converting to TB disease is reduced by chemoprophylaxis for any given individual. The best estimates suggest 60–90% protection.

  • Some MTB organisms are more virulent than others, both in terms of the severity of the disease and infectivity.

  • BCG is most effective in preventing young children from disseminated disease and TBM (overall reduced relative risk of 0.2–0.5). It is less effective in protecting children and adults from pulmonary TB.

  • In contrast to adults who have reactivation disease, young children who have primary TB infection are not highly infectious. They rarely develop cavitating disease, and, in the absence of cavitating disease, their sputum carries few organisms. Adolescents can have adult-type reactivation open TB.

  • Once chemotherapy has been started for a susceptible organism, an adult with smear-positive TB will usually become non-infectious after 2 weeks.

Table 22.1 Age-specific risk of progression to disease after primary infection with MTB in immunocompetent children

Risk of progression to disease (%)

Age at primary infection (years)

No disease

Pulmonarydisease

Miliary disease or TBM

1

50

30–40

10–20

1–2

75–80

10–20

2–5

2–5

95

5

0.5

5–10

98

2

0.5

>10

80–90

10–20

0.5

Note that there is a bimodal distribution of pulmonary disease risk—highest in infancy, but increasing again in the over 10-year-olds. Also note that these are average figures and will vary according to the virulence of each particular MTB organism.

Reprinted with permission of the American Thoracic Society. Ben J. Marais et al, 2006, Childhood Pulmonary Tuberculosis: Old Wisdom and New Challenges, American Journal of Respiratory and Critical Care Medicine, Vol. 173, No. 10. Copyright © 2014 American Thoracic Society.

At-risk groups

Children at increased risk of TB infection are those with a high risk of exposure due to:

  • close contact with someone with cavitatory pulmonary disease;

  • living in a community with a high incidence of TB infection;

  • travel to, or exposure to visitors from, countries with a high incidence of TB infection.

Children at increased risk of developing TB disease, once infected, are those:

  • with immune deficiency, including HIV infection;

  • <2 years of age.

Children with a high risk of exposure to TB should be vaccinated with BCG in the neonatal period. In countries with a low incidence (<40/100 000) of TB infection, BCG should not be given to infants who are known to have, or who are at high risk of having, HIV infection, including infants of HIV-positive mothers, because of the increased risk of disseminated infection with BCG. In high incidence countries, the risk of TB is greater than the risk of disseminated BCG, and BCG should be given.

Symptoms and signs

The majority of primary TB disease in children will be pulmonary (in this book, pulmonary disease includes isolated hilar lymphadenopathy as well as parenchymal lung lesions). In around 50% of children with a positive TST/IGT and an abnormal CXR, there will be no symptoms or signs of TB disease. In the remainder, the commonest symptoms are:

  • weight loss;

  • malaise;

  • fever;

  • cough.

In some older children who may present with reactivation TB, there may also be night sweats. The cough is usually dry. Haemoptysis may occur rarely. Breathlessness only occurs in late disease when there has been extensive lung destruction or when there is a large pleural effusion.

More rarely, the site of primary TB is within the peripheral lymph nodes, mainly the cervical lymph nodes. The enlarged nodes are usually painless, with an absence of redness or heat, making the classic ‘cold abscess’. The overlying skin may become discoloured, and sinus formation with discharge can occur. Atypical mycobacterial infection is an important differential diagnosis for this type of cervical lymphadenopathy.

Other forms of tuberculosis disease

TB disease affecting other sites can occur at any time after the primary infection, and all forms of TB disease can be seen during childhood.

  • Miliary TB. Symptoms are non-specific and usually of a few weeks’ duration, with malaise and fevers.

  • TB meningitis. Symptoms come on over a period of 2–6 weeks, initially with altered behaviour, poor feeding, and vomiting. Later, irritability, drowsiness, and seizures may occur. There may be focal neurological signs, including cranial nerve palsies.

  • Bone and joint TB. This most often affects the spine where abscess formation can cause spinal cord or nerve root compression.

  • Renal TB may present with dysuria, haematuria, and loin pain. Systemic symptoms (fever, weight loss) are not common.

  • GI TB usually causes abdominal pain with a palpable mass. Intestinal obstruction can also occur.

  • Congenital TB. This is seen in around 5% of infants born to mothers with active untreated TB. The mother may appear relatively well at the time of delivery, with her illness only being diagnosed months later. Transfer of infection is thought to be either haematogenous from an infected endometrium or as a result of fetal ingestion or fetal breathing of infected amniotic fluid. The infant may present with liver lesions, pulmonary lesions, or miliary disease. Co-infection with HIV is a risk factor for developing congenital TB. Mortality from congenital TB is around 50%.

Investigations

Imaging

CXR findings (Fig. 22.1) include:

  • mediastinal and hilar lymph node enlargement;

  • areas of parenchymal opacification that may be single or multiple;

  • lobar consolidation;

  • areas of atelectasis;

  • pleural effusion;

  • miliary deposits—the size of the lesions can vary;

  • calcification, either of hilar nodes or of the parenchymal primary focus.

Fig. 22.1 Primary progressive TB. CXR of a 9-month-old boy presenting with persistent fever and poor weight gain. CXR shows an area of consolidation with cavity formation in the right middle lobe and widening of the upper mediastinum consistent with adenopathy. Early morning gastric aspirates were positive for MTB.

Fig. 22.1
Primary progressive TB. CXR of a 9-month-old boy presenting with persistent fever and poor weight gain. CXR shows an area of consolidation with cavity formation in the right middle lobe and widening of the upper mediastinum consistent with adenopathy. Early morning gastric aspirates were positive for MTB.

The most frequent radiological finding in children with pulmonary TB disease in the UK is hilar adenopathy, without evidence of parenchymal lung disease. Although there are some reports to the contrary, we consider isolated hilar lymphadenopathy as indicative of active disease, and treat accordingly.

Tuberculin skin tests

  • TSTs involve intradermal injections of purified proteins derived from MTB (tuberculin proteins).

  • TSTs do not measure protective immunity to MTB. Rather they measure delayed-type hypersensitivity responses to tuberculin.

  • Two types of TSTs were previously available in the UK: the Heaf test and the Mantoux test.

    • The Heaf test used a gun with six injectors arranged in a circle to drive the tuberculin into the skin. This gun had the advantage of being easy to use, even in wriggling toddlers. The tuberculin used for this test is no longer available, so this test is no longer performed.

    • The Mantoux test involves an intradermal injection of tuberculin in a volume of 0.1 mL, using a syringe and 26-gauge needle. It is essential that the injection is intradermal (producing a wheal of 6 mm) for the test to be valid. SC injections will leave no wheal and will almost always be negative. The previous standard dose was 10 tuberculin units (TUs). This has now been changed to 2 TUs. The lower dose gives the same information but reduces the number of severe reactions. Where there is a high index of suspicion and the test with 2 TUs is negative, a repeat test using 10 TUs can be carried out. Mantoux tests should be read 48–72 h after injection. The size of induration (not redness) is measured. Best practice is to measure the transverse and longitudinal diameters of induration and calculate the average.

  • Following BCG vaccination, a proportion of children will develop some response to subsequent TSTs. There remains debate in the literature, but the majority view is that the presence of detectable delayed-type hypersensitivity by skin tests after BCG does not correlate with protection for TB disease.

  • In most studies, the proportion of children with some measurable response (>1 mm induration) to TSTs >12 months after neonatal BCG is only 10–20%, and, by 5 years of age, 95% of children who received neonatal BCG will have a TST reaction of <5 mm.

  • The interpretation of the Mantoux test depends on the clinical situation. In children who have not had BCG, an induration of 6 mm or more following a Mantoux test should be considered to have been infected with MTB. If BCG has been given (85–90% will have a scar as a result of BCG vaccination), an induration of up to 15 mm may represent the effects of the BCG, rather than TB infection. If the clinical suspicion of TB is high, or the child is in a high-risk group (e.g. under 2 years of age exposed to smear-positive TB), an induration of >6 mm may indicate infection—where there is doubt, an IGT may help. An induration of >15 mm indicates TB infection in all situations.

  • Exposure to environmental atypical mycobacteria can also contribute to Mantoux reactions of up to 15 mm.

  • A delayed-type hypersensitivity response to TB can take up to 6 weeks to develop after exposure to TB.

  • In immunodeficient children, including those with HIV infection or receiving chemotherapy, TSTs can be negative, despite active TB disease. TSTs can also be negative in cases of severe disseminated TB.

  • The size of reaction to a TST does not correlate with either the likelihood of disease (as opposed to TB infection) or with disease severity.

  • ‘Boosting’ refers to an enhanced response to repeat TST as a result of stimulation of the immune system by a previous TST. It only occurs in individuals (nearly always adults) who had a previous exposure to TB infection, but in whom the immune response has waned to such a low level that the first TST response is <6 mm of induration. Exposure to the TST reactivates the immune response, so that the second TST results in a larger reaction. Boosting effects can be seen up to 2 years after the first TST. The second TST is a more valid reflection of the person’s TB status. The difference between the first and second tests must be <10 mm of induration. A greater change than this is thought to indicate conversion—a result of exposure to TB infection between the two tests.

Interferon-gamma tests

  • These tests (such as QuantiFERON®-TB Gold and T-SPOT® TB) have been available since 2005. They measure the interferon-gamma production by TB-specific T-cells.

  • They require white cells from the person being tested to be incubated with peptides derived from specific MTB proteins (so-called RD1 antigens such as ESAT-6 and CFP-10). Results usually take 24–48 h.

  • RD1 proteins are not found in BCG or most atypical mycobacteria (with the exception of Mycobacterium kansasii and Mycobacterium marinum), and hence IGT results are not affected by exposure to most atypical mycobacteria or prior BCG.

  • IGTs correlate more strongly with exposure to TB than TSTs.

  • IGTs are not infallible—a small number of children who have a positive TST, but a negative IGT, may subsequently develop TB disease. Thus, where there a strong clinical suspicion (e.g. contact plus an abnormal CXR or an unwell child) or the risk of progression is high (e.g. in children under 5 years of age), treatment decisions should be based on either test being positive.

  • The clinical significance of a positive IGT test, combined with a negative TST, in a well child who has had contact with TB is not known. It is likely that a positive IGT represents exposure to MTB, although whether this is associated with a significant risk of later disease, and therefore the need for chemoprophylaxis, is not known.

  • IGTs, like TSTs, may be false negative in children with immune deficiency.

  • IGTs (unlike TSTs) may revert to being negative after chemoprophylaxis for TB infection.

Microscopy, polymerase chain reaction, and culture

  • Identification of the infecting MTB organism is important for a definitive diagnosis, drug susceptibility testing, and contact tracing.

  • In children with TB infection, but not TB disease, cultures are very likely to be negative, and treatment will be based on the MTB identified in the index case.

  • In unwell children with TB disease, attempts should be made to culture the organism, even if an index case has been identified.

  • Culture for TB can take 6 weeks or longer.

  • PCR tests are available that appear to be both sensitive (95%) and specific (100%) in the diagnosis of TB in both smear-positive and smear-negative adult patients. PCR may then provide a more rapid method of making the diagnosis than culture. Rifampicin resistance can also be identified by the same PCR test (it is commonly due to one or more of several possible mutations of the rpoB gene), and a positive result would indicate the likely presence of MDR-TB.

  • Most children with TB disease are not sputum producers, and the likelihood of spontaneous smear-positive sputum is low and age-dependent. In adolescents who are more likely to have reactivation, rather than primary disease, about 10% are smear-positive (20% have positive cultures). In children <10 years of age, <2% are smear-positive (5–10% have positive cultures).

  • Microscopy and culture of early morning gastric aspirates is the most commonly used method to isolate MTB in children with pulmonary TB disease. Samples are taken on 3 consecutive days. Overall, about 10–25% of children with suspected TB disease (positive TST, contact, and CXR changes) will have positive gastric aspirate cultures, and about half of this number will have acid-fast bacilli seen at microscopy of the aspirate.

  • Induced sputum techniques can be used successfully in children, including infants. In one study at least, this seemed to be more successful than gastric aspirates—one induced sputum sample had the same success rate as three gastric aspirates. Appropriate infection control measures need to be in place to protect staff and other patients when performing induced sputum techniques in children with suspected TB.

  • Bronchoscopy is not usually necessary in children. In high-risk children, e.g. those with immune deficiency where a positive diagnosis is needed and TST/IGT may be false negative, bronchoscopy can be helpful. Lavage can be performed in one lobe of each lung, and, at least in adults, this has been shown to increase the yield of smear and culture results in patients who are sputum smear-negative or not sputum producers. Appropriate infection control measures need to be in place to protect staff undertaking bronchoscopy for this indication.

Most children with TB in developed countries will present to a respiratory service as a consequence of contact tracing. More rarely, children will present with TB disease where the index case is unknown.

Contact tracing

For the purposes of contact tracing, the definitions of close and casual contact are not explicit and will vary between centres. For practical purposes, close contact can be taken to mean contact for more than an hour or so per day, either within the household or elsewhere (e.g. close friends or children in the same class at school), and with a cumulative contact of 8 h or more. Casual contact can be taken to mean brief contact only outside the household, e.g. attending the same school.

For the purposes of contact tracing, all children who are close contacts of an index case will be screened. If the index case is smear-positive (i.e. tubercle bacilli are seen in the sputum), casual contacts <5 years of age or any immunocompromised children (or adults) will also be screened. If the index case has been shown to be highly infectious (>10% of close contacts infected), all casual contacts (irrespective of age) are screened.

Managing a well child who has been in contact with tuberculosis

  • A careful history should be taken, including identifying the index case, whether the index case is or was smear-positive, and the number of people who have been infected. Symptoms suggestive of TB disease (weight loss, cough, malaise, fever, night sweats) should be sought. The child’s BCG status, including the presence or absence of scar, should be noted.

  • Risk factors for MDR-TB should be sought: index case previously treated for TB, or has HIV, or is a known contact of MDR-TB, or has prolonged smear-positive disease despite chemotherapy, or has failed to show clinical improvement on treatment, or comes from a country with a high incidence of MDR-TB.

  • The drug sensitivities of the organism should be identified, if known.

  • What happens next depends on the age of the child, their BCG status, and whether the index case was smear-positive. The recommendations described are in line with those produced by NICE (UK) in 2011.

Children aged over 5 years of age

  • A Mantoux test should be performed. If this is positive (taking into account the BCG status), offer IGT. If the IGT is positive, assess for disease, and, depending on this assessment, recommend chemoprophylaxis or full treatment. If the IGT is negative, no further action is required. Some practitioners (including the authors) would act on a positive Mantoux test, without proceeding to the IGT.

Children aged 2 to 5 years of age

  • Exposed to a smear-negative index case:

    • a Mantoux test should be performed. If this is positive (taking into account the BCG status), assess for disease, and, depending on this assessment, recommend chemoprophylaxis or full treatment. IGT not required;

    • if the Mantoux test is negative, no further action is required. IGT not required.

  • Exposed to a smear-positive index case:

    • a Mantoux test should be performed. If this is positive (taking into account the BCG status), assess for disease, and, depending on this assessment, recommend chemoprophylaxis or full treatment;

    • if the initial Mantoux test is negative, carry out an IGT. If this is positive, assess for disease, and, depending on this assessment, recommend chemoprophylaxis or full treatment;

    • if the IGT is negative, repeat the Mantoux test (or the IGT or both) after 6 weeks. If the Mantoux test is now positive, assess for disease, and, depending on this assessment, recommend chemoprophylaxis or full treatment;

    • if the repeat Mantoux test is negative, no further action is required. If the child has not had BCG, offer BCG.

Children aged 4 weeks to 2 years of age

  • As for children aged 2–5 years, except if the child has not had BCG and has been exposed to a smear-positive index case. In this situation, these children are at increased risk of disseminated disease, and so, if their initial assessment is negative, they should be given chemoprophylaxis with isoniazid in the 6-week period, whilst awaiting the repeat assessment.

Children aged 0 to 4 weeks of age

  • Neonates who have close contact (i.e. someone living in the same household) with a smear-positive index case who has not, at the time of first contact, received 2 weeks of effective chemotherapy (this means the sensitivity of the organism should be known):

    • should be immediately protected by being given isoniazid. After 3 months on isoniazid, the infant should then have a Mantoux test;

    • if the Mantoux is positive, a disease assessment should be made—if the assessment is negative, then isoniazid should be continued for a total of 6 months;

    • if the Mantoux test at 3 months is negative, an IGT should be performed. If this is also negative, the isoniazid can be stopped, and BCG given. If the IGT is positive, a disease assessment should be made—if the assessment is negative, then isoniazid should be continued for a total of 6 months.

  • There is no clear guidance for what to do if the index case is smear-negative. A reasonable approach would be to give BCG immediately, monitor the infant closely for signs of ill health, and then perform an IGT at 3 months.

  • If the index case has been on effective chemotherapy for 2 weeks at the time of first contact, the infection risk is very low. BCG should be given. Further assessment should not be required, provided the index case is successfully treated.

Recommended chemoprophylaxis

Chemoprophylaxis for TB infection is either isoniazid alone for 6 months or isoniazid and rifampicin for 3 months. Most centres now use rifampicin and isoniazid for 3 months.

Managing suspected pulmonary tuberculosis

  • In children, the diagnosis of TB infection is based on clinical features, CXR, and TST/IGT results.

  • If the child has been identified by contact tracing, the likely infecting organism may have already been identified and cultured and antibiotic sensitivities known. If this is not so or the child has systemic symptoms, attempts should be made to obtain the organism from the child, either by induced sputum, or gastric aspirates, or lymph node or pleural biopsy, if necessary. If the child is unwell, the inability to identify an organism should not unduly delay treatment.

  • The most common finding on a CXR will be hilar adenopathy. In addition, there may be segmental or lobar collapse, collapse–consolidation or hyperinflation, bronchopneumonia, or miliary opacification. Cavitation is rarely encountered but may be seen in progressive primary disease or reactivation disease in older adolescents.

Children with a positive TST/IGT and either abnormal clinical findings or an abnormal CXR should receive full treatment for TB.

  • Four drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol) should be used in the initial phase of treatment.

  • For uncomplicated respiratory TB, a 6-month regime is adequate: 2 months of four drugs, followed by 4 months of isoniazid and rifampicin. Routine use of pyridoxine is not required in children.

  • If the organism is not identified (and thus drug sensitivities not known), four drugs should be used in the first 2 months, followed by three drugs in the subsequent 4 months (in most cases, ethambutol will be stopped).

  • For other forms of TB disease, specialist advice should be sought. For TB meningitis, 12 months’ treatment will be needed.

  • Isoniazid can cause hepatitis. This is rare in children, and routine monitoring of liver function is not required.

  • Ethambutol can be associated with ocular toxicity. This is very rare (<0.5%) at a dose of 15 mg/kg, and, when used for only 2 months, routine eye testing is not necessary. For longer-term use in children >5 years of age, visual acuity and colour vision should be assessed at the beginning of treatment and monthly thereafter. This risk of toxicity may be reduced by using a three times per week schedule. Children <10 years of age are unlikely to report visual disturbance. If ocular toxicity occurs, it is reversible in more than half of cases.

  • Children undergoing chemotherapy for TB disease should be reviewed with a repeat CXR after 2 months of treatment. Close attention to compliance is required. If the child is improving, the chemotherapy can be adjusted to isoniazid and rifampicin for the final 4 months of treatment. There is no evidence that further follow-up is necessary, but some centres elect to see children at the end of treatment, and this assessment may include a final CXR.

Multidrug-resistant tuberculosis

  • MDR-TB is defined as resistance to rifampicin and isoniazid.

  • Extreme drug resistance TB (XDT-TB) has now also emerged where there is, in addition, resistance to quinolones.

  • MDR-TB is uncommon in the UK, accounting for around 1% of infections, but the incidence is increasing, largely due to immigration of individuals from higher-incidence countries.

  • MDR-TB usually arises in conditions of poor adherence to treatment protocols. There is an increased risk of MDR-TB in children if the index case:

    • is known to have MDR-TB;

    • has previously been treated for TB;

    • has HIV infection;

    • remains smear-positive after 6 weeks of treatment;

    • comes from a country with a high incidence of MDR-TB.

  • Treatment of MDR-TB is difficult and requires combination chemotherapy that includes quinolones and at least one IV agent, usually amikacin. Usually, five drugs are needed—the choice of drugs is guided by the results of in vitro drug sensitivity testing.

  • Treatment is often continued for 18–24 months.

  • The use of directly observed therapy is strongly recommended to ensure adherence to treatment.

  • Patients with MDR-TB need to be treated in isolation facilities, until they are no longer infectious.

  • Expert help should be obtained. The WHO has produced a helpful document to assist treatment planning (refer to the references at the end of the chapter).

Complications

Failure to improve

In children with TB disease who fail to improve on apparently adequate therapy, three possibilities should be considered.

  • There is an alternative or additional cause for the symptoms or CXR findings.

  • The child is not taking their therapy. This likelihood can be minimized by clear instructions to parents at the start of treatment. Directly observed therapy is rarely needed for children with TB (except MDR-TB, when it is recommended).

  • The disease is caused by a drug-resistant organism (MDR-TB).

Paradoxical reaction to treatment

  • Worsening of disease and the appearance of new lesions can be part of a paradoxical reaction to TB treatment and is seen in around 10% of cases.

  • The most likely explanation for paradoxical reactions is a heightened CMI directed against MTB, resulting in an increased local inflammation.

  • Paradoxical reactions usually occur after 4–6 weeks of treatment but may occur from a few days to many months after starting treatment.

  • There may be new changes on CXR, including pleural effusion, and new symptoms can include fever. There may be bronchial compression from enlarging hilar lymph nodes.

  • Paradoxical reactions can be a particular problem in the CNS where enlargement of existing lesions can cause pressure effects, e.g. on the spine.

  • It can be difficult to distinguish a paradoxical reaction from treatment failure, drug resistance, or another infection. Careful history to establish adherence to therapy and knowledge of the MTB sensitivity are important factors. There is anecdotal evidence for the use of steroids in the treatment of paradoxical reactions, and these can be tried for troublesome symptoms. Otherwise, paradoxical reactions will resolve on continuation of standard chemotherapy.

Endobronchial tuberculosis

  • Enlarged hilar lymph nodes may cause bronchial compression and most usually affect the right middle lobe bronchus.

  • Endobronchial TB refers to a more progressive process, in which the disease has spread from the adjacent lymph node tissue into the airway wall and then into the airway lumen.

  • Bronchial obstruction may be apparent at diagnosis and can also occur during the first 6 weeks of therapy as part of a paradoxical response to TB treatment.

  • Bronchial compression is usually detected either by a routine repeat CXR after 2 months of treatment (one lung looks hyperinflated, or there are areas of collapse) or by symptoms of breathlessness or wheeze.

  • Further investigation should include bronchoscopy or CT scan. At bronchoscopy, granulation tissue may be seen within the airway lumen.

  • Provided the child is taking effective antituberculous chemotherapy, treatment of endobronchial TB with oral prednisolone is usually effective (2 mg/kg per day) for a week, then on alternate days for a further week. Benefit is usually seen after 3–4 days. If obstruction is not relieved after 7 days’ treatment, surgery to decompress the lymph nodes will need to be considered.

  • Occasionally, bronchial stenosis can develop at the site of compression when healing occurs.

Pleural effusion

  • Pleural effusions can occur during primary infection with TB and may be the mode of presentation. They are more frequently seen in older children and are usually unilateral.

  • In some countries, TB is one of the commonest causes of pleural effusion in children.

  • Children with tuberculous pleural effusions (TPEs) may present acutely with fever and chest pain. The clinical presentation of TPE may be indistinguishable from that of acute bacterial pneumonia with effusion.

  • TPE usually complicates primary TB. It arises as a result of an immune response (delayed hypersensitivity) to mycobacterial proteins released into the pleural cavity. Typically, this results from rupture of subpleural caseous foci, generally 6–12 weeks after the primary infection. Rarely, TPE may represent spread from a tuberculous focus in the spine.

  • Occasionally, TPE will develop 6–8 weeks after antituberculous treatment has been started—another example of a paradoxical response to chemotherapy (Fig. 22.2).

  • A definitive diagnosis of TPE requires either the identification of the bacillus in cultures of pleural fluid or pleural biopsy tissue, the presence of pleural granulomata, or MTB seen on pleural biopsy.

  • Pleural fluid should be aspirated for analysis. This will show a high protein level and lymphocytosis. MTB organisms are scanty; Ziehl–Neelsen stains are positive in 5%, and cultures are positive in only 25–30% of cases. A finding of high levels (>40 U/L) of the enzyme adenosine deaminase (ADA) in pleural fluid is reported to have a high sensitivity (99%) and specificity (93%) for TPE.

  • Pleural biopsy may be needed to make a definitive diagnosis; granulomata may be seen, and pleural culture for MTB is positive in 60–80% of cases.

  • CXR usually shows no abnormality other than the effusion (Fig. 22.2). Pulmonary infiltrates may be visualized in up to 30% of cases. The effusion usually affects less than two-thirds of the hemithorax.

  • Antituberculous treatment is given as for primary TB. The effusion will reabsorb slowly, and most will be gone by 3 months.

  • Chest tube drainage is not usually required, unless there is respiratory embarrassment or evidence of tuberculous empyema, with the development of thick pus containing MTB organisms. Where there is an empyema, chest tube drainage, with or without intrapleural fibrinolytic treatment, will be needed. Pneumothorax may also complicate TPE and will also need to be treated with a chest drain.

  • There is anecdotal evidence that prednisolone may help to speed the resolution of the effusion and fever. There is no evidence that steroid treatment will prevent pleural thickening.

  • Pleural thickening can occur in up to 50% of children and persist for 12 months or more. Rarely, the pleura can contract during healing, causing chest wall deformity and scoliosis.

Fig. 22.2 CXR of a 12-year-old boy diagnosed with TB 6 weeks earlier and started on antituberculous chemotherapy. On clinical review, he was found to have a mild fever, with signs of an effusion. The CXR shows a right-sided pleural effusion and widening of the right side of the mediastinum. The pleural fluid was tapped and showed a mild lymphocytosis and raised protein. Stain for MTB was negative, and the fluid subsequently failed to grow any organisms. The infecting organism had been isolated from an adult index case and was fully sensitive, and the boy was compliant with his treatment. His fever settled on simple antipyretics, and his antituberculous therapy was continued. His effusion resolved 3 weeks later and was thought to be part of a paradoxical reaction to therapy.

Fig. 22.2
CXR of a 12-year-old boy diagnosed with TB 6 weeks earlier and started on antituberculous chemotherapy. On clinical review, he was found to have a mild fever, with signs of an effusion. The CXR shows a right-sided pleural effusion and widening of the right side of the mediastinum. The pleural fluid was tapped and showed a mild lymphocytosis and raised protein. Stain for MTB was negative, and the fluid subsequently failed to grow any organisms. The infecting organism had been isolated from an adult index case and was fully sensitive, and the boy was compliant with his treatment. His fever settled on simple antipyretics, and his antituberculous therapy was continued. His effusion resolved 3 weeks later and was thought to be part of a paradoxical reaction to therapy.

Miliary tuberculosis

  • Miliary TB refers to generalized disease, resulting from haematogenous spread of MTB from the primary focus. In children, miliary TB is usually a complication of the primary TB infection and occurs within 6 months of infection.

  • It most commonly occurs in young children (<2 years old) but can occur at any age.

  • The history is usually short: 1–2 weeks of lethargy, followed by the onset of fever. Examination most often shows an obviously ill child with an intermittent fever. Hepatosplenomegaly and enlarged lymph nodes are found in 50% of affected children. Occasionally, children can look surprisingly well, with little to find.

  • The lungs are nearly always involved, although there may be no abnormal physical findings.

  • CXR shows widespread multiple lesions. The size of the lesion depends on the extent of the host response. They may be classic millet-sized (1–2 mm) lesions or much larger (1–2 cm) nodules. If the CXR is not conclusive, chest CT scan will show well-defined nodules.

  • Head CT or MRI may show intracerebral lesions. A lumbar puncture can be carried out after the CT scan to look for evidence of TBM.

  • Fundoscopy should be carried out and may show retinal tubercles.

  • Untreated miliary TB is always fatal, usually as a result of TBM.

  • Progressive respiratory distress can occur and may result in respiratory failure, requiring mechanical ventilation.

  • Specialist infectious disease advice should be sought.

    • Treatment is four antituberculous drugs.

    • There is anecdotal evidence that prednisolone may help resolve respiratory distress in children with miliary lung disease.

    • Prednisolone is also recommended during the first 3–6 weeks of treatment of TBM.

    • Rifampicin and isoniazid can be given IV. Pyrazinamide and ethambutol are given orally, even in very sick patients, using an NG tube, if necessary.

Notification/surveillance

All forms of TB are compulsorily notifiable in the UK under the Public Health (Control of Disease) Act 1984. The doctor making or suspecting the diagnosis is legally responsible for notification. A decision to commence treatment (but not chemoprophylaxis) indicates a level of suspicion that should trigger notification. Notification must be made to the local ‘proper officer’, usually the consultant in communicable disease control.

Further information

Cheng VC, Ho PL, Lee RA, et al. (2002). Clinical spectrum of paradoxical deterioration during antituberculosis therapy in non-HIV-infected patients. Eur J Clin Microbiol Infect Dis 21, 803–9.Find this resource:

National Institute for Health and Clinical Excellence (2011). Tuberculosis: clinical diagnosis and management of tuberculosis and measures for its prevention and control. Available at: <http://www.nice.org.uk>.

Pai M, Riley LW, Colford JM Jr (2004). Interferon-gamma assays in the immunodiagnosis of tuberculosis: a systematic review. Lancet Infect Dis 4, 761–76.Find this resource:

Ray M, Dixit A, Vaipei K, et al. (2002). Congenital tuberculosis. Indian Pediatr 39, 1167–8.Find this resource:

Traore H, van Deun A, Shamputa IC, Rigouts L, Portaels F (2006). Direct detection of Mycobacterium tuberculosis complex DNA and rifampin resistance in clinical specimens from tuberculosis patients by line probe assay. J Clin Microbiol 44, 4384–8.Find this resource:

World Health Organization (2011). Guidelines for the programmatic management of drug-resistant tuberculosis. Emergency update 2011. Available at: <http://www.who.int/publications/en/>.