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Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. 2nd edition. Geneva: World Health Organization; 2014.

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Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children. 2nd edition.

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3Diagnosis of TB in children

3.1. Chapter objectives

This chapter outlines recent novel techniques for diagnosing and confirming TB and their application to children. It also describes the recommended approach to diagnosis of TB in children.

Diagnosis of TB refers to the recognition of an active case of TB disease, i.e. a patient with current disease due to M. tuberculosis.

3.2. Introduction to diagnosis of TB in children

The diagnosis of TB in children relies on thorough assessment of all the evidence derived from a careful history of exposure, clinical examination and relevant investigations. The proposed approach to diagnosing TB in children (discussed in detail below and summarized in Box 1) is based on limited published evidence (1-4), and rests heavily on expert opinion.

Box Icon

Box 1

Guidance on approach to diagnosis of TB in children. Careful history (including history of TB contact and symptoms consistent with TB) Clinical examination (including growth assessment)

Most children with TB have pulmonary TB. Although bacteriological confirmation of TB is not always feasible, it should be sought whenever possible by microscopy, culture or WHO-endorsed genotypic (molecular) testing (i.e. Xpert MTB/RIF) of respiratory or non-respiratory samples as indicated by clinical presentation. A trial of treatment with anti-TB medications is not recommended as a method of diagnosing TB in children.

The key risk factors for TB in children are outlined in Box 2 (5).

Box Icon

Box 2

Key risk factors for TB in children. Household or other close contact with a case of pulmonary TB (especially smear-positive or culture-positive pulmonary TB) Age less than 5 years

Existing diagnostic tests for TB in children have shortcomings, and the full range of tests - including bacteriological culture and tuberculin skin testing (TST) - is often unavailable in settings where the majority of TB cases occur. The development of affordable diagnostic tests for TB in children in low-resource settings should be a priority for researchers and policy-makers.

3.3. Recent improvements in diagnostics

Since the first edition of this guidance was published in 2006, novel approaches to confirmation of TB have been developed and evaluated. These include more rapid culture techniques and genotypic (molecular) techniques that improve detection of M. tuberculosis. For example, commercially available liquid culture systems and molecular line probe assays for rapid detection of MDR-TB have been endorsed by WHO (6, 7) although their uptake is constrained in resource-limited settings by their cost and complexity.

Xpert MTB/RIF

The development that has received most attention recently is that of the Xpert MTB/RIF assay. This is a fully automated real-time DNA based test which can detect both TB and resistance to rifamipicin in less than 2 hours.

Following successful clinical evaluation in adults with TB in a variety of settings, WHO endorsed the Xpert MTB/RIF assay in 2010 and published recommendations in 2011. However, in 2011, published data from children on the performance of Xpert MTB/RIF assay were limited and the policy statement of 2011 therefore made no recommendations for its use that were specific to children.

Encouraging data, mainly concerned with sputum samples, are emerging from children that show an improved yield and sensitivity compared with smear microscopy (8, 9, 10, 11), although two of these studies also considered nasopharyngeal aspirate (8) and gastric lavage (9). However, sensitivity of Xpert MTB/RIF is still lower than culture confirmation or clinical diagnosis. More data are needed from children, including more evaluation of specimens other than sputum, plus operational evaluation of the role of Xpert MTB/RIF in the diagnostic evaluation of children with suspected TB (see Chapter 9).

Given the amount of additional data on Xpert MTB/RIF having emerged since 2010, an update of the current WHO policy guidance was warranted. WHO therefore commissioned three systematic reviews to update and revise current policy guidance, including the utility of Xpert MTB/RIF for the diagnosis of tuberculosis and rifampicin resistance in pulmonary, extra-pulmonary and paediatric TB. An updated review of published studies on the affordability and cost-effectiveness of Xpert MTB/RIF was also done. In May 2013, WHO convened an Expert Group to evaluate the data and formulate recommendations (12). The recommendations on the use of Xpert MTB/RIF in children were approved by the WHO Guideline Review Committee in October 2013 and no additional searches for evidence were undertaken since October 2013.

The recommendations are grouped in two categories: (i) Xpert MTB/RIF for the diagnosis of pulmonary TB and rifampicin resistance in children; and (ii) Xpert MTB/RIF for the diagnosis of extrapulmonary TB in children. The technology is recommended, especially in severely ill children when rapid diagnosis is crucial. It is important to note that a negative Xpert MTB/RIF result does not exclude TB in children and a clinical decision should be made in all such cases.

Xpert MTB/RIF for the diagnosis of pulmonary TB and rifampicin resistance in children

  • Recommendation 1
    Xpert MTB/RIF should be used rather than conventional microscopy and culture as the initial diagnostic test in children suspected of having MDR TB or HIV-associated TB
    (Strong recommendation, very low quality of evidence)
    Source: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy Update. Geneva: World Health Organization; 2013. [PubMed: 25473701].
  • Recommendation 2
    Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial test in all children suspected of having TB
    (Conditional recommendation acknowledging resource implications, very low quality of evidence)
    Source: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy Update. Geneva: World Health Organization; 2013. [PubMed: 25473701].

Remarks for recommendations 1 and 2:

  1. These recommendations apply to the use of Xpert MTB/RIF in processed and unprocessed sputum specimens.
  2. These recommendations also apply to gastric lavage and aspirates.
  3. Children suspected of having pulmonary TB but with a single Xpert MTB/RIF-negative result should undergo further diagnostic testing, and a child with high clinical suspicion for TB should be treated even if an Xpert MTB/RIF result is negative or if the test is not available.

Xpert MTB/RIF for the diagnosis of extrapulmonary TB in children

  • Recommendation 3
    Xpert MTB/RIF may be used as a replacement test for usual practice (including conventional microscopy, culture, and/or histopathology) for testing of specific non-respiratory specimens (lymph nodes and other tissues) from children suspected of having extrapulmonary TB
    (Conditional recommendation, very low quality of evidence)
    Source: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy Update. Geneva: World Health Organization; 2013. [PubMed: 25473701].
  • Recommendation 4
    Xpert MTB/RIF should be used in preference to conventional microscopy and culture as the initial diagnostic test in testing cerebrospinal fluid specimens from children suspected of having TB meningitis
    (Strong recommendation given the urgency of rapid diagnosis, very low quality of evidence)
    Source: Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy Update. Geneva: World Health Organization; 2013. [PubMed: 25473701].

Remarks for recommendations 3 and 4 :

  1. Children suspected of having extrapulmonary TB but with a single Xpert MTB/ RIF-negative result should undergo further diagnostic testing, and those with high clinical suspicion for TB should be treated even if an Xpert MTB/RIF result is negative or if the test is not available.
  2. For CSF specimens, Xpert MTB/RIF should be preferentially used over culture if the sample volume is low or additional specimens cannot be obtained, in order to reach quick diagnosis. If sufficient volume of material is available, concentration methods should be used to increase yield.
  3. Pleural fluid is a suboptimal sample for the bacterial confirmation of pleural TB, using any method. A pleural biopsy is the preferred sample. The sensitivity of Xpert MTB/RIF in pleural fluid is very low. Nevertheless, any positive Xpert MTB/ RIF result based on pleural fluid should be treated for pleural TB, while those with a negative Xpert MTB/RIF result should be followed by other tests.
  4. These recommendations do not apply to stool, urine or blood, given the lack of data on the utility of Xpert MTB/RIF on theses specimens.

Blood tests

A number of blood tests have been developed that aim to measure the immune response to infection with M. tuberculosis.

IGRAs measure the in vitro response to specific M. tuberculosis antigens. While these assays are more specific than TST (BCG does not cause a false-positive result), they have not been found to perform better than TST. Current evidence for IGRA use in children from TB-endemic settings was reviewed in the process of preparing this guidance (Annex 1): it is limited, of low quality and conflicting, and there is almost no evidence from studies of infants and young children. Nonetheless, this additional evidence published since 2011 made the Panel agree to revise the quality of the evidence from very low to low.

IGRAs should not be used for the diagnosis of TB disease. A positive IGRA, like a positive TST, only indicates infection and so does not confirm a diagnosis of TB disease. Equally, a negative IGRA, like a negative TST, does not rule out a diagnosis of TB. Moreover, IGRAs are expensive and technically difficult to implement in resource-limited settings, and indeterminate results are common, especially in young children.

  • Recommendation 5
    Interferon-gamma release assays (IGRAs) should not replace the tuberculin skin test (TST) in low- and middle-income countries for the diagnosis of latent TB infection in children or for the diagnostic work-up of children (irrespective of HIV status) suspected of TB disease in these settings
    (Strong recommendation, low quality of evidence)
    Source: Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries: policy statement. Geneva: World Health Organization; 2011. (WHO/HTM/TB/2011.18) [PubMed: 26269875]

In some settings, commercial serodiagnostics are marketed as diagnostic tests for TB. In children as in adults, these should not be used to diagnose TB.

In 2011, WHO published recommendations against the use of commercial serodiagnostics, and included specific policy to discourage the use of IGRAs in low- and middle-income setting, including in children (see Annex 1) (13, 14).

  • Recommendation 6
    Commercial serodiagnostics should not be used in children suspected of active pulmonary or extrapulmonary TB, irrespective of their HIV status
    (Strong recommendation, very low quality of evidence for the use of commercial serodiagnostics)
    Source: Commercial serodiagnostic tests for diagnosis of tuberculosis: policy statement. Geneva: World Health Organization; 2011. (WHO/HTM/TB/2011.5)

HIV testing

An HIV test is a very important “point-of-care” test that is already widely available. Making a diagnosis of HIV infection has obvious implications for the management of TB as well as HIV (see Chapter 6). Exclusion of co-infection with HIV also has important implications because it often makes the clinical diagnosis of TB more straightforward.

  • Recommendation 7
    Routine HIV testing should be offered to all patients, including children, with presumptive and diagnosed TB
    (Strong recommendation, low quality of evidence)
    Source: WHO policy on collaborative TB/HIV activities: guidelines for national programmes and other stakeholders. Geneva: World Health Organization; 2012. (WHO/ HTM/TB/2012.1)

HIV testing is routinely recommended for all children who are to be evaluated for TB or are TB patients in HIV-endemic settings and in populations at risk for HIV infection (see Annex 1 ) (15, 16).

3.4. Recommended approach to diagnosis of TB in children

Careful history (including history of TB contact and symptoms consistent with TB)

Contact

Close exposure to a source case with TB involves sharing a living or working space with them. A source case with sputum smear-positive TB is much more likely to infect contacts than cases with sputum smear-negative TB. A household contact is often found to be the source of infection in children under 5 years of age with TB; infants and young children are especially likely to have contracted TB at home. Contact with the source case is usually recent because children who develop TB usually do so within 1 year following exposure and infection (5).

The approach to screening and management of children who are contacts of TB cases is presented in more detail in Chapter 5. The following points concerning contacts are of importance for diagnosing TB in children (5).

  • All children aged 0–4 years (regardless of symptoms) and children aged 5 years and above who are symptomatic, who have been in close contact with a TB case, must be evaluated for TB.
  • Children of all ages living with HIV who have been in close contact with a TB case must be evaluated for TB.
  • When any child is diagnosed with TB, efforts should be made to detect the source case (if not already identified) and any other undiagnosed cases in the household.
  • If a child presents with infectious TB, other child contacts must be sought and screened, as for any smear-positive source case. Children should be regarded as infectious if they have sputum smear-positive pulmonary TB or cavitary TB on chest X-ray (not uncommon in older children and adolescents).

Symptoms

In most cases, children with symptomatic TB develop chronic unremitting symptoms, i.e. symptoms that persist for more than 2 weeks without sustained improvement or resolution following appropriate treatment for other potential diagnoses (e.g. antibiotics for pneumonia; antimalarials for fever; nutritional support for failure to thrive). The commonest symptoms include:

cough

fever

not eating well/anorexia

weight loss or failure to thrive

fatigue, reduced playfulness, decreased activity.

In addition to asking about weight loss or failure to thrive, it is important to look at the child's growth chart if available. Other or additional symptoms will be present in various forms of extrapulmonary TB (i.e. TB of organs other than the lungs) and will depend on the site of disease (e.g. enlarged lymph nodes, back swelling, seizures).

The specificity of symptoms for the diagnosis of TB depends on how strict the definitions of the symptoms are. However, no definite cut-offs, e.g. duration of symptoms, have been validated and accuracy will depend on context. Strict symptom criteria have lower sensitivity and specificity in those at greatest risk of severe disease and poor outcome such as infants or very young children (under 3 years), children living with HIV, or severely malnourished children (1). These groups pose the greatest challenge for clinical diagnosis.

Clinical examination (including growth assessment)

There are no specific features on clinical examination that can confirm that the presenting illness is due to pulmonary TB. Some clinical signs, although uncommon, are highly suggestive of extrapulmonary TB. Other signs are less specific, but should still prompt a diagnostic evaluation for TB. Important physical signs are:

  • Physical signs highly suggestive of extrapulmonary TB:

    gibbus, especially of recent onset (resulting from vertebral TB);

    non-painful enlarged cervical lymphadenopathy, with or without fistula formation.

  • Physical signs requiring investigation to exclude extrapulmonary TB:

    meningitis not responding to antibiotic treatment, with a subacute onset and/ or raised intracranial pressure;

    pleural effusion;

    pericardial effusion;

    distended abdomen with ascites;

    non-painful enlarged lymph nodes without fistula formation;

    non-painful enlarged joints.

Children who are receiving therapeutic nutritional treatment or nutritional supplementation but are still not gaining weight, or are continuing to lose weight, should be considered as having a chronic disease, such as TB.

Tuberculin skin test

A positive TST indicates that a person is or was infected with M. tuberculosis but does not necessarily indicate TB disease. It is a test that measures immune response, not the presence/absence of bacteria. The TST can be a useful tool in the assessment of a child with suspected TB, especially when there is no positive history of TB contact, because a positive TST indicates that the child has been infected at some point.1 It may therefore be used as an adjunct in diagnosing TB in children with signs and symptoms of TB and in conjunction with other diagnostic tests. The TST can also be used to screen children exposed to TB (such as household contact with TB), although contact screening and management can still be undertaken even if the TST is not available (see Chapter 5).

There are a number of methods for performing TSTs, but the Mantoux method is recommended. The TST should be standardized for each country using either 5 tuberculin units (TU) of tuberculin purified protein derivative (PPD-S) or 2 TU of tuberculin PPD RT23, which give similar reactions in children infected with M. tuberculosis. Health care workers must be trained in performing and reading TSTs (see Annex 3).

A TST should be regarded as positive:

in children who are immunosuppressed (including HIV-positive children and severely malnourished children, i.e. those with clinical evidence of marasmus or kwashiorkor): >5 mm diameter of induration;

in all other children (whether they have received a BCG vaccination or not): >10 mm diameter of induration.

There can be false-positive as well as false-negative TST results; possible causes of these are shown in Annex 3. It is important to note that a negative TST does not rule out infection with M. tuberculosis or the possibility of a diagnosis of TB in a child.

Bacteriological confirmation whenever possible

Every effort should be made to confirm diagnosis of TB in a child using whatever specimens and laboratory facilities are available. Appropriate specimens from the suspected sites of involvement should be obtained for microscopy and culture (and histopathological examination in extrapulmonary TB whenever possible), although this will depend on the availability of facilities and resources. Appropriate clinical samples include sputum (expectorated or induced), gastric aspirates and other specimens depending on the site of TB disease (e.g. lymph node biopsy). Fine-needle aspiration of enlarged lymph glands – for staining of acid-fast bacilli (AFB), culture and histology – has been shown to be useful, with a high bacteriological yield (16).

In young children TB is usually a paucibacillary disease, meaning that culture is much more likely than microscopy to yield a positive diagnosis. In addition, culture differentiates M. tuberculosis from non-tuberculous mycobacteria and allows drug susceptibility testing. Bacteriological confirmation is especially important for children who have:

suspected drug-resistant TB

HIV infection

complicated or severe cases of TB disease

an uncertain diagnosis

been previously treated.

Note that TB in older children and adolescents is often similar to adult-type disease (and so is not paucibacillary). In this age group, sputum is often readily available and is often AFB-positive.

HIV testing

Routine HIV testing should be offered to all patients, including children, with presumptive and diagnosed TB (17). Chapter 6 gives further information on the management of TB in children living with HIV.

Investigations relevant for suspected pulmonary TB and suspected extrapulmonary TB

Suspected pulmonary TB

Chest radiography is useful in the diagnosis of TB in children. In most cases, children with pulmonary TB have radiographic changes suggestive of TB; the commonest picture is one of persistent opacification in the lung together with enlarged hilar or subcarinal lymph glands. A miliary pattern of opacification in HIV-negative children is highly suggestive of TB.

Adolescent patients with TB have radiographic changes similar to adult patients, with large pleural effusions and apical infiltrates with cavity formation being the most common forms of presentation. Adolescents may also develop primary disease with hilar adenopathy and collapse lesions.

Good-quality chest radiographs (including lateral view, if and where possible) are essential for proper evaluation and should preferably be read by a radiologist or a health care worker trained in their reading. A practical guide for interpreting chest radiographs of children with suspected TB has been developed (18).

Suspected extrapulmonary TB

Table 2 shows the investigations normally used to diagnose the common forms of extrapulmonary TB. In most of these cases, TB will be suspected from the clinical picture and confirmed by histology or other special investigations.

Table 2. Common forms of extrapulmonary TB in children.

Table 2

Common forms of extrapulmonary TB in children. Note: All fluid (CSF, pleural, ascetic, joint or pericardial) must be subjected to biochemical analysis (protein and glucose concentrations), cell count, AFB stain and culture whenever possible.

Other tests

Specialized tests, such as computerized chest tomography and bronchoscopy, are not recommended for the routine diagnosis of TB in children.

Some countries use scoring systems for diagnosing TB in children. However, these systems have rarely been evaluated or validated against a “gold standard”; when they have been evaluated, they have performed poorly and variably. They perform particularly poorly in children suspected of pulmonary TB (the most common form) and in children who are also HIV-positive. At this point, therefore, WHO cannot give a recommendation regarding the use of scoring systems to diagnose TB (4).

References

1.
Marais BJ, et al. A refined symptom-based approach to diagnose pulmonary tuberculosis in children. Pediatrics. 2006;118:e1350–1359. [PubMed: 17079536]
2.
Schaaf HS, Zumla A, editors. Tuberculosis: a comprehensive clinical reference. London, UK: Saunders Elsevier; 2009.
3.
Perez-Velez CM, Marais BJ. Tuberculosis in children. New England Journal of Medicine. 2012;367(4):348–361. [PubMed: 22830465]
4.
Graham SM. The use of diagnostic systems for tuberculosis in children. Indian Journal of Pediatrics. 2011;78(3):334–339. [PubMed: 21165720]
5.
Recommendations for investigating contacts of persons with infectious tuberculosis in low- and middle-income countries. Geneva: World Health Organization; 2012. (WHO/HTM/TB/2012.9) [PubMed: 24404639]
6.
Use of liquid TB culture and drug susceptibility testing (DST) in low and medium income settings. Summary report of the Expert Group Meeting on the use of liquid culture media, Geneva, 26 March 2007. Geneva: World Health Organization; 2007.
7.
Molecular line probe assays for rapid screening of patients at risk of multidrug-resistant tuberculosis (MDR-TB): policy statement. Geneva: World Health Organization; 2008.
8.
Zar HJ, et al. Rapid molecular diagnosis of pulmonary tuberculosis in children using nasopharyngeal specimens. Clinical Infectious Diseases. 2012;55(8):1088–1095. [PMC free article: PMC3529610] [PubMed: 22752518]
9.
Bates M, et al. Assessment of the Xpert MTB/RIF assay for diagnosis of tuberculosis with gastric lavage aspirates in children in sub-Saharan Africa: a prospective descriptive study. Lancet Infectious Diseases. 2013;13(1):36–42. [PubMed: 23134697]
10.
Nicol MP, et al. Accuracy of the Xpert MTB/RIF test for the diagnosis of pulmonary tuberculosis in children admitted to hospital in Cape Town, South Africa: a descriptive study. Lancet Infectious Diseases. 2011;11(11):819–824. [PMC free article: PMC4202386] [PubMed: 21764384]
11.
Rachow A, et al. Increased and expedited case detection by Xpert MTB/RIF assay in childhood tuberculosis: a prospective cohort study. Clinical Infectious Diseases. 2012;54:1388–1396. [PubMed: 22474220]
12.
Automated real-time nucleic acid amplification technology for rapid and simultaneous detection of tuberculosis and rifampicin resistance: Xpert MTB/RIF system for the diagnosis of pulmonary and extrapulmonary TB in adults and children. Policy Update. Geneva: World Health Organization; 2013. [PubMed: 25473701]
13.
Use of tuberculosis interferon-gamma release assays (IGRAs) in low- and middle-income countries: policy statement. Geneva: World Health Organization; 2011. (WHO/HTM/ TB/2011.18) [PubMed: 26269875]
14.
Commercial serodiagnostic tests for diagnosis of tuberculosis: policy statement. Geneva: World Health Organization; 2011. (WHO/HTM/TB/2011.5)
15.
Guidance on provider-initiated HIV testing and counselling in health facilities. Geneva: World Health Organization; 2007.
16.
Wright CA, Warren RM, Marais BJ. Fine needle aspiration biopsy: an undervalued diagnostic modality in paediatric mycobacterial disease. International Journal of Tuberculosis and Lung Disease. 2009;13(12):1467–1475. [PubMed: 19919763]
17.
WHO policy on collaborative TB/HIV activities : guidelines for national programmes and other stakeholders. Geneva: World Health Organization; 2012. (WHO/HTM/TB/2012.1)
18.
Gie R. Diagnostic atlas of intrathoracic tuberculosis in children: a guide for low-income countries. Paris: International Union Against Tuberculosis and Lung Disease; 2003.

Footnotes

1

However, prior BCG vaccination of the child is a potential cause of a false-positive TST result. The TST might also yield a false-negative result in HIV-positive children and children with severe TB disease, among others, as further discussed in Annex 3

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