Guidance for National Tuberculosis Programmes on the management of tuberculosis in children - an update

Abstract

About one million children develop tuberculosis (TB) annually worldwide. Childhood TB is common in Malawi accounting for about 12% of all TB cases. Childhood TB differs from TB in adults in ways that have important implications for the prevention, diagnosis and treatment of TB in children. Young children living in close contact with a case of smear-positive pulmonary TB are at particular risk of infection and TB disease. Screening of the household contacts of an infectious source case is therefore recommended to identify children with TB and enable their prompt treatment, and to provide children who do not have TB with isoniazid preventive treatment. It is recognised that there is a need to improve the diagnosis and management of children with TB, the prevention of TB in children and to ensure their inclusion under the implementation of the Stop TB strategy by National TB Programmes. A subgroup of the WHO DOTS Expansion Working Group called the Stop TB Partnership Childhood TB Subgroup published guidelines for the management of child TB in 2006. The guidelines are designed to complement current national and international guidelines on the implementation of the Stop TB Strategy and existing guidelines, but also to fill existing gaps to ensure that children with M. tuberculosis infection and TB disease are identified early and managed effectively. This paper summarises some of the most important information and recommendations put forward in those guidelines.

Introduction

A nationwide survey by the Malawi National Tuberculosis Control Programme (NTP) was undertaken in 1998 and reported that 12% of all TB cases were children.¹ Difficulties with diagnosis make it difficult to be certain as to how accurately this reflects the true burden of TB disease in Malawian children. However, it is consistent with global estimates and what might be expected in a TB endemic country such as Malawi where sputum smear positive disease is common.² The source of infection of most children is an infectious adult in their close environment (usually the household). In the majority of cases, the resultant cell-mediated immunity contains the disease process at this stage. Risk of disease progression is increased in the very young and in immune compromised children such as those with HIV or severe malnutrition. Progression of disease occurs by 1) extension of the primary focus with or without cavitation; 2) the effects of pathological processes caused by the enlarging lymph nodes or by 3) lymphatic and/ or haematogenous spread.

Implementation of the Stop TB Strategy³ (see Table 1), which builds on the DOTS strategy developed by the World Health Organization (WHO) and the International Union Against Tuberculosis and Lung Disease has a critical role to play in reducing the worldwide burden of disease and thus in protecting children from infection and disease. The management of children with TB should be in line with the Stop TB Strategy, taking into consideration the particular epidemiology and clinical presentation of TB in children.

Table 1.

Components of the Stop TB Strategy and implementation approaches

Pursue high-quality DOTS expansion and enhancement Political commitment with increased and sustained financing Case detection through quality-assured bacteriology Standardised treatment with supervision and patient support An effective drug supply and management system Monitoring and evaluation system, and impact measurement Address TB-HIV, MDR-TB and other challenges Implement collaborative TB-HIV activities Prevent and control multidrug-resistant TB Addressing prisoners, refugees and other high-risk groups and special situations Contribute to health system strengthening Actively participate in efforts to improve system-wide policy, human resources, financing, management, service delivery and information systems Share innovations that strengthen systems, including the Practical Approach to Lung Health Adapting innovations from other fields Engage all care providers Public-public and public-private mix (PPM) approaches International Standards for TB Care (ISTC) Empower people with TB and communities Advocacy, communication and social mobilisation Community participation in TB care Patients' Charter for Tuberculosis Care Enable and promote research Programme-based operational research Research to develop new diagnostics, drugs and vaccines

For NTPs to successfully manage TB in children, standardised approaches based on the best available evidence are required. The engagement of all who provide care to children (including paediatricians and other clinicians) is crucial. These standardised approaches need to be incorporated into existing guidelines and strategies that have been developed by NTPs. Reducing the burden of TB in children will require changing and improving many existing practices, such as those that relate to contact investigations.

Diagnosis

The diagnosis of TB in children relies on careful and thorough assessment of all the evidence derived from careful history, clinical examination and relevant investigations, e.g., the tuberculin skin test (TST), chest radiograph (CXR) and sputum smear microscopy. Although bacteriological confirmation of TB is not always possible, it should be sought whenever possible, e.g., by sputum microscopy in children with suspected pulmonary TB who are old enough to produce a sputum sample. A trial of treatment with TB medications is not recommended as a method of diagnosing TB in children. The decision to treat a child should be carefully considered, and once such a decision is made, the child should be treated with a full course of therapy.

Most children with TB have pulmonary TB. The proposed approach to the diagnosis of TB in children (Table 2) is based on limited published evidence and rests heavily on expert opinion. In most immunocompetent children, TB presents with symptoms of a chronic disease after they have been in contact with an infectious source case. Infection with M. tuberculosis can be demonstrated by a TST, and CXR changes typical of TB are usually present. The presentation in infants may be more acute, resembling acute severe pneumonia, and should be suspected when there is poor response to antibiotics. There is often an identifiable contact, usually the infant's mother, in this situation. Table 3 shows key features suggestive of TB, and Table 4 key risk factors.

Table 2.

Recommended approach to diagnose TB in children

Careful history (including history of TB contact and symptoms consistent with TB) Clinical examination (including growth assessment) Tuberculin skin testing (TST) Bacteriological confirmation whenever possible Investigations relevant for suspected 1) pulmonary TB, and 2) extra-pulmonary TB HIV testing

Table 3.

Key features suggestive of TB

The presence of three or more of the following should strongly suggest the diagnosis of TB

Chronic symptoms suggestive of TB Physical signs highly of suggestive of TB A positive tuberculin skin test Chest radiograph suggestive of TB

Table 4.

Key risk factors for TB

Household contact with a newly diagnosed smear-positive case Age < 5 years HIV infection Severe malnutrition

Some countries and NTPs use score charts for the diagnosis of TB in children, although these have rarely been evaluated and validated against a ‘gold standard’.⁴ They should therefore be used as screening tools and not as a means of making a firm diagnosis. Score charts perform particularly poorly in children suspected of pulmonary TB (the most common form) and in children who are also HIV-infected.

Recommended approach to diagnose TB in children

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

1. Contact: A close contact is defined as living in the same household or in frequent contact with a source case (e.g., care giver) with sputum smear-positive TB. Source cases who are sputum smear-negative but culture-positive are also infectious, but to a much lesser degree. The following points concerning contact are of importance for children:

   • Children (especially those < 5 years of age) who have been in close contact with a case of smear-positive TB must be screened for TB.
   • After TB is diagnosed in a child or adolescent, an effort should be made to detect the adult source cases, and especially other undiagnosed household cases.
   • If a child presents with infectious TB, then childhood contacts must be sought and screened as for any smear-positive source case. Children should be regarded as infectious if they are sputum smear-positive or have a cavity visible on CXR.

2. Symptoms: Children with symptomatic disease develop chronic symptoms in most cases. The commonest symptoms are chronic, unremitting cough, fever and weight loss. The specificity of symptoms for the diagnosis of TB depends on how strict the definitions of the symptoms are.

   • Chronic cough: an unremitting cough that is not improving and has been present for > 3 weeks.

   • Fever: of >38C for 14 days after common causes such as malaria or pneumonia have been excluded.

   • Weight loss or failure to thrive: always ask about weight loss or failure to thrive and look at the child's growth chart.

b) 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 signs, although uncommon, are highly suggestive of extra-pulmonary TB and the threshold to initiate treatment should be lower. Other signs are common and should initiate investigation as to the possibility of childhood TB.

1. Physical signs highly suggestive of extra-pulmonary TB:

   • Gibbus, especially of recent onset (vertebral TB)
   • Non-painful enlarged cervical lymphadenopathy with fistula formation
2. Physical signs requiring investigation to exclude extra-pulmonary TB:

   • Meningitis not responding to antibiotic treatment, with a sub-acute onset or raised intracranial pressure
   • Pleural effusion
   • Pericardial effusion
   • Distended abdomen with ascites
   • Non-painful enlarged lymph nodes without fistula formation
   • Non-painful enlarged joint

Documented weight loss or failure to gain weight, especially after being treated in a nutritional rehabilitation programme, is a good indicator of chronic disease in children, and TB may be the cause.

c) Tuberculin skin test (TST)

A positive TST occurs when a child is infected with M. tuberculosis. However, in children, TST can also be used as an adjunct in diagnosing TB disease, when it is used in conjunction with signs and symptoms of TB and other diagnostic tests. There are a number of TSTs available, but the Mantoux skin test is the recommended test. The TST should be standardised using either 5TU (tuberculin units) of tuberculin purified protein derivative (PPD) S or 2 TU of tuberculin PPD RT23, as these give similar reactions in infected children. Health care workers must be trained in performing and reading a TST.

TST should be regarded as positive as follows:

• High-risk children: TST ≥ 5 mm induration (high risk includes HIV-infected children and severely malnourished children, i.e., those with clinical evidence of marasmus or kwashiorkor)

• All other children: TST ≥ 10 mm induration is regarded as positive whether or not they have been BCG vaccinated.

A positive TST indicates that the child has been infected with TB but does not necessarily indicate disease. However, when used in a child with symptoms and other evidence of TB disease (such as an abnormal CXR), it is a useful tool in making the diagnosis of TB in a child. The TST is useful in HIV-infected children to identify those with dual TB-HIV infection although fewer HIV-infected children will have a positive test.

Unfortunately, TST is not usually available in Malawi.

d) Bacteriological confirmation whenever possible

It is always preferable to make a bacteriological diagnosis of TB in a child using whatever specimens and laboratory methods are available. Samples include sputum, gastric aspirate and other material (e.g., lymph node biopsy or any other material that is biopsied). Sputum for smear microscopy is a useful test and should always be obtained in adults and older children (≥ 10 years of age) who are pulmonary TB suspects. Among younger children, especially children < 6 years of age, sputum is difficult to obtain and most children are ‘sputum smear-negative’.

e) Investigations relevant for suspected pulmonary and extra-pulmonary TB

Relevant for suspected pulmonary TB, i.e., CXR: In the majority of cases, children with pulmonary TB have CXR changes suggestive of TB. The commonest picture is that of persistent opacification in the lung together with enlarged hilar or subcarinal lymph glands. A miliary pattern of opacification in non-HIV-infected children is highly suggestive of TB. Patients with persistent opacification that does not improve after a course of antibiotics should be investigated for TB.

Adolescent patients with TB have CXR 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 visible on CXR.

Chest radiography is useful in the diagnosis of TB in children, and CXRs should preferably be read by a radiologist or a health care worker trained in their reading. Good quality CXRs are essential for proper evaluation. A practical guide for interpreting CXRs has been developed (available at www.iuatld.org).⁵

Table 5 shows the usual investigations used to diagnose the common forms of extra-pulmonary TB. In most of these cases, TB will be suspected from the clinical picture and confirmed by histology or other special investigations.

Table 5.

Common forms of extra-pulmonary TB in children

Site	Practical approach to diagnosis
Peripheral lymph nodes	Lymph node biopsy or fine needle aspiration (FNA)
Miliary TB	CXR
TB meningitis	Lumbar puncture (and CT where available)
Pleural effusion	Pleural tap chemistry and culture
Abdominal TB	Abdominal ultrasound and ascitic tap
Osteoarticular incl spinal	Radiograph, joint tap
Pericardial TB	Ultrasound and pericardial tap

f) HIV testing

In an HIV-endemic country such as Malawi, HIV counselling and testing is indicated for all TB patients as part of their routine management.

Standardised case definitions of TB in children

The diagnosis of TB refers to the recognition of an active case, i.e., a patient with symptomatic disease due to M. tuberculosis. Beyond the diagnosis of TB disease, the type of TB case should also be defined to enable appropriate treatment to be given and the outcome of treatment evaluated. The case definition is determined by: 1) site of disease, 2) result of any bacteriology, 3) severity of TB disease, and 4) history of previous TB treatment. All children with TB should be registered with the NTP as smear-positive pulmonary, smear-negative pulmonary TB, or extra-pulmonary TB, and as a new case or a previously treated case. The standard case definitions are the following:

1 Pulmonary TB, sputum smear-positive

• Two or more initial sputum smear examinations positive for AFB, or

• One sputum smear examination positive for AFB plus radiographic abnormalities consistent with active pulmonary tuberculosis as determined by a clinician, or

• ne sputum smear positive for AFB plus sputum culture positive for M. tuberculosis.

Children with smear-positive disease are more likely to be adolescent patients or children of any age with severe intrathoracic disease.

2 Pulmonary TB, sputum smear-negative

A case of pulmonary TB that does not meet the above definition for smear-positive TB. This group includes cases without smear result, which should be exceptional in adults but are relatively more frequent in children. In keeping with good clinical and public health practice, diagnostic criteria for pulmonary TB should include:

• At least three sputum specimens negative for AFB, and

• Radiographic abnormalities consistent with active pulmonary TB, and

• No response to a course of broad spectrum antibiotics, and

• Decision by a clinician to treat with a full course of tuberculosis chemotherapy.

3 Extra-pulmonary TB

Children with only extra-pulmonary TB (i.e., TB of organs other than the lungs) should be classified under this case definition. Children who have both pulmonary and extra-pulmonary TB should be classified under the case definition of pulmonary TB.

Management of children in contact with TB

It is recommended that all NTPs screen household contacts for symptoms of disease and offer isoniazid preventive therapy (IPT) to children aged < 5 years and to all human immunodeficiency virus (HIV) infected children who are household contacts. Young children living in close contact with a case of smear-positive pulmonary tuberculosis (PTB) are at particular risk of M. tuberculosis infection and TB disease. If this case causes infection or disease in a contact, the case is referred to as a ‘source’ case. The risk of infection is greatest if the contact is close and prolonged, such as the contact between an infant or toddler and a mother or other care-givers in the household. The risk of developing disease after infection is much greater for infants and young children aged < 5 years than it is for older children. If disease does develop, it usually does so within 2 years of infection, but in infants the time-lag can be as short as a few weeks. Daily isoniazid (INH) for at least 6 months as preventive therapy for young children with infection who have not yet developed disease will greatly reduce the likelihood of developing TB during childhood. IPT is often referred to as ‘isoniazid prophylaxis’.

The main purposes of childhood contact screening are to:

1. identify symptomatic children (i.e., children of any age with undiagnosed TB disease)

2. rovide IPT for susceptible individuals (i.e., asymptomatic children aged < 5 years in close contact with smear-positive PTB cases).

The usual method to detect TB infection is using the TST. CXR is used to screen for TB disease. However, in Malawi, this is often not possible because tuberculin solution is unavailable and getting a CXR is often problematic. Contact screening and management can be conducted on the basis of simple clinical assessment. Clinical assessment alone is sufficient to decide whether the contact is well or symptomatic. Routine assessment of exposed contacts does not require routine CXR or TST (see Figure). This approach applies to contacts of smear-positive PTB cases, but screening should also be available for contacts of smear-negative PTB cases. If the contact of a source case with smear-negative PTB is symptomatic, the diagnosis of TB needs to be investigated as above, whatever the contact's age.

Figure.

Clinical algorithm approach to contact screening

Recommended treatment for a healthy contact aged < 5 years is INH 5 mg/kg daily for 6 months. Follow-up should be at least every 2 months until treatment is complete. If TB is suspected at initial assessment or at subsequent follow-up, then appropriate investigation is required. Referral to a district hospital may be necessary when there are uncertainties about the diagnosis. Contacts with TB disease should be registered and treated according to TB treatment guidelines.

Special circumstances

1. Child contact is known to be HIV-infected

   If the child contact is HIV-infected and otherwise well, consider IPT for all ages, including those aged > 5 years. As with other contacts, active disease should be ruled out, and only HIV-infected children who are healthy should be offered IPT. HIV-infected children who have symptoms should be carefully evaluated for TB, and if found to have TB disease, they should be referred to the NTP for registration and initiation of treatment.

2. Management of a baby born to mother diagnosed with infectious PTB

   Once a pregnant woman has been on treatment for at least 2–3 weeks, she is generally no longer infectious. If a pregnant woman with TB has been on treatment for TB for several weeks before delivery, it is less likely that the baby will become infected. The risk is highest if a mother is diagnosed at the time of delivery or shortly thereafter. If a pregnant woman is found to have pulmonary TB shortly before delivery, then the baby, and if possible, the placenta, should be investigated for evidence of congenital TB infection and, if found, the baby should be treated.

A breastfeeding infant has a high risk of infection from a mother with smear-positive PTB, and has a high risk of developing TB. The infant should receive 6 months of IPT, followed by BCG immunisation.³

Breastfeeding can be continued safely during this period. An alternative policy is to give 3 months of IPT, then perform a TST. If the test is negative, INH should be stopped and BCG vaccination given. If the test is positive, INH should be continued for another 3 months, after which it should be stopped and BCG given.

Managing child contacts within the NTP

Close contact screening and management is recommended by most NTPs, but rarely happens in low-resource settings, where the majority of childhood TB occurs—although for the majority of child contacts assessment can be a straightforward procedure that simply requires clinical evaluation. In addition to lack of resources, the other major obstacle is that there is usually no provision for the management of contacts within the NTP structure, e.g., children started on IPT are not usually registered.

There is no need to create a separate structure for contact screening and management. It is possible to work within the existing NTP structure and with existing specialist support. It is useful to establish a ‘contact clinic’, i.e., a set time and place each week where child contacts can be assessed clinically. This clinic can be at first referral level, whether district hospital or health centre.

It would be best if responsibility for contact tracing and subsequent management lay with the same healthcare worker who registers and/or supervises the treatment of the source case. This health care worker could then also provide IPT or treatment to the children. This is likely to be more convenient for the household or family and to improve compliance by all concerned.