The most compelling reason to make treating children with tuberculosis in high-burden settings a priority is the fact that they suffer severe morbidity and mortality. Tuberculosis rivals acute pneumonia as the most common respiratory cause of death in African children older than 6 months.1 In addition, older children (older than age 8) may develop adulttype cavitating disease and contribute to disease transmission within the community.2·3 The fact that children infected with Mycobacterium tuberculosis contribute to a reservoir of latent infection is less relevant in high-burden settings, where the vast majority of adult disease results from recent transmission and not from reactivation.4
In high-burden settings, children represent a significant proportion of the tuberculosis caseload.5 Our particular research area includes two suburbs in Cape Town, South Africa, with a total population of 38,656.6 The suburbs have a high burden of tuberculosis (average reported rate of new bacteriologically confirmed tuberculosis cases is 320 per 100,000 population) and a low prevalence of HIV infection (5.2% among women attending antenatal clinics in 1998).6 In this area, children constitute more than one-third (39%) of the total tuberculosis caseload.5 It remains extremely difficult to assess the true effect of tuberculosis on child health in the developing world, because accurate data on childhood tuberculosis are not available.7 Although some official figures are reported, these are severely limited by the absence of accurate diagnostic tools and the fact that specific disease entities are not adequately identified.8
A new approach to the diagnosis of childhood tuberculosis is required, especially in high-burden settings where many children are infected with M. tuberculosis. The natural history of the disease illustrates that primary infection, as demonstrated by tuberculin skin test (TST) conversion, erythema nodosum, or transient radiological signs indicative of a Ghon complex, is a low-risk event in the average immune competent child. Fewer than 5% experience disease progression following primary infection.3 However, this is not true for all children. Primary infection after age 10 poses a high risk of future adult-type (cavitory) disease (10% to 15%), while infection in those age 2 or younger and in immune-compromised children poses a high risk of Ghon complex associated disease (10% to 30%) and dissemination (5% to 10%).39 The challenge in a resource-limited setting is to separate these risk groups and direct treatment intervention at those children who are at highest risk of disease progression.10 Infection is a high-risk event in very young and immunocompromised children, which justifies prophylactic chemotherapeutic intervention. However, infection is a low-risk event in older, immune-competent children, which requires that treatment intervention focus on the small minority with established disease when resources are limited.
ILLUSTRATIVE CLINICAL CASES
The following represent typical pediatric cases seen in a high-burden setting, illustrating the challenges of tuberculosis intervention and control in children.
An 11-year-old girl developed adult-type (cavitary) tuberculosis 8 months after primary infection as indicated by erythema nodosum. Young children in the household were not screened for infection or disease, because she was not viewed as an adult case even though she was sputum smear-positive. National Tuberculosis Control Program (NTCP) guidelines did not acknowledge the transmission risk that this girl posed to her family. She frequently took care of her 1-year-old sister, who received no prophylaxis. This sister developed a chronic cough and dense segmental consolidation on chest radiograph. Tuberculosis was diagnosed after she failed to respond to a course of antibiotics and was referred to the local hospital.
Transmission occurs via inhalation of small, aerosolized infectious droplets. These droplets are produced mainly by untreated sputum-smear positive people regardless of their age,2 although smearnegative cases also contribute.8 Transmission may occur anywhere, but the risk of transmission is determined by both the intensity and the duration of exposure. Most small children develop primary infection following exposure in the household.8
Persistent, Nonremitting Symptoms
A 3-year-old boy presented with chronic, nonremitting respiratory symptoms of cough and wheezing. He failed to respond to multiple courses of antibiotics and was treated as an asthmatic. Tuberculosis was not considered because of the absence of a smear-positive household source case. Progressive symptoms and additional failure to thrive prompted a TST (18-mm induration), and the child was diagnosed with large airway obstruction secondary to subcarinal and hilar lymph adenopathy, identified on chest radiograph. Bronchoscopy confirmed large caseated lymph nodes obstructing the right main bronchus.
Persistent, nonremitting symptoms are typical of progressive tuberculosis and precede serious disease progression in older children, providing a window of opportunity for clinical diagnosis and therapy.3 In a high-burden setting, children often are infected following unknown exposure in the community.8
A 1 -year-old girl with poor weight gain received a TST as a screening test before food supplementation was provided. The TST was positive (17-mm induration), and the chest radiograph was normal. In accordance with NTCP guidelines, chemoprophylaxis was started, and she gained adequate weight on food supplementation. No inquiry about possible source cases at home (source case tracing) was done. The child's uncle, who lived with her family, was diagnosed with advanced sputum smearpositive tuberculosis 3 months later. At the same time, a 7-year-old sibling presented with a pleural effusion. All children younger than 5 in the household were actively screened for disease, and a 4-year-old girl had hilar adenopathy and a positive TST. She was started on treatment while the other children received chemoprophylaxis.
Source case tracing is a valuable but often overlooked tool for early identification and treatment of infectious cases. The fact that this young girl was infected (as indicated by her TST response) pointed toward a possible source case at home. Simple symptom-based questioning could have identified the uncle as the most likely source, 3 months before his ultimate presentation. Hilar adenopathy and pleural effusion both are disease manifestations indicating recent primary TB infection.3
A 9-month-old child was treated with unsupervised prophylaxis after her father was diagnosed with sputumsmear-positive tuberculosis. The social circumstances were poor, the mother and father had an unstable relationship, and both had alcohol dependency. Compliance with prophylaxis was poor but the mother was not recalled when she failed to collect the child's monthly supply of prophylactic isoniazid (INH). The child presented 2 months later with focal convulsions and a depressed level of consciousness. Tuberculous meningitis (TBM) was diagnosed.
Unsupervised chemoprophylaxis is advised by all the major treatment guidelines. As this case illustrates, supervision may be essential in settings where expected compliance is poor and the risk posed to the child is very high.
A 2-year-old child received LNH prophylaxis after a sputum-smear-positive adult source case was diagnosed in the household. The source case did not respond to therapy clinically, and multidrug-resistant (MDR) tuberculosis was confirmed after 5 months of conventional therapy. At this point, the child contacts of the source case were not retraced, and the child presented 1 month later with advanced MDR disease despite receiving standard INH prophylaxis.
Prophylaxis for MDR TB is controversial because source case sensitivities and alternative child-friendly formulations often are unavailable. The principle is to re-screen the child contacts for infection and disease following confirmation of MDR disease in the source case.12 Those children at high-risk of progressive disease following infection should be offered chemoprophylaxis. Effective chemoprophylaxis requires at least two second-line drugs to which the organism is expected to be sensitive for a duration of 9 to 12 months.
Hearth System Delay
The mother of a 1 -year-old girl brought her to the clinic with concerns regarding her recent unexplained anorexia, weight-loss, and lethargy. She mentioned that the child is in regular contact with her grandmother, who had been recently diagnosed with tuberculosis. The grandmother did not live in the same house but frequently looked after the child. The child received a TST, which was negative, and received no prophylaxis. The mother brought the child back repeatedly because of persistent concern regarding the child's unusual lethargy and the additional onset of fever. The child was referred to the local hospital and evaluated for tuberculosis meningitis. Early stage 1 disease was diagnosed. The child had an excellent long-term outcome due to early intervention.
Health system delay may have dire consequences in small children, as compared with adults. Persistent, nonremitting symptoms of lethargy or fever always should be taken seriously, especially when there is a history of probable tuberculosis exposure. This case underlines the importance of well-informed and vigilant caregivers.
Tuberculosis is a major cause of childhood morbidity and mortality in high-butden settings, particularly in the third-world settings. Effective intervention in these resource-limited areas requires a clear focus on high-risk groups. Children rarely contribute to disease transmission, but their disease is the direct result of continued transmission within the community. The burden of childhood tuberculosis reflects the level of epidemiological control achieved within the adult population. Adequate diagnosis and treatment should be available for every child, but reducing the burden of childhood disease requires a conceited effort to contain the epidemic.
1. Chintu C, Mudenda V. Lucas S. et.al. Lung diseases at necropsy in African children dying from respiratory illnesses: a descriptive necropsy study. Lancet. 2002:36019338):985-990.
2. Curtis AB, Ridzon R, Vogel R, et.al. Extensive transmission of Mycobacterium tuberculosis from a child. N Engl J Med. 1999:341(20): 1491-1495.
3. Marais BJ, Gie RP, Schaaf HS, et.al. The natural history of childhood intra-thoracic tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004;8(4):392-402.
4. Van Rie A, Warren R, Richardson M et.al. Exogenous reinfection as a cause of recurrent tuberculosis after curative treatment. N Engl J Med. 1999; 341 : 1 1741179
5. Donald PR. Childhood tuberculosis: out of control? Curr Opin Pulm Med. 2002;83): 178-182.
6. Verver S, Warren RM, Munch Z, et al. Proportion of tuberculosis transmission that takes place in households in a high-incidence area. Lancet. 2004; 363(9404):212-214.
7. Walls T, Shingadia D. Global epidemiology of paediatric tuberculosis. J Infect. 2004;48( 1 ): 13-22.
8. Marais BJ, Gie RP. Schaaf HS et.al. The clinical epidemiology of childhood pulmonary tuberculosis: a critical review of literature from the pre-chemotherapy era. Int J Tuberc Lung Dis. 2004;8(3):278-285.
9. Marais BJ, Gie RP, Schaaf HS, et al. A proposed radiologic classification of childhood intra-thoracic tuberculosis. Pediatr Rad. 2004. In press.
10. Marais BJ. On the definition of relevant disease. Arch Dis Child. 2004:89(5 ):497.
11. Donald PR. van Zyl LE, de Villiers J. BCG vaccination status of children with tuberculous meningitis and the use of unsupervised isoniazid prophylaxis. 5 AfrMedJ. 1995:85(3): 167-170.
12. Schaaf HS, Shean K, Donald PR. Culture confirmed multidrug resistant tuberculosis: diagnostic delay, clinical features, and outcome. Arch Dis Child. 2003:88(12): 1106-1111.