Abstract

Objectives: To ascertain childhood tuberculosis (TB) trends, human immunodeficiency virus (HIV) co-infection rates and multi-drug resistant TB (MDR-TB) prevalence rates in Zambia.

Methods: A retrospective review of Zambian annual TB notification data and National TB Programme reports for a 7 year period (2004–2011). TB trends were stratified by age and HIV status.

Results: The total number of children notified during this period with all forms of TB was 40 976. A total of 2670 of 40 976 (6%) were smear-positive cases. Notification rates of all forms of childhood TB show a decline in trends from 135 per 100 000 population in 2004, to 69 per 100 000 population in 2011.

Conclusions: Childhood TB is an important but neglected problem in Zambia highlighted by the fact that no data exists on HIV co-infection and MDR-TB. Strengthening of the National TB Programme and diagnostics services/algorithms are required to accurately define the TB burden, HIV co-infection and MDR-TB rates in children in Zambia.

Introduction

The World Health Organization (WHO) estimates the global tuberculosis (TB) burden to be ∼9 million new cases each year, of which up to 500 000 were multi-drug resistant TB (MDR-TB) [1]. A total of 10–20% of the global burden of TB cases are thought to occur in children (aged <15 years) [2, 3], although country-specific figures are highly unreliable and variable. National TB Programmes (NTPs) focus on sputum smear-positive adult pulmonary TB cases, as they are responsible for transmission of Mycobacterium tuberculosis and are a public health hazard [2, 4]. Children have traditionally not been seen to pose a public health hazard, as they rarely develop lung cavities, and most of them do not produce sputum [5, 6]. Accurate diagnosis of TB in children remains difficult [7, 8] and poses several diagnostic challenges [4]. Clinical diagnostic algorithms have been complicated by co-infection with human immunodeficiency virus (HIV), malnutrition and the non-specific nature of most symptoms and signs [7, 9]. Children often develop extra-pulmonary TB, such as lymph node disease or meningitis, which are easily overlooked.

Childhood TB represents recent transmission [10, 11]. Apart from having the highest TB incidence rates, sub-Saharan Africa (SSA) is also affected by a large HIV/acquired immune deficiency syndrome epidemic [8, 12]. HIV infection has led to a huge rise in the number of TB cases since 1990, and also appears to have introduced a pronounced age and gender shift, affecting more women of child bearing age [8, 13, 14]. Thus, children, both HIV infected and uninfected, are more vulnerable to infection with M. tuberculosis and to developing TB. Reported figures on childhood TB from most high-burden countries probably represent a gross under-estimate of TB case load. Furthermore, the burden of co-infection of childhood TB with HIV and that of MDR-TB in children has not been accurately defined. Sputum microscopy is often the only diagnostic test available at points of care in most sub-Saharan African countries (SSA), and it performs poorly in children because of the inability to obtain sputum samples from children and the paucibacillary nature of sputum from those co-infected with HIV. Furthermore, the burden of MDR-TB in children in SSA has been poorly defined.

Surveillance data and reporting systems on childhood TB are weak in SSA because of these reasons. There is a need to fully understand and quantify the actual contribution of childhood TB to the overall TB burden, especially in SSA [4]. There were no surveillance data available before 2004 on childhood TB. We conducted a retrospective review of childhood TB notifications in Zambia, from 2004 to 2011, to ascertain the childhood TB trends, HIV co-infection rates and MDR-TB prevalence rates to guide future investments in childhood TB services of the Zambia NTP.

Methods

We reviewed annual Ministry of Health TB notification data for the past 7 years, from 2004 to 2011, based on surveillance data records and compared trends in adults and children. Surveillance data are compiled from patient record cards at the health facility or hospital, and the data are entered in a TB register and notified as a TB case based on national guideline definitions as adapted from WHO. A TB case is defined as a patient presenting with signs and symptoms consistent with TB, for whom bacteriological examination, the mainstay, which is light microscopy of sputum or gastric lavage specimens, was performed. Each case is defined as either smear positive, smear negative or extrapulmonary TB.

All patients diagnosed with TB are offered diagnostic counselling and testing routinely, but they can opt out if they so wish. The data from facilities are later consolidated into a district register and consequently reported to the provincial level as an aggregation of all cases notified. The national data are aggregated from the respective provincial levels. Verification and validation of data are performed through supervisory visits by staff from the higher level to the lower levels on a quarterly basis to ensure good quality data are compiled.

During the period under review, there was no change in case definition or treatment regimens except for the introduction of child drug formulations in 2009. There was 100% reporting from all the facilities during the review period. Further analysis was based on the NTP reports, reviewed for the same period. In addition, NTP review reports for 2005 and 2010, and available published data were analysed to understand reasons for the discrepancies in notifications of the different age bands. Population data were collected from Zambia Central Statistics Office reports; the population figures for the children <15 years of age was based on two census points (2000 and 2010), and the population data for the period under review were projected estimates according to the Zambia Central Statistics Office. Key policy documents, the National TB/HIV Manual, National TB/HIV guidelines and programme-specific reports were also used to provide relevant information on childhood TB management issues.

Ethics Statement

This study was approved by the Ministry of Health, Lusaka, Zambia. This study was a retrospective review of Ministry of Health returns and did not involve information that would compromise patient confidentiality, and anonymity of identity was maintained.

Results

There were no data on HIV co-infection rates in children with TB, or on MDR-TB in children during this period.

Table 1 depicts trends in all forms of TB case notification rates (CNRs) from 2004 to 2011 (≥15 vs. <15 years). Children accounted for 10% (40 976/406 248) of the total notifications of all forms of TB from 2004 to 2011. As a proportion of the notification in the overall general population, the childhood TB notification rate represented only 11% (60 per 100 000 population) in 2004 and 8% (32 per 100 000 population) in 2011. Notification rates of all forms of childhood TB show a decline in trends from 135 per 100 000 population in 2004, to 69 per 100 000 population in 2010. When the data were segregated by type of TB, a downward trend was observed in all TB types. Children accounted for only 2% (2670/110 463) of the total smear-positive TB cases notified during the period from 2004 to 2011. There were more cases (74%) notified from the urban provinces (Lusaka, Copper belt, Central and Southern provinces), referred to as ‘along the line of rail’, compared with notifications (26%) from the rural provinces (Eastern, Western, North-Western, Luapula and Northern Provinces). Generally there was a downward trend in the notifications of adult cases aged >15 years from 463 to 330 per 100 000 population in 2004–11, respectively.

Table 1

Childhood TB CNRs per 100 000 population—2004–2011

 2004 2005 2006 2007 2008 2009 2010 2011 
Type of TB 
    All forms <15 years 135 118 103 90 79 94 70 69 
    SS − ve <15 years 80 74 56 46 40 53 38 34 
    EPTB <15 years 34 29 33 31 28 28 24 26 
    Retreatment <15 years 11 
    SS + ve <15 years 
General population 
    All forms of TB <15 years 60 53 46 40 35 41 32 30 
    All forms of TB ≥15 years 463 415 388 375 343 335 335 330 
    All forms of TB total 524 468 434 415 378 376 366 361 
 2004 2005 2006 2007 2008 2009 2010 2011 
Type of TB 
    All forms <15 years 135 118 103 90 79 94 70 69 
    SS − ve <15 years 80 74 56 46 40 53 38 34 
    EPTB <15 years 34 29 33 31 28 28 24 26 
    Retreatment <15 years 11 
    SS + ve <15 years 
General population 
    All forms of TB <15 years 60 53 46 40 35 41 32 30 
    All forms of TB ≥15 years 463 415 388 375 343 335 335 330 
    All forms of TB total 524 468 434 415 378 376 366 361 

SS−ve, sputum smear negative; EPTB, extra-pulmonary TB; SS+ve, sputum smear positive

The total number of children <15 years notified during the study period with all forms of TB was 40 976, of which only 2529 (6%) were smear-positive cases; 56% (22 746/40 976) were smear negative; 31% (12 610/40 976) extra pulmonary TB and 7% (2950) retreatment cases. There were more female children notified than male children with smear-positive TB throughout the study period [1557/2670 (57%)]. Although female subjects were over-represented among sputum smear-positive cases, in total, slightly more male TB cases [21 333/40 976 (52%)] were notified than female cases throughout the study period (Fig. 1).

Fig. 1.

Childhood TB notification rates by gender—2004–11.

Fig. 1.

Childhood TB notification rates by gender—2004–11.

There were more children between the ages of 5 and 14 years notified compared with children <5 years in all the provinces in 2011 as shown in Table 2. There were no age-stratified data for the remaining years of the study period.

Table 2

TB CNRs (per 100 000 population) by age groups and gender per province—2011

 0–4 years
 
5–14 years
 
Province 
Lusaka 91.23 75.30 124.01 120.57 
Copper belt 36.07 30.25 61.96 68.94 
Southern 59.51 48.12 44.14 61.58 
Central 24.18 18.92 31.54 23.65 
Eastern 14.76 13.93 32.03 22.98 
Western 32.91 22.10 46.04 47.89 
Luapula 19.17 11.41 37.09 36.52 
Northern 4.97 4.97 14.98 16.81 
N-Western 31.87 28.86 65.40 61.64 
Zambia 36.50 29.73 51.71 52.67 
 0–4 years
 
5–14 years
 
Province 
Lusaka 91.23 75.30 124.01 120.57 
Copper belt 36.07 30.25 61.96 68.94 
Southern 59.51 48.12 44.14 61.58 
Central 24.18 18.92 31.54 23.65 
Eastern 14.76 13.93 32.03 22.98 
Western 32.91 22.10 46.04 47.89 
Luapula 19.17 11.41 37.09 36.52 
Northern 4.97 4.97 14.98 16.81 
N-Western 31.87 28.86 65.40 61.64 
Zambia 36.50 29.73 51.71 52.67 

Discussion

Bacillus Calmette-Guerin (BCG) coverage was consistently above 90% for the whole period under review according to the WHO and the United Nations Children's Fund (UNICEF) estimates of national immunization coverage (2010 revision). Despite this, childhood TB is a major cause of morbidity and mortality in low/middle-income countries like Zambia [10] and poses multiple diagnostic challenges [13, 15], which are even more pronounced in HIV-infected children [7, 16]. Important findings from our study are as follows: (i) although the TB burden in adult Zambians is high, comparatively less than expected childhood TB cases were notified during the study period. (ii) Data on HIV co-infection and MDR-TB in children are non-existent. (iii) A total of 10% of 350 000 TB cases notified are in children, mostly in those older than 5 years of age, and gross under-reporting of TB occurs because of continued reliance on sputum microscopy for TB diagnosis. (iv) Improved diagnostic services and diagnostic criteria for childhood TB are required in Zambia, and (v) strengthening of the NTP is required to accurately define the TB burden, HIV co-infection and MDR-TB rates in children.

The majority of adult pulmonary TB cases reported from Zambia are in the reproductive age group 25–44 years [17], and thus, a high proportion of these patients will have transmitted it to their children. During the 7 year study period, >350 000 TB cases were notified [17]. In our review period, childhood TB in all forms only accounted for only 10% of TB cases, mostly older than 5 years of age (Table 2). This is lower than the expected case burden of up to 20% in high TB endemic countries with on-going transmission [18]. This may reflect that TB diagnosis in Zambian children is based mainly on clinical diagnostic criteria or on sputum smear microscopy, a sample difficult to obtain from children <5 years, who are more susceptible to TB regardless of their HIV status. Smear microscopy is the mainstay for TB diagnosis in Zambia [8, 19]. The majority of childhood TB cases have no microbiological confirmation and are treated empirically. Children rarely develop cavitary disease and more often than not tend to have paucibacillary TB [3, 20, 21]; therefore, low microscopy yield is expected. Nonetheless, programmes for the prevention of mother-to-child transmission of HIV infection were well implemented and scaled-up during the study period [22]. These programmes could have led to decreased incidence of HIV infection at birth and could have contributed to the decrease in TB incidence among children.

Many of the cases had either sputum smear-negative or extrapulmonary TB. It is difficult to validate how accurate the diagnoses were in each of these cases, but most cases were diagnosed at referral centres by experienced clinical personnel. It is likely that the low notifications in the rural provinces was also because of lack of qualified medical personnel with enough skills and knowledge to confidently diagnose TB in children, implying a huge barrier to treatment access, especially in more remote areas. To fully address the challenges of childhood TB, it is necessary to develop and evaluate new improved accessible and cost effective diagnostics that should be available at point-of-care in all the areas and provinces in low-resource settings like Zambia.

Despite a landmark autopsy study, performed a decade ago, of 164 children dying of respiratory illness in Lusaka, Zambia, which identified TB as the cause of death in 24% of these children [7], childhood TB remains a poorly quantified problem in SSA and Zambia. Many of these undiagnosed TB cases had been missed at points of care, even at tertiary referral centres, indicating that a huge childhood TB burden was missed and remained untreated. Similar results were obtained in subsequent autopsy studies conducted in Botswana [16, 23]. A prospective descriptive study from Durban, South Africa, confirmed that M. tuberculosis is a common pathogen among children with community-acquired pneumonia not responding to a course of antibiotics [24]. Other reports support these findings, indicating that TB remains a major cause of death in children [7, 25, 26], and children in resource-limited settings die undiagnosed because of poor diagnostic tools [23–25].

Our study found that 74% of childhood TB cases were notified from the more urbanized areas situated along the ‘line of rail’, and only 26% were notified from the rural provinces [27]. One reason attributable for this difference could be that the majority of the 213 TB laboratory diagnostics facilities (55%) are concentrated in urbanized areas [17], although other determinants need to be considered. Extension of laboratory services to the rural areas is required.

Although, generally, there are more male than female TB cases notified [8], the opposite was the case in smear-positive childhood TB, with more female than male smear-positive childhood TB cases notified. It is well documented that adolescent female subjects tend to develop adult-type sputum smear-positive TB more frequently than male subjects, from 10 to 15 years of age [28]. HIV co-infection in children with TB is responsible for a large proportion of deaths in SSA children [7, 29]. A total of 70% of all adult TB cases notified in Zambia are co-infected with HIV [8]. In Zambia, actual data on HIV co-infection in children with TB, and the load of MDR-TB in children, remain undefined. This needs further study so as to align TB and HIV services and to incorporate early antiretroviral therapy with anti-TB treatment in those co-infected.

Our data indicate that although the Zambia NTP has made some progress in overall TB control [8, 17], there has been minimal improvement in childhood TB case detection rates. Efforts should be focused on developing strategies that specifically address childhood TB diagnosis and management. Childhood TB services need to be strengthened in terms of diagnostic capacity through training of care providers, use of newer and novel diagnostics and improvement of the current diagnostic tools. There is a need to explore the use of new TB diagnostic tools and to develop consensus childhood TB diagnostics algorithms such as that recently proposed by Graham and colleagues [9] to improve the standard of care for childhood TB and increase case detection rates. Fine needle aspiration biopsy has been proven to increase the yield of childhood TB cases [30, 31] and may be applied in addition to Ziehl Neelsen microscopy in areas where there may be challenges in accessing radiology and LED and fluorescence microscopy. Unfortunately, it is not yet used in Zambia. The Xpert MTB/RIF assay is a new molecular diagnostic tool that has been demonstrated to be more accurate than microscopy for the detection of childhood TB and could be used as a proxy for obtaining data on MDR-TB [32]. Its potential in rural settings in Zambia must be investigated.

Improved health services delivery to children in rural and resource-limited settings is required. These include improved diagnosis of sputum smear-positive TB in adults to limit transmission, and implementation of simple symptom-based screening strategies to improve provision of preventive therapy to high-risk children following documented TB exposure [33]. Although isoniazid preventive therapy is recommended in the WHO guidelines, its implementation has been minimal within the Zambia NTP [34]. Efforts need to be intensified to ensure isoniazid preventive therapy is provided to children based on symptom screening [18].

Currently available diagnostics for TB and MDR-TB in children are insufficient, and the number of cases detected does not accurately reflect the actual TB burden in children. Smear microscopy performs poorly, and the inability to obtain sputum samples from children, the paucibacillary nature of sputum from those co-infected with HIV and the inability to identify MDR-TB are the main challenges of identifying and quantifying the actual childhood TB load in resource-poor high TB/HIV endemic settings. Where optimal culture facilities are available, confirmation is delayed, and the combination of sputum smear and culture still misses many cases of childhood TB. Identifying feasible strategies to prevent, diagnose and treat childhood TB is an important but neglected responsibility of many NTPs in TB endemic countries. It is reasonable to assume that a reduction in the incidence of childhood TB (which may pass undetected) would also lower under-5 mortality and assist countries to meet important millennium development goals [35].

Funding

UBS Optimus Foundation, Zurich, Switzerland (to A.Z.); UK National Institute for Health Research UCLH-CBRC (to A.Z.); University College London Hospitals National Health Service Foundation Trust (to A.Z.); EuropeAID ADAT grant (to A.Z., P.M., J.O.G. and M.B.); UK Medical Research Council (to A.Z.); European and Developing Countries Clinical Trials Partnership-PANACEA grant (to A.Z.) and European and Developing Countries Clinical Trials Partnership-TB-NEAT grant (to A.Z., P.M., J.O. and M.B.).

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