Childhood TB has been neglected for decades, but in the past few years the WHO has begun to realise its real impact in terms of incidence, prevalence and mortality. By R. PRASAD
THE number of annual new tuberculosis (TB) cases in India has been nearly 2.2 million for the past couple of years. Many of these infected people would have been in contact with children aged under five years before being diagnosed and, in all probability, would have already passed on the infection to them.
It is well documented that children living in the same household as an adult who has recently been diagnosed with sputum smear-positive pulmonary TB (index case) are at great risk of getting infected and diseased and also of dying of TB. This is why the World Health Organisation (WHO) recommends in its 2006 “Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children” that contact screening of children younger than five for TB disease/infection be undertaken whenever there is an index case in the same household. Yet, India’s Revised National Tuberculosis Control Programme (RNTCP) has no data on the actual number of young children who are infected or diseased. “The actual burden of paediatric TB is not known due to diagnostic difficulties but it has been assumed that 10 per cent of the total TB load [in the country] is found in children,” notes the 2012 RNTCP annual report. The RNTCP is completely in the dark regarding the paediatric caseload though it adopted the WHO’s 2006 recommendation on contact screening.
On the basis of information from the relatively few papers on the subject published in scientific journals, the incidence of childhood TB in high-burden countries, India included, is pegged at 10 to 20 per cent of the total number of TB patients. It can rise up to 40 per cent in some select communities. For instance, in 1993, children accounted for 20 per cent of the total caseload in South Africa, notes a study published in 1995; in a community in Cape Town in South Africa, children constituted 39 per cent of the total caseload, according to a 1999 study. According to a 2006 WHO report, children (younger than 15) in the 22 high-burden countries accounted for about 75 per cent of the one million childhood cases found across the world. In contrast, children in the low-burden developed countries accounted for only about 5 per cent of the global TB caseload.
Besides the greater possibility of TB-diseased adults who are yet to start treatment infecting their children aged under five and the high incidence of TB in India, the population pyramid is such that children under the age of 15 years constitute a high percentage of the total population. All these factors increase the likelihood of children getting exposed to the TB bacilli at a young age and, as a consequence, getting infected and diseased.
In addition, India’s TB control programme continues to follow the passive case detection system, wherein TB patients are required to walk into a health facility to get diagnosed. This means there is a lag period before a TB-diseased adult is correctly diagnosed and started on treatment. People with active disease tend to infect 10 to 15 people through close contact every year until treatment is initiated.
Contact screening of young children has twin advantages. While those with TB disease would be put on treatment well before it progresses to a severe form, providing the WHO-recommended preventive therapy—10 mg/kg of isoniazid mono-drug treatment daily for at least six months—to asymptomatic children as well as to those who are infected but are yet to develop the killer disease would cut down on the number of children who would suffer from it. “Isoniazid preventive therapy [IPT] for young children with infection who have not yet developed the disease will greatly reduce the likelihood of [their] developing TB during childhood,” the WHO states in its 2006 recommendation.
However, a study undertaken in 2009 by the Chennai-based National Institute for Research in Tuberculosis (NIRT) in four TB centres—two in Vellore (rural) and two in Chennai —found that only 19 per cent of the screened children aged under six had been initiated on preventive treatment. A follow-up study undertaken by the same team after it had provided health workers with basic training on all aspects of contact screening and preventive treatment found a tremendous improvement. Sixty-one per cent of the children aged below six had been screened for TB disease and put on preventive treatment; 74 per cent of those initiated on treatment had completed it. The NIRT study revealed many shortcomings in the implementation of contact screening and the initiation of IPT. For instance, it brought to light the ignorance of health workers, particularly in the rural areas, about the need to undertake contact screening and start preventive treatment even in those children who were found to be disease-free. The TB centres had no separate preventive therapy register and treatment cards for children who had been started on preventive treatment. This is despite the 2007 official statement of the Childhood TB subgroup of the Stop TB Partnership: “Children recommended for IPT should be registered separately and have their own IPT card… on which the details of the source case are also recorded. A prophylaxis register can be used to keep track of the contact.”
Innumerable studies have shown that children from five to 10 years of age are less likely to get infected than those under five even if they are in close contact with an index case in the same household. The WHO also recommends contact screening only in those younger than five. Yet, the RNTCP has implemented contact screening in those aged under six, thereby increasing the number of children to be screened. A few other studies have also pointed out that the implementation of the RNTCP’s contact screening and preventive treatment is “suboptimal” at best.
The WHO has placed much emphasis on contact screening because the risk of developing disease after infection is much greater in the case of infants and children younger than five than in other people. The progression from infection to disease is as short as two years in the case of young children, with nearly 90 per cent becoming TB infected within the first year, and in hardly a few weeks in the case of infants. In children younger than two, “various elements of the primary complex and also overwhelming dissemination of TB [such as military TB and TB meningitis] are particularly likely to occur”, notes a 2007 WHO report—“A Research Agenda for Childhood Tuberculosis”. “In all analyses from many countries, morbidity and mortality are excessively high among children < 1 year, and are still considerable among children aged 1-4 years before children enter the so-called ‘safe school age’ of 5-10 years.” Children aged 10 years and above tend to develop adult-type TB disease.
In the case of infants and those younger than five, parents or caregivers who have been recently diagnosed with sputum smear-positive pulmonary TB disease are by rule the source of infection. The risk of children getting infected and diseased depends on the proximity and duration of contact and the severity of the disease (TB bacilli load) in the index case. In fact, when any infant or child younger than five is diagnosed with TB disease but no adult in the household has been diagnosed with it, all adults in the household must immediately be tested for the disease.
Four key risk factors
According to the WHO’s “Guidance for National Tuberculosis Programmes…”, the four key risk factors for TB are household contact with a newly diagnosed smear-positive case, age less than five, human immunodeficiency virus (HIV) infection, and severe malnutrition. Index cases who are sputum microscopy smear-negative but culture-positive are also infectious but to a much lesser degree than those who are sputum microscopy smear-positive. According to the WHO, contacts who need to be screened are those aged under five years (whether sick or well) and children five years or older if symptomatic and are in close contact with a source case. Although children can present with TB disease at any age, the “most common age is between one and four years”.
Every child who presents with TB disease “represents an opportunity missed by the health system to have prevented the disease”, notes the WHO’s recently released report titled “Roadmap for Childhood Tuberculosis”. “This is particularly true in the case of infants and young children.” In fact, the very occurrence of TB in young children is a prime index of the ongoing transmission and prevalence of TB in the community. For instance, the resurgence of childhood TB in the United States in the 1990s, when the prevalence shot up to 20 per cent, was because childhood TB incidence touched a peak of 40 per cent. “The resurgence was driven mainly by immigration from endemic areas and the breakdown of basic tuberculosis control practices such as case reporting, contact tracing and screening, and the use of preventive therapy,” notes a 2006 paper in American Journal of Respiratory and Critical Care Medicine.
MDR-TB in children
The prevention, diagnosis and management of multi-drug-resistant TB (MDR-TB) in children is complicated. To start with, “there is no data on the [total] global burden of MDR-TB, but it is likely to be considerable given that up to half a million people fall ill worldwide,” the “Roadmap” report notes. Although not much is known about MDR-TB burden in children, the WHO has made a strong statement in its “Global Tuberculosis Report 2013”: “A child with TB was shown to be as likely as an adult with TB to have MDR-TB. It is therefore essential that the identification of MDR-TB in children be strengthened. Efforts should be made to systematically conduct household contact investigation of all patients with MDR-TB, including children.”
There is strong evidence from South Africa on why such attention is needed in the case of children with MDR-TB. Researchers there found that about “75 per cent” of children aged under 15 have the possibility of getting infected with MDR-TB when they come into contact with an adult with this form of TB. The chances must be much higher in case of children aged under five who are in close contact with an index case with MDR-TB in the same household. They also found that about 90-95 per cent of children with drug-resistant TB infection progress to a diseased state within one year. Even if they do not become diseased, the infected children carry a lifelong risk of coming down with MDR-TB when their immune system weakens or gets compromised.
Treating children with MDR-TB is riddled with problems. As there are no second-line paediatric drugs currently available to treat children with MDR-TB, it becomes necessary to break or powder drugs meant for adults. This leads to either under-dosing or overdosing children and thereby complicating the treatment further. The second-line drugs have “pronounced adverse effects” and the treatment period, according to the revised 2011 WHO guidelines for the programmatic management of drug-resistant tuberculosis published in European Respiratory Journal, is 20 months, with the intensive treatment lasting for at least eight months.
Moreover, notes a 2012 paper published in the journal Tuberculosis, “robust information is lacking regarding their [second-line drugs] pharmacokinetic properties, adverse effects, and drug interactions, especially in children”. The WHO is yet to come out with an MDR-TB preventive treatment recommendation for children as the effectiveness of such a treatment has yet to be established. Despite that, the U.S. already has a preventive treatment policy in place. “Following the European CDC [Centre of Disease Prevention and Control] Expert meeting on this issue, it seems as if there is a swing of the pendulum towards favouring preventive therapy for MDR-TB contacts,” stated Prof. H. Simon Schaaf from the Department of Paediatrics and Child Health, Faculty of Health Sciences, Desmond Tutu TB Centre, Stellenbosch University, South Africa, in an email to this correspondent.
Although several studies estimate childhood TB to be 10-20 per cent in high-burden countries, the recorded numbers are very low. According to “Global Tuberculosis Report 2013”, childhood TB globally is estimated to be about half a million, or 6 per cent of the total TB load. Incidentally, in 2011, the WHO estimated the prevalence to be around one million. According to a 2010 paper in the journal Clinical Infectious Diseases, in 2007, children below 12 years with smear-positive TB disease comprised hardly 0.6-3.6 per cent of all the reported cases.
Although data on the actual burden of childhood TB remain elusive, “clinical and autopsy data from the sub-Saharan African region show that TB is a major cause of morbidity and mortality in children”, notes a 2011 paper in the journal Paediatric Respiratory Reviews. For instance, the 2006 paper in American Journal of Respiratory and Critical Care Medicine reveals that the severity of the disease in children came to light in Zambia when an autopsy study was conducted: TB was found to rival acute pneumonia as a “major cause of death from respiratory disease in children from endemic areas”.
A closer inspection of the data reveals why the true burden of childhood TB is grossly underestimated. For instance, only HIV-negative children with TB disease have been taken into account to arrive at the global childhood TB burden. Also, as the “Roadmap for Childhood Tuberculosis” report highlights, national TB control programmes routinely report only the sputum smear-positive cases. Nearly 85-90 per cent of TB in children below 12 is sputum smear-negative, and these go unreported, leading to a gross global caseload underestimation. Extra-pulmonary TB in children alone accounts for 25-30 per cent of the TB cases and requires specimens other than sputum for disease confirmation.
TB disease cannot be diagnosed in children, particularly the young ones, because of the non-availability of effective diagnostic tests. In fact, diagnosing childhood TB is one of the biggest challenges that the global TB control programme is facing today and is the reason why estimating the true burden—globally and at a country-level—becomes very difficult. Children younger than five find it difficult to produce sputum; they tend to swallow it. But a sputum specimen is essential for diagnosing pulmonary TB. Different invasive techniques are available to collect sputum samples. But even when samples are thus collected, they, by default, contain very few TB bacilli, which is why paediatric TB is called a paucibacillary disease.
Sputum smear microscopy is the most widely used technique in developing countries for diagnosing pulmonary TB, but its sensitivity is rather poor—15-20 per cent depending on age, disease severity and the number of bacteria in the sputum specimen. “Bacteriological confirmation, the accepted gold standard, is of limited use in children because of the paucibacillary nature of the disease and poor bacteriological yields,” states a 2006 paper in American Journal of Respiratory and Critical Care Medicine. But the sensitivity is good in children older than 10 with adult-type disease.
The sensitivity of the GeneXpert MTB/Rif assay, a rapid molecular diagnostic technology that was approved by the WHO in December 2010, is far superior to that of smear microscopy. Its lower limits of detection are just 131 colony-forming units (CFU)/ml in the sputum sample; smear microscopy needs much higher levels. Hence, it is capable of detecting a high proportion of children who are culture positive. However, GeneXpert does not perform well in the case of culture-negative children. “A negative test with Xpert still does not rule out TB in a child since many children with active TB may not have enough mycobacteria present to have disease bacteriologically confirmed,” Dr Anne Detjen, Technical Consultant, The Union North America Office, International Union Against Tuberculosis and Lung Disease, New York, said in an email to this correspondent. “And smear positive is a proxy for more advanced disease.”
Children present with non-specific clinical manifestations of TB disease. Young children who are diseased commonly present with cough persisting for over three weeks, fever (over 38° C) for two weeks and weight loss. Although these clinical manifestations do not necessarily indicate TB disease, they call for detailed examination using smear microscopy, the tuberculin skin test (TST) and chest X-rays. While a positive TST indicates that the child is infected with TB, it does not necessarily indicate TB disease. In the same way, “a negative TST never rules out a diagnosis of TB in a child”, the WHO notes. Malnutrition can result in negative TST result, as can recent infection—it takes two to three months after infection takes place for a tuberculin test to become positive; this is called the window period.
Although nearly 40 per cent of the people of India are infected with TB and the chances of having a positive TST result are fairly high in older children and adults, there is a very low likelihood of infants and children younger than five returning a positive TST result unless they were infected. Clinical symptoms, though not truly typical, a suggestive chest X-ray, a positive TST result and contact with a known adult TB case from the same household together are highly suggestive of TB disease. But the national TB control programme insists that bacteriological confirmation is mandatory. But advanced techniques, which are available only in hospitals and tertiary centres, are required to collect the sputum, and even when it is collected, the probability of the specimen having sufficient TB bacilli is low. Currently, in the absence of a bacteriological report, children are denied treatment by India’s TB programme. This holds true even in the case of children with MDR-TB, including those who are seriously sick with meningitis. This is why the “Roadmap for Childhood Tuberculosis” report has identified research on diagnostic tests as one of its priorities.
Probably, better diagnostic technologies would have become available long ago if the WHO had realised years back that the “actual burden of TB in children is likely higher [than its estimates]”. The WHO’s 2007 “A Research Agenda for Childhood Tuberculosis” report summarises the plight of those with paediatric TB. “Childhood TB is a neglected aspect of the TB epidemic, despite constituting 20 per cent or more of the TB caseload in many countries with high TB incidence. This ‘orphan disease’ exists in the shadow of adult TB and is a significant child health problem, but is neglected because it is usually smear-negative and is thus considered to make a relatively minor contribution to the spread of TB,” the report noted.
As a result, paediatric TB, especially in those younger than five years, until recently, was largely ignored as it was not a “main priority of global TB control efforts for various reasons”. “Childhood TB has historically been neglected by the global TB community and the health community in general,” acknowledges the “Roadmap for Childhood Tuberculosis” report.
“Childhood tuberculosis is neglected in endemic areas with resource constraints, as children are considered to develop mild forms of disease and to contribute little to the maintenance of the tuberculosis epidemic,” notes a 2006 paper in American Journal of Respiratory and Critical Care Medicine. But a 1997 paper in The International Journal of Tuberculosis and Lung Diseases brings out the repercussions of ignoring TB in children: “Although childhood TB has a limited influence on the immediate spread and epidemiology of TB… [it] contributes to a pool from which TB may arise in the future.” It goes further and states that in developing countries “considerable numbers of young children may be infected before the age of five years and thus be exposed to the risk of subsequent disease”.
But the tide is turning. “After decades of being relegated to the shadows, the childhood TB epidemic” is getting its due attention. In the past few years, the global health body has begun to realise the real impact of childhood TB in terms of incidence, prevalence and mortality. The “childhood TB epidemic is now in the global spotlight”.
The WHO’s annual “Global Tuberculosis Report” has been including the estimates of the global TB burden in children below 15 years since last year. For the first time, in “Global Tuberculosis Report 2013”, the WHO made a mention of MDR-TB in children. In 2010, the WHO revised the anti-TB drug dosage for children after it became abundantly clear that children were being treated with suboptimal dosages. There is also focussed attention on making available child-friendly, first-line, fixed-dose combination drugs.
The sentinel project
The Sentinel Project on Paediatric Drug-Resistant Tuberculosis—“a global partnership of researchers, caregivers, and advocates who share a vision of a world where no child dies from this curable disease”—is contributing its mite to MDR-TB management in children. The virtual network with over 300 experts and non-experts from over 50 countries has already come out with a field guide to help medical practitioners manage children with MDR-TB disease. It has also provided broad guidelines on preventive therapy for children who are in close contact with adults with MDR-TB disease.
(R. Prasad, Science Editor, The Hindu, is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB.)