With 8.6 million people across the world developing tuberculosis in 2012 and nearly 1.3 million succumbing to the disease, and with the number of people with multi-drug resistant TB (MDR-TB) and extremely-drug resistant TB (XDR-TB) increasing every year, the focus has been on increasing case-detection and improving treatment rates.

In the process, no significant measures have been undertaken to prevent the disease. This is true in the case of developing countries, particularly in high-burden countries, including India.

This is despite the fact that we know one third of the global population (and nearly 40 per cent of the Indian population) is estimated to be latently infected with TB. Since 5-20 per cent of these latently infected people develop the disease at some point in their lifetime, the infected people serve as a huge reservoir.

One more glaring blind spot in our war against TB has been the near-neglect of children. This is despite ample evidence that many children who are infected when young become diseased as they age, even if they do not become diseased soon after infection.

But the focus is now shifting, and childhood TB is slowly getting its due attention. For the last two years, WHO in its annual report has been including the estimates of global TB burden in children below 15 years. And for the first time ever, WHO recently came up with a Roadmap for Childhood Tuberculosis. In 2010, WHO had come out with Rapid Advice for Treatment of Tuberculosis in Children. The global health body had earlier come out with guidelines for implementing contact tracing of children belonging to the most vulnerable group — under five years from families where an adult had been diagnosed with active pulmonary TB.

But countries, especially the developing ones, have shown little inclination in undertaking contact tracing despite knowing that many of the infected children become diseased in a matter of weeks and the mortality rate is also significantly high.

In a long-winding interview over email, Dr Greg Fox, Post-doctoral Research Fellow at McGill University, Montreal explains to R. Prasad why and how important contact tracing of children aged under five is to win the war against TB.

How high are the chances of children below five years becoming diseased in households where a person has been recently diagnosed with active pulmonary TB?

See our meta-analysis (2013 paper in the European Respiratory Journal by Gregory J. Fox et al.,) with data for children for the rates of disease and infection in children. Our study found: “In 95 studies from low- and middle-income settings, the prevalence of active TB in all contacts was 3.1 per cent, microbiologically proven TB was 1.2 per cent, and latent TB infection was 51.5 per cent.”

What is the minimum time for a child below five years to get infected with TB when an adult in the household with active pulmonary TB is yet to start treatment?

If you define infection as the time from exposure to tuberculin skin test (TST) positivity, then there can be a delay of 8-12 weeks before TST becomes positive.

Compared with an adult, how vulnerable are children in this age group to TB infection when an adult in the household who is infected with active pulmonary TB is yet to start treatment?

In terms of disease, young children under five have a higher risk of disease than older children. A 2010 paper by Brooks-Pollock in PLoS ONE journal shows the age distribution of mortality in Ukraine. Young children are therefore very susceptible, and probably more susceptible than younger adults.

The susceptibility to infection is a different question. It is difficult to say, since the lifetime cumulative incidence of TST positivity increases over the lifetime. By the time a person is in the 30s, in a high prevalence country, he/she will usually have a high prevalence of latent TB infection (LTBI). The incremental effect of additional life-time exposure in this group [under five years of age] is small.

Aren’t children who have taken BCG vaccine on time naturally protected against TB, particularly in the first few years after vaccination?

[BCG vaccine does not prevent primary TB infection.] A 2010 paper in Clinical Infectious Diseases journal by Soumya Swaminathan and Banu Rekha states: “BCG vaccine has been shown to be protective against disseminated forms of TB in young children, with a summary protective estimate of 73 per cent (range, 67 per cent –79 per cent) against TB meningitis and 77 per cent (range, 58 per cent–87 per cent) against miliary disease.”

In a TB-endemic setting like India, will children not be at risk of getting infected with TB from contacts outside the household?

Yes. Community transmission is probably the bulk of transmission in high prevalence settings. The evidence of the proportion of transmission that occurs in the household is limited to a few small studies using molecular epidemiology in the context of household contact investigation. For example, a January 17, 2004 paper by Suzanne Verver in The Lancet shows this. The evidence is limited in India, to my knowledge.

What is the rationale for having a cut-off age of five years? Will children older than five years not gain from preventive therapy?

The WHO guidelines recommend that children under five years (i.e. 0-4 years) should be a priority for contact investigation. As in studies such as those by Brooks-Pollard, there is a clearly higher risk of mortality in children of 0-4 years. Hence this is a priority for screening. Of course, there is still benefit for all other ages — however the ages 5-18 have a substantially lower rate of mortality.

How effective is isoniazid as a prophylactic? For how long does the protective effect last?

The sustained effect is primarily related to the reduction in transmission that occurs as a result of the latent TB infection (LTBI) treatment in the community, but depends upon factors including treatment completion rates, the uptake of LTBI therapy in the community etc.

Is the six-month treatment a standard treatment regimen across the world or are there different timeframes depending on how endemic TB is in a region?

Six months is inferior to 12 months. Many countries use nine months. It also depends upon the proportion of treatment that is actually taken (completion of >80 per cent of a 12-month course results in a 90 per cent reduction, compared to a 60 per cent overall observed effect in real life setting.

Does the isoniazid drug cause any side-effects in children, especially those who are one year and two years of age?

The risk of complications of isoniazid is lower in younger children, but nonetheless they do occur.

How accurately is the dosage of 10 mg per kg calculated in reality? Are there any problems when the dosage is more?

This depends on how accurately the child is weighed. The theoretical risk of drug induced liver injury increases with dose, which has been shown in animal models.

[WHO “Rapid advice for TB treatment in children” for current dosing guidelines states: “Infants (aged 0–3 months) with suspected or confirmed pulmonary tuberculosis should be promptly treated with the standard treatment regimens. The treatment may require adjustment of dosages to reconcile the effect of age and possible toxicity in young infants. The decision to adjust dosages should be taken by a clinician experienced in managing paediatric tuberculosis.”]

How prudent is it to expose young children, especially one-year-old and two-year-old children, to X-rays when they don’t even have the disease?

Child contacts with suspected TB (on the basis of symptoms) should have a chest X-ray. The risk of a single chest X-ray is minimal. The advantage of diagnosing potentially life-threatening TB is substantial. Given the high risk of TB disease in child contacts, the risk-benefit calculus strongly favours an X-ray. In child contacts, where available, chest X-ray is a useful screening test for active TB (note that TST is often not available in many settings). However, symptom screening alone has been shown to be effective if this is all that is available.

How aware are health-care workers and doctors of the need for undertaking contact screening of children aged under five in high-burden countries?

Contact investigation is not frequently undertaken. A 2011 paper in the International Journal of Tuberculosis and Lung Diseases by T.J. Hwang et al., states: “Contact investigation contributes to improving early case detection of tuberculosis (TB). However, its implementation in low-income, high TB-burden countries remains limited.”

As a norm, are children in the developing countries on prophylactic treatment regularly followed-up for any symptoms of TB disease? How frequent are such follow-ups?

Follow-up depends on the setting. Generally, most programmes have single screening interventions near the time of exposure. The WHO recommends only a single-screening intervention.

On average what is the default rate? Which developing country has the highest adherence rate to drug treatment (six months)?

A 2012 paper in Cochrane Database Systems Review has some good examples. In countries like Canada, the U.S. and Australia, treatment completion rates can be very good because there is close supervision and regular follow-up during the entire treatment.

When children with latent TB default after some time, do they become more vulnerable to developing resistance to isoniazid?

The risk of developing isoniazid resistance is very low and not clinically significant in the treatment of children with latent TB infection where active disease is excluded. If a child stops taking isoniazid, then there is no selective pressure to develop isoniazid resistance again. If they repeatedly stop and start isoniazid during active disease, then yes, this would predispose them to increased risk — but that is why active disease should be excluded (clinically and/or radiologically).

On average, what is the success rate of putting children on prophylactic treatment for the number of children contacted, both in the developing and developed countries?

There is little information on this as no data is routinely collected by different national TB programmes. A 2012 paper in BMC Research Notes by Merrin E. Rutherford et al., is a good illustration of how this can be done (in Indonesia, they found compliance was only about 25 per cent).

How much do poor nutrition, small dwellings and crowded settings facilitate children developing the disease when an adult in the household has been recently diagnosed with active pulmonary TB?

The risk of infection and disease will vary depending upon the local epidemiology. If the prevalence of active disease is higher, then the risk of TB would also be higher.

The risk factors you identify (poor nutrition, overcrowding) are certainly recognised to be associated with increased incidence of TB. Social determinants of disease are important. An April 2011 paper in the American Journal of Public Health is informative.

How cost effective is contact screening of children and putting them on treatment?

Cost-effectiveness of treating latent TB infection varies substantially depending upon local factors. One study in Canada (2008 paper in Value Health journal) is informative.

Is there a difference in children easily developing latent/active TB when an adult is infected either with drug-resistant TB or drug-sensitive TB?

The rate of infection in contacts of MDR-TB and drug susceptible tuberculosis appears to be similar (see September 24, 2013 paper in Clinical Infectious Diseases journal by Shah et al.,). However, there are arguments about the fitness cost of drug resistance (see 2009 paper by Borrell et al). However, as MDR-TB typically has a prolonged period of infectiousness, relating to delayed diagnosis, probably overall contacts have a higher risk of developing infection and disease.

Do you think mass awareness campaign like what was done in the case of HIV/AIDS would help in increasing the awareness level of contact screening in the community and increase/change the health-seeking attitude of people?

Mass awareness campaigns need to be carefully designed, or they can reinforce the stigma associated with TB. Generally speaking, childhood TB contact investigation should be seen as a part of the broader approach to TB control — with the message that there can be benefit to the children from being assessed. World TB Day often provides a time for countries to focus upon TB in high-risk groups, such as child contacts, although I cannot quantify what proportion of countries make children a focus. Certainly the WHO Roadmap for Childhood TB is a part of an attempt to raise awareness of this issue. It is as much a challenge to educate policy makers and TB services about childhood TB as it is to educate patients, their contacts and the general public.

(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB.)