Wednesday, September 4, 2019

Why is TB Testing So Difficult in Children?

Have you ever had your child tested for tuberculosis (TB)? It's not required in all American school districts, but in our school it's required of all 8th graders before they head off to service projects in the fall. Chances are you might have had this done if you are in a caregiving profession like daycare or occupational therapy. Whenever I hear Americans surprised that tuberculosis still even exists, it's further evidence to me that my global advocacy work on tuberculosis treatment and prevention is still needed. This bacterial infection is still found in EVERY country in the world and it is the leading infectious cause of death worldwide. TB sickens 10.4 million people a year and kills 1.7 million of them. Since 2015, it has been the leading global infectious disease killer, surpassing even HIV/AIDS! Tuberculosis is a global pandemic that kills one person about every 18 seconds, according to TB Alliance

Happily, TB is treatable and - in almost all cases - curable. Yet at the RESULTS International Conference for the past two years, I've been hearing about how the main problems with the fight against TB have to do with lack of advances in methods of treatment as well as diagnostics. With a highly infectious airborne disease like TB, diagnosis is of critical importance. If you can't find it, you can't fight it. We're failing to deliver quality treatment to 40% of people in the world who are sick with TB. And who is bearing the biggest burden of this failure? Children. 

Dr. Jeffrey Starke, director of Children's Tuberculosis Clinic at Texas Children's Hospital, told Infectious Diseases in Children, "Children are the most neglected group of individuals regarding controlling TB." Today, 90% of children with TB go untreated. Combine that with the fact that children usually respond very well to TB treatment, even for drug-resistant TB, and that tells me that a lot of kids could be saved if we could better diagnose them. 

My question of the day is: "Why is it so hard to accurately test kids with TB?"

First, let's be clear about two kinds of TB since each requires a different test. There is TB infection, which is when someone has inhaled the bacteria and the body contains the infection in the lungs. At that stage it is serious and requires a course of preventive antibiotics, but it is NOT ACTIVE and it is NOT CONTAGIOUS. Then, there is the active form when the relatively dormant infection becomes TB disease. Active TB, usually found in the lungs, is life-threatening and must be treated with antibiotics. When occurring in the lungs, it can be spread through coughing, though once a patient is on effective treatment they quickly become non-infectious. 

In the US, 9105 people developed the disease in 2017 and another 13 million have the infection according to the CDC. According to an estimate published in the Lancet in 2019, more than 30,000 people in the US have a form of TB infection that is multi-drug resistant. 

Clinical Exams
Let's start with the simple clinical examinations. Most people associate tuberculosis with a persistent cough, but for kids a cough is not a prominent way TB presents. Adults can describe other symptoms like night sweats, and weight loss, but tiny kids might not be as verbal about such things. If an x-ray machine is available, the disease will show up there for adults. But children don't usually get cavities in their lungs that would indicate the presence of TB. That makes it harder, but not impossible, to make an accurate diagnosis.

Good news! No bump.
My daughter doesn't have TB!
PPD Injection Test
Now let's look at the injection test that my child just had. In the U.S., we have a standard purified protein derivative (PPD) test that is given to both kids and adults. A small shot of PPD is administered just under the top layer of skin, which will cause a small bump to form. After 2 days, a medical professional needs to check to see that the bump disappeared to indicate the patient doesn't have TB. There are a few problems with this.
  1. The test takes 2 days for a result, so that is obviously inconvenient.
  2. Many kids in developing countries get a BCG vaccine, which helps prevent some forms of childhood tuberculosis and would test positive. That would be a false positive, however, since it would not indicate TB infection. 

Hold up right there. A TB vaccine? Why doesn't everyone use that? Because the BCG vaccine isn't a reliable way to prevent kids from being infected with TB or developing TB disease. It does protect younger children against certain complicated and lethal forms of TB, but the efficacy varies and it does not protect against TB disease in the lungs, which is the most common form. So, it's better than nothing in countries with a high TB burden, but it screws up PPD test results.

Ok, so that PPD test doesn't work for a lot of situations. What's next?

IGRA Blood Test
The best alternative to the PPD skin test is a blood test for infection called IGRA. This is a rapid test and will not be affected by BCG, but it is more expensive than PPD and so it is not available everywhere.

Sputum Test
The usual method for diagnosing active TB disease is to test sputum, a mixture of saliva and mucus coughed up from the respiratory tract. One problem with this method is that is that it's hard for little kids to cough up the sputum. But you can get a sample from the stomach because children often swallow the sputum. You can also find TB germs sometimes in spinal fluid or lymph nodes, but those samples aren't super easy to collect. A low-tech way to test the sputum is to look at it under a microscope, but those tricky kids tend to have fewer bacteria and the TB might not be detectable that way. Only 1 in 3 children with TB test actually positive with a sputum test.

If a community is lucky, they can test using a GeneXpert system that can rapidly detect TB and whether it's a drug-resistant strain in under two hours. Wow! No wonder this was heralded as a breakthrough tool. It's still a relatively new tool as it was launched in 2010. It takes a while for something like GeneXpert to get to underfunded medical facilities in communities of extreme poverty. The commonly used system costs about US$17,000, not to mention a widely varying installation cost of US$2600-7000. So, "wow" indeed. I can see why everyone doesn't have one yet. 

So, now you and I both know a bit more about TB testing. Probably the main reason testing is so difficult for both the infection and the disease is that very little money has been put into the research and development of new tests, particularly ones that are work for kids. TB is vast problem and this is one of the many reasons why we need a spirit of global cooperation among governments to tackle this disease the way we fight HIV/AIDS and polio. The best thing that you and I can do about TB right now is to call our senators right now and ask them:

"Would you support U.S. efforts to control and treat TB and drug-resistant TB? I'd like to senator to sign onto the Stop TB Now Act, which has the number S. 2438.  It updates old and, in some cases, obsolete instructions to USAID about how to end TB. It imposes new requirements, including a full program evaluation and better coordination."