Cover Story

Children with TB: A global public health crisis

WHO estimates that 1 million children become ill with tuberculosis every year, and approximately 230,000 die. Children made up one-tenth of the estimated 10 million people worldwide who developed TB in 2017, but confirming diagnosis in children is challenging, creating critical delays in starting treatment.

“Over 90% of the pediatric cases never get treatment,” Jeffrey R. Starke, MD, professor of pediatrics at Baylor College of Medicine and director of Children’s Tuberculosis Clinic at Texas Children’s Hospital, told Infectious Diseases in Children. “They are either never determined to have TB, or children are dying so quickly that they are not getting on treatment. It is not just a TB issue. It is a child survival issue.”

On Sept. 26, 2018, at a U.N. General Assembly high-level meeting on TB, heads of state reaffirmed their promise to end the epidemic by 2030.

Malgorzata Grzemska, MD, PhD, MPH, the coordinator of the global tuberculosis program at WHO, said new tools are needed to end the global TB epidemic, especially an effective vaccine.
Source: WHO, Geneva, Switzerland

However, Starke said that goal may not be possible.

“While a large decrease in the annual number of cases and deaths from TB can be achieved in a relatively short period of time, the number of persons living with untreated tuberculosis infection ensures that a substantial number of cases will continue to occur,” he said.

There are persistent gaps in detection and treatment, and experts have warned that the global burden of TB is not shrinking fast enough to meet goals set by WHO’s End TB Strategy, which aims to reduce TB deaths by 90% and new cases by 80% by 2030, compared with 2015 rates. WHO’s goal for 2035 is a 95% reduction in death and a 90% reduction in the TB incidence rate — or fewer than 10 per 100,000 people.

Moreover, according to the 2018 WHO Global Tuberculosis Report, although global funding for diagnosing, preventing and treating TB has more than doubled since 2006, it continues to fall short of what is needed. Among the 119 low- and middle-income countries that reported data, funding reached $6.9 billion in 2018 — well short of the estimated $10.4 billion required.

Infectious Diseases in Children asked pediatric and ID specialists if the 2030 goal was realistic, and about some of the persistent challenges of treating, preventing and diagnosing TB in children.

‘Quite ambitious’

“There is no question that TB is a global epidemic in children,” said Starke, an Infectious Diseases in Children Editorial Board member. “Children are the most neglected group of individuals regarding controlling TB.”

Starke said that before 2012, there was no clear picture of the burden of pediatric TB globally. In its first global estimate, WHO showed that there were 500,000 annual pediatric cases and 75,000 deaths. As better evidence became available, the numbers shot up before slightly declining to their current levels.

Jeffrey R. Starke

In a recent MMWR, CDC epidemiologist Adam MacNeil, PhD, MPH, and colleagues estimated that in 2017, 10 million incident cases of TB occurred, representing a 1.8% decline from 2016, and 1.57 million TB deaths occurred, a 3.9% decline from the previous year. Numbers of TB cases and disease incidence were highest in Southeast Asia and Africa, and 9% of cases occurred among people infected with HIV.

“These numbers demonstrate only modest progress in reducing TB, as measured by the number of cases of disease, death and drug resistance,” MacNeil told Infectious Diseases in Children.

According to MacNeil, multiple strategies are needed to reduce TB worldwide.

“These strategies include innovative approaches to case finding; scale-up of TB preventive treatment, especially among populations at high risk; use of newer TB treatment regimens; and the prevention and control of HIV infection,” he said.

In another MMWR, Amish Talwar, MD, MPH, an Epidemic Intelligence Service officer at the CDC, and colleagues wrote that the number of new TB cases in the U.S. in 2018 was 9,029 — the lowest number ever recorded — but the rate of progress toward the goal of eliminating TB in the U.S. has slowed.

Specifically, they noted that TB incidence declined an average of 1.6% per year from 2014 to 2018 — a slower rate of decline compared with the 4.7% annual decrease seen from 2010 to 2014.

“The current level of progress remains insufficient to eliminate TB in the United States in this century,” Talwar told Infectious Diseases in Children.

Nicole Salazar-Austin, MD, assistant professor at the Johns Hopkins School of Medicine, said the U.N.’s 2030 goals were “quite ambitious,” but she is cautiously optimistic that they can be achieved.

“We need to gain control of and end the TB epidemic,” she said, but “it will take significant commitment and large efforts by many stakeholders to make that happen by 2030.”

New tools are needed, including a point-of-care diagnostic test that can be used by health workers at the community level, in addition to much shorter treatment regimens, according to Malgorzata Grzemska, MD, PhD, MPH, the coordinator of the global tuberculosis program at WHO.

She said the length of current TB treatment is between 6 and 18 months.

“We definitely need something much shorter, less toxic and more affordable in cost, but most of all we need a good vaccine that will be very effective, both pre- and post-exposure,” Grzemska told Infectious Diseases in Children. “If we have all those tools by 2025, we should be able to bend the curve and achieve the goals toward ending TB.”

Grzemska said that at the U.N. General Assembly meeting, WHO member states agreed to provide treatment for 40 million people with TB and to provide preventive treatment for 30 million people, including household contacts and people living with HIV and other conditions that would affect their immunity.

“Currently, this is not happening,” she said. “This is one of the toughest things to do — accelerate this very cost-effective intervention. In children, it can be lifesaving.”

Treatment challenges

First-line drugs used to treat active TB in children have not changed in decades, according to Salazar-Austin. The combination of rifampin, isoniazid and pyrazinamide continues to be used with or without ethambutol — just like it is in adults. The drugs were first developed in the 1950s and 1960s and eventually became part of the standard TB treatment in the 1980s.

Nicole Salazar-Austin

“For a long time, we were probably underdosing children with TB medications,” Salazar-Austin said. “In the last 10 years, we have optimized dosing for first-line TB drugs in children, but concerns remain about dosing in malnourished children.”

To meet the U.N.’s goal of elimination of the TB epidemic by 2030, Starke said the development of new drugs and drug regimens is essential, and researchers should begin testing those agents in children as early as possible, before licensing.

“It is imperative to know the pharmacokinetics and safety profiles of the drugs for children ASAP,” he said.

To improve adherence, all new drugs should have child-friendly formulations before licensing as well, Starke added.

Grzemska noted that the first fixed-dose combination of rifampin, isoniazid and pyrazinamide in one tablet was approved in 2015. The tablet, which disperses in water, is used for the intensive phase of treatment of active, susceptible TB in the first 2 months. Then, a fixed-dose combination of rifampin and isoniazid is administered for 4 months. She added that the two-drug, fixed-dose combination of rifampin and isoniazid can also be used to treat latent TB infection in children who weigh less than 25 kg.

To improve adherence, the tablet has a fruity flavor.

“Children actually like it,” Grzemska said.

WHO’s last pediatric TB guideline came out in 2014. The organization is expected to update its guidance in 2020, “given that there are a few trials and observational studies ongoing on several aspects of prevention, diagnosis and treatment,” Grzemska said.

Starke said the earlier TB is identified in children, the more effective treatment can be.

“The key to this is contact tracing,” he said.

Grzemska agreed, suggesting that the early diagnosis of TB in children and the early initiation of treatment “could lead to a 100% cure rate.”

Prevention challenges

WHO recommends that the bacillus Calmette-Guérin, or BCG, vaccine be given to children in high-burden countries. Grzemska said its efficacy ranges from 0% to 100%.

“BCG vaccine does not prevent children from being infected with TB,” she said. “However, the big effectiveness of this vaccine is that it has been proven to protect younger children against complicated forms of TB, including TB meningitis or disseminated TB. It protects them from developing lethal forms of TB.”

BCG vaccine is not used in the U.S. Because it can cause a positive tuberculin skin test, experts in the U.S. decided in the 1950s they would rely on contact tracing to find and treat TB cases instead of using the vaccine, according to Starke. Contact tracing may allow the disease to occur, he said, but TB can be found and treated before it develops into active disease.

David L. Cohn, MD, an attending physician at Denver Public Health and professor of medicine in the division of infectious diseases at the University of Colorado School of Medicine, said another reason that the U.S. does not use BCG vaccine is that the country has a very low prevalence of TB. Most countries that have lower incidences of TB, including countries in Europe, stopped using BCG vaccine many years ago.

David L. Cohn

“The juice isn’t worth the squeeze,” he said.

Although BCG vaccine prevents a large proportion of newborns from developing life-threatening TB, it does not protect them when they become adults, Starke added.

“It protects small children, but it is not an instrument of disease control,” he said.

Starke warned that TB elimination will never be achieved unless “a truly effective vaccine” is developed.

“The BCG vaccines are not that vaccine,” he said. “There has never been a disease that spreads through the air that has not been curtailed, let alone eliminated, without a highly effective vaccine.”

Starke mentioned some ongoing vaccine trials “but no real breakthroughs yet.”

“At present, the monetary investment in TB vaccine research is a pitifully low amount given the burden and economic consequences of the disease,” he said.

A 2018 review in F1000Research by Gerald Voss, PhD, and colleagues reported that few TB vaccine candidates have entered clinical trials in the last 5 years, and most vaccines in clinical trials have failed to progress to efficacy trials.

Challenges in diagnosis

Many experts agree that the clinical presentation of TB is more difficult to identify in young children compared with adults.

“The clinical presentation of TB in adults includes cough, fever, night sweats, anorexia and weight loss. And they can tell you that they are sick,” Cohn said.

In adults, the disease is evident in X-ray images. Adults are able to produce sputum that can be examined under the microscope, and there is more TB in the sputum of adults compared with that of children.

Salazar-Austin said that even if a child a could cough to produce sputum, “it would be very challenging in many cases to find that bacilli in their chest,” with only one in three children with TB disease having a positive sputum.

In addition, young children might experience some fever and weight loss associated with TB disease, but cough is not a prominent feature, and children do not usually get cavities in the lungs, which would appear in X-rays, according to Cohn.

“Children are diagnosed on the basis of knowing they have been exposed, a positive skin test or blood test [interferon-gamma release assay], an abnormal chest x-ray, and symptoms,” Starke said. “That is how we diagnose the vast majority of children.”

Moreover, TB symptoms in children overlap with those of other diseases, Salazar-Austin said, further complicating diagnosis.

“Throughout the world, TB presents similarly to pneumonia, meningitis and malnutrition — all common causes of child mortality” she said.

She added that “an astute pediatrician” can distinguish between TB and other diseases, but there is a limited number of pediatric-trained clinicians in the world, so TB often gets misdiagnosed.

Modeling studies suggest that up to 95% of pediatric TB deaths are not diagnosed or treated before the child dies.

“The problems and challenges in diagnosing pediatric TB result in a large number of child deaths,” Salazar-Austin said.

Starke said researchers have not yet found “the magic bullet,” beyond identifying the organism.

“If we could create a microbiologic test or immunologic test, or some signal marker, that would be the holy grail for pediatric TB,” he said.

‘A precipitous drop’

All nations have committed to improve their surveillance of TB.

“We will see how that goes,” Starke said.

What is known is that certain countries, including India, China and Indonesia, have a disproportionate number of TB cases. The chances of the TB epidemic being eliminated worldwide by 2030 are going to depend on how just a few countries are able to control the disease, Starke said.

“The main problem is that in most high-burden countries, they have their hands so full caring for people sick with TB, and they have paid very little attention to preventing it from happening in the first place,” Starke said.

He added that, until very recently, high-burden countries did not have the capacity or the knowledge to conduct contact tracing.

“It is something we do quite well in the U.S., and we are trying to help high-burden countries find ways they can do it,” Starke said.

If high-risk nations are successful at developing contact tracing, the number of TB cases worldwide would plummet, according to Starke.

“Within just a few years, we will see a precipitous drop in the number of TB cases and the number of people who have drug-resistant TB, which is so much more difficult and expensive to treat,” he said. – by Bruce Thiel

Disclosures: Starke reports serving on a data safety monitoring board for Otsuka Pharmaceuticals’ pediatric trials for a new drug to treat multidrug-resistant TB. Cohn, Grzemska, MacNeil, Salazar-Austin and Talwar report no relevant financial disclosures.

WHO estimates that 1 million children become ill with tuberculosis every year, and approximately 230,000 die. Children made up one-tenth of the estimated 10 million people worldwide who developed TB in 2017, but confirming diagnosis in children is challenging, creating critical delays in starting treatment.

“Over 90% of the pediatric cases never get treatment,” Jeffrey R. Starke, MD, professor of pediatrics at Baylor College of Medicine and director of Children’s Tuberculosis Clinic at Texas Children’s Hospital, told Infectious Diseases in Children. “They are either never determined to have TB, or children are dying so quickly that they are not getting on treatment. It is not just a TB issue. It is a child survival issue.”

On Sept. 26, 2018, at a U.N. General Assembly high-level meeting on TB, heads of state reaffirmed their promise to end the epidemic by 2030.

Malgorzata Grzemska, MD, PhD, MPH, the coordinator of the global tuberculosis program at WHO, said new tools are needed to end the global TB epidemic, especially an effective vaccine.
Source: WHO, Geneva, Switzerland

However, Starke said that goal may not be possible.

“While a large decrease in the annual number of cases and deaths from TB can be achieved in a relatively short period of time, the number of persons living with untreated tuberculosis infection ensures that a substantial number of cases will continue to occur,” he said.

There are persistent gaps in detection and treatment, and experts have warned that the global burden of TB is not shrinking fast enough to meet goals set by WHO’s End TB Strategy, which aims to reduce TB deaths by 90% and new cases by 80% by 2030, compared with 2015 rates. WHO’s goal for 2035 is a 95% reduction in death and a 90% reduction in the TB incidence rate — or fewer than 10 per 100,000 people.

Moreover, according to the 2018 WHO Global Tuberculosis Report, although global funding for diagnosing, preventing and treating TB has more than doubled since 2006, it continues to fall short of what is needed. Among the 119 low- and middle-income countries that reported data, funding reached $6.9 billion in 2018 — well short of the estimated $10.4 billion required.

Infectious Diseases in Children asked pediatric and ID specialists if the 2030 goal was realistic, and about some of the persistent challenges of treating, preventing and diagnosing TB in children.

‘Quite ambitious’

“There is no question that TB is a global epidemic in children,” said Starke, an Infectious Diseases in Children Editorial Board member. “Children are the most neglected group of individuals regarding controlling TB.”

PAGE BREAK

Starke said that before 2012, there was no clear picture of the burden of pediatric TB globally. In its first global estimate, WHO showed that there were 500,000 annual pediatric cases and 75,000 deaths. As better evidence became available, the numbers shot up before slightly declining to their current levels.

Jeffrey R. Starke

In a recent MMWR, CDC epidemiologist Adam MacNeil, PhD, MPH, and colleagues estimated that in 2017, 10 million incident cases of TB occurred, representing a 1.8% decline from 2016, and 1.57 million TB deaths occurred, a 3.9% decline from the previous year. Numbers of TB cases and disease incidence were highest in Southeast Asia and Africa, and 9% of cases occurred among people infected with HIV.

“These numbers demonstrate only modest progress in reducing TB, as measured by the number of cases of disease, death and drug resistance,” MacNeil told Infectious Diseases in Children.

According to MacNeil, multiple strategies are needed to reduce TB worldwide.

“These strategies include innovative approaches to case finding; scale-up of TB preventive treatment, especially among populations at high risk; use of newer TB treatment regimens; and the prevention and control of HIV infection,” he said.

In another MMWR, Amish Talwar, MD, MPH, an Epidemic Intelligence Service officer at the CDC, and colleagues wrote that the number of new TB cases in the U.S. in 2018 was 9,029 — the lowest number ever recorded — but the rate of progress toward the goal of eliminating TB in the U.S. has slowed.

Specifically, they noted that TB incidence declined an average of 1.6% per year from 2014 to 2018 — a slower rate of decline compared with the 4.7% annual decrease seen from 2010 to 2014.

“The current level of progress remains insufficient to eliminate TB in the United States in this century,” Talwar told Infectious Diseases in Children.

Nicole Salazar-Austin, MD, assistant professor at the Johns Hopkins School of Medicine, said the U.N.’s 2030 goals were “quite ambitious,” but she is cautiously optimistic that they can be achieved.

“We need to gain control of and end the TB epidemic,” she said, but “it will take significant commitment and large efforts by many stakeholders to make that happen by 2030.”

New tools are needed, including a point-of-care diagnostic test that can be used by health workers at the community level, in addition to much shorter treatment regimens, according to Malgorzata Grzemska, MD, PhD, MPH, the coordinator of the global tuberculosis program at WHO.

PAGE BREAK

She said the length of current TB treatment is between 6 and 18 months.

“We definitely need something much shorter, less toxic and more affordable in cost, but most of all we need a good vaccine that will be very effective, both pre- and post-exposure,” Grzemska told Infectious Diseases in Children. “If we have all those tools by 2025, we should be able to bend the curve and achieve the goals toward ending TB.”

Grzemska said that at the U.N. General Assembly meeting, WHO member states agreed to provide treatment for 40 million people with TB and to provide preventive treatment for 30 million people, including household contacts and people living with HIV and other conditions that would affect their immunity.

“Currently, this is not happening,” she said. “This is one of the toughest things to do — accelerate this very cost-effective intervention. In children, it can be lifesaving.”

Treatment challenges

First-line drugs used to treat active TB in children have not changed in decades, according to Salazar-Austin. The combination of rifampin, isoniazid and pyrazinamide continues to be used with or without ethambutol — just like it is in adults. The drugs were first developed in the 1950s and 1960s and eventually became part of the standard TB treatment in the 1980s.

Nicole Salazar-Austin

“For a long time, we were probably underdosing children with TB medications,” Salazar-Austin said. “In the last 10 years, we have optimized dosing for first-line TB drugs in children, but concerns remain about dosing in malnourished children.”

To meet the U.N.’s goal of elimination of the TB epidemic by 2030, Starke said the development of new drugs and drug regimens is essential, and researchers should begin testing those agents in children as early as possible, before licensing.

“It is imperative to know the pharmacokinetics and safety profiles of the drugs for children ASAP,” he said.

To improve adherence, all new drugs should have child-friendly formulations before licensing as well, Starke added.

Grzemska noted that the first fixed-dose combination of rifampin, isoniazid and pyrazinamide in one tablet was approved in 2015. The tablet, which disperses in water, is used for the intensive phase of treatment of active, susceptible TB in the first 2 months. Then, a fixed-dose combination of rifampin and isoniazid is administered for 4 months. She added that the two-drug, fixed-dose combination of rifampin and isoniazid can also be used to treat latent TB infection in children who weigh less than 25 kg.

PAGE BREAK

To improve adherence, the tablet has a fruity flavor.

“Children actually like it,” Grzemska said.

WHO’s last pediatric TB guideline came out in 2014. The organization is expected to update its guidance in 2020, “given that there are a few trials and observational studies ongoing on several aspects of prevention, diagnosis and treatment,” Grzemska said.

Starke said the earlier TB is identified in children, the more effective treatment can be.

“The key to this is contact tracing,” he said.

Grzemska agreed, suggesting that the early diagnosis of TB in children and the early initiation of treatment “could lead to a 100% cure rate.”

Prevention challenges

WHO recommends that the bacillus Calmette-Guérin, or BCG, vaccine be given to children in high-burden countries. Grzemska said its efficacy ranges from 0% to 100%.

“BCG vaccine does not prevent children from being infected with TB,” she said. “However, the big effectiveness of this vaccine is that it has been proven to protect younger children against complicated forms of TB, including TB meningitis or disseminated TB. It protects them from developing lethal forms of TB.”

BCG vaccine is not used in the U.S. Because it can cause a positive tuberculin skin test, experts in the U.S. decided in the 1950s they would rely on contact tracing to find and treat TB cases instead of using the vaccine, according to Starke. Contact tracing may allow the disease to occur, he said, but TB can be found and treated before it develops into active disease.

David L. Cohn, MD, an attending physician at Denver Public Health and professor of medicine in the division of infectious diseases at the University of Colorado School of Medicine, said another reason that the U.S. does not use BCG vaccine is that the country has a very low prevalence of TB. Most countries that have lower incidences of TB, including countries in Europe, stopped using BCG vaccine many years ago.

David L. Cohn

“The juice isn’t worth the squeeze,” he said.

Although BCG vaccine prevents a large proportion of newborns from developing life-threatening TB, it does not protect them when they become adults, Starke added.

“It protects small children, but it is not an instrument of disease control,” he said.

Starke warned that TB elimination will never be achieved unless “a truly effective vaccine” is developed.

“The BCG vaccines are not that vaccine,” he said. “There has never been a disease that spreads through the air that has not been curtailed, let alone eliminated, without a highly effective vaccine.”

PAGE BREAK

Starke mentioned some ongoing vaccine trials “but no real breakthroughs yet.”

“At present, the monetary investment in TB vaccine research is a pitifully low amount given the burden and economic consequences of the disease,” he said.

A 2018 review in F1000Research by Gerald Voss, PhD, and colleagues reported that few TB vaccine candidates have entered clinical trials in the last 5 years, and most vaccines in clinical trials have failed to progress to efficacy trials.

Challenges in diagnosis

Many experts agree that the clinical presentation of TB is more difficult to identify in young children compared with adults.

“The clinical presentation of TB in adults includes cough, fever, night sweats, anorexia and weight loss. And they can tell you that they are sick,” Cohn said.

In adults, the disease is evident in X-ray images. Adults are able to produce sputum that can be examined under the microscope, and there is more TB in the sputum of adults compared with that of children.

Salazar-Austin said that even if a child a could cough to produce sputum, “it would be very challenging in many cases to find that bacilli in their chest,” with only one in three children with TB disease having a positive sputum.

In addition, young children might experience some fever and weight loss associated with TB disease, but cough is not a prominent feature, and children do not usually get cavities in the lungs, which would appear in X-rays, according to Cohn.

“Children are diagnosed on the basis of knowing they have been exposed, a positive skin test or blood test [interferon-gamma release assay], an abnormal chest x-ray, and symptoms,” Starke said. “That is how we diagnose the vast majority of children.”

Moreover, TB symptoms in children overlap with those of other diseases, Salazar-Austin said, further complicating diagnosis.

“Throughout the world, TB presents similarly to pneumonia, meningitis and malnutrition — all common causes of child mortality” she said.

She added that “an astute pediatrician” can distinguish between TB and other diseases, but there is a limited number of pediatric-trained clinicians in the world, so TB often gets misdiagnosed.

Modeling studies suggest that up to 95% of pediatric TB deaths are not diagnosed or treated before the child dies.

“The problems and challenges in diagnosing pediatric TB result in a large number of child deaths,” Salazar-Austin said.

Starke said researchers have not yet found “the magic bullet,” beyond identifying the organism.

“If we could create a microbiologic test or immunologic test, or some signal marker, that would be the holy grail for pediatric TB,” he said.

PAGE BREAK

‘A precipitous drop’

All nations have committed to improve their surveillance of TB.

“We will see how that goes,” Starke said.

What is known is that certain countries, including India, China and Indonesia, have a disproportionate number of TB cases. The chances of the TB epidemic being eliminated worldwide by 2030 are going to depend on how just a few countries are able to control the disease, Starke said.

“The main problem is that in most high-burden countries, they have their hands so full caring for people sick with TB, and they have paid very little attention to preventing it from happening in the first place,” Starke said.

He added that, until very recently, high-burden countries did not have the capacity or the knowledge to conduct contact tracing.

“It is something we do quite well in the U.S., and we are trying to help high-burden countries find ways they can do it,” Starke said.

If high-risk nations are successful at developing contact tracing, the number of TB cases worldwide would plummet, according to Starke.

“Within just a few years, we will see a precipitous drop in the number of TB cases and the number of people who have drug-resistant TB, which is so much more difficult and expensive to treat,” he said. – by Bruce Thiel

Disclosures: Starke reports serving on a data safety monitoring board for Otsuka Pharmaceuticals’ pediatric trials for a new drug to treat multidrug-resistant TB. Cohn, Grzemska, MacNeil, Salazar-Austin and Talwar report no relevant financial disclosures.