ID treatment in children: Slow to evolve, impossible to ignore

The pediatric population is one that relies primarily on adults for health advocacy and care, and as such, their protection and medical treatment is an ethical as well as a scientific mandate. Yet despite global improvements in research and disease control, the risk, burden and mortality associated with pediatric infectious diseases remain considerable. “Diseases of poverty,” such as tuberculosis, malaria and HIV/AIDS, continue to take a toll on children in the world’s poorest countries.

Even in the face of these worrisome realities, there is a distinct lack of pediatric infectious disease clinical trials and a commensurately slow rate of new pediatric drugs in development. Some of this is due to the challenge of designing clinical trials to address the changing dosages and modalities unique to the pediatric population. However, according to some experts, at least part of the explanation for the delay in bringing new treatments to market lies in a lack of profitability.

Source: Brian Strickland/UNC

“Our market-based system of pharmaceutical development is constantly looking either for ‘blockbuster’ drugs for chronic illness that people can take for years, or ultra-niche, super-expensive drugs for cancer and heart disease,” Ravi Jhaveri, MD, professor of pediatrics in the division of infectious diseases at the University of North Carolina School of Medicine, told Infectious Diseases in Children. “Pediatric infectious disease is a small market in most cases, so development is a challenge.”

Infectious Diseases in Children spoke with numerous experts about the burden of infectious diseases that children continue to bear and the challenges of developing desperately needed therapies for this vulnerable patient population.

‘Not all shapes and sizes are the same’

Although there are numerous infections that pose a danger to children, some are particularly devastating at certain ages, according to Sharon Nachman, MD, professor and chief of the division of pediatric infectious diseases and director of the office of clinical trials at Stony Brook University School of Medicine.

“When we talk about the high-risk diseases in children, not all shapes and sizes are the same,” Nachman said. “It depends on the age of the child. If a 6-year-old gets [respiratory syncytial virus, or RSV], it’s usually a runny nose, cough, cold — no big deal. But a 4-month-old who gets RSV is often much sicker and will end up in the hospital.”

When a child is born, they are endangered by a very small, focused group of pathogens, Nachman said. Some neonates may be exposed to group B streptococcus, which is found in the vagina or rectum of approximately 25% of all pregnant women. Group B streptococcal infection can cause sepsis, pneumonia or meningitis in infants.

“Unfortunately, we have no vaccines for this,” Nachman said. “We screen mothers so that babies don’t get it within the first 7 days, but a fair amount of them get it after that.”

Other dangerous bacteria such as Escherichia coli, as well as viruses like herpes simplex, can affect neonates; similarly, no vaccines exist for these diseases.

Another goal for researchers in terms of age-specific presentations is to better understand why certain infections are so much more severe in infants and younger children compared with adults, Jhaveri said.

“Herpes simplex is a great example,” he said. “When an infant acquires the virus, the manifestations can be meningoencephalitis, hepatitis and disseminated severe infection. The same is true for enterovirus infections. However, when these same infections are acquired by older children and adults, there are fewer symptoms.”

Jhaveri said that although these disproportionately severe infections are largely attributed to infants’ immature immune systems, he believes there are other factors at work. He mentioned research that has shown that the brains and livers of infants, in their incomplete development, still have patterns that are “stem cell-like.”

“Very little research has been done to understand infections during this ‘stem cell-like’ period compared to infections in fully developed tissues,” he said. “It was demonstrated with hepatitis C virus that replication in fetal hepatocytes in vitro was sustained, while replication in adult hepatocytes in vitro was not detectable. This is one example, but it may be illustrative of a broader phenomenon.”

Geographic location is also a major factor in terms of which infections pose the greatest risk to children. According to Jason G. Newland, MD, professor of pediatrics and director of the antimicrobial stewardship program at Washington University in St. Louis and St. Louis Children’s Hospital, it is essential for U.S. researchers to look beyond the health challenges of U.S. children and adopt a more global perspective.

“More effort should be placed on reaching out beyond our borders to improve the health of children worldwide: the prevention of antibiotic-resistant pathogens, the improvement of antibiotic use and the prevention of infant mortality are one of many examples,” he said. “The underlying conditions, resources and even political environment have an impact on infectious diseases. Whether it’s health service research or basic science research, I think we have to focus beyond ourselves.”

‘Nothing we can do’ about RSV

According to Robert Welliver, MD, chief of pediatric infectious diseases at the University of Oklahoma College of Medicine and Children’s Hospital Foundation Hobbs-Recknagel Endowed Chair in Pediatrics, the most significant worldwide threats to children are diseases that cause pneumonia.

“RSV would be a leader in that respect, with pneumococci and TB up there as well,” he said. “Diarrheal illness would come in second, but the scope of those are decreasing as rotavirus vaccines are being used more globally.”

Welliver said RSV causes around 160,000 infant deaths globally each year, and 99% of those deaths are in developing countries. In the U.S. alone, RSV accounts for approximately 250 infant deaths and 125,000 hospitalizations annually.

“Right now, there’s nothing we can do,” he said. “There is a monoclonal antibody called palivizumab, but it’s so expensive that it’s only used for high-risk infants. There is no licensed vaccine, and there are no antivirals that are useful for RSV. Researchers are working on these areas.”

‘Urgent’ need for TB treatment

According to WHO, an estimated 1 million children became ill with TB in 2016, and 250,000 of these children died. Although TB in children is generally much more of a problem in resource-poor countries than in resource-endowed settings, drug-resistant infections and difficult treatment regimens still pose a challenge, according to Andi L. Shane, MD, interim chief of the division of infectious diseases and associate professor of pediatric infectious diseases and global health at Emory University School of Medicine and Children’s Healthcare of Atlanta.

“Overall, I think that rates of pediatric tuberculosis disease are decreasing, but locally in Georgia and in other places around the country, we are still seeing clusters of multidrug-resistant TB in adults and consequently in pediatric contacts,” she said. “It’s very difficult to treat drug-resistant TB in children due to the limited availability of the multiple drugs that are required, the potential adverse effects, and to the requirement for directly observed therapy to optimize compliance.”

Researchers are currently planning a study of Sirturo (bedaquiline, Janssen Therapeutics) in pediatric patients, but enrollment is not yet complete, Nachman said. In the meantime, Nachman and colleagues have been studying an age-adapted dose of the adult formulation.

“Right now, we’re in the middle of a study in which we crush the adult formulation and give it to children, studying the pharmacokinetics (PK) of it,” she said. “That tells you how urgent the need is. We are years behind knowing how to use these drugs in children compared to adults.”

Another drug, Deltyba (delamanid, Otsuka), is made in a pediatric formulation, Nachman said, and the manufacturer is currently enrolling patients in a pediatric study.

“The company is very interested in learning how to dose it in children,” she said. “They will get a dose across all the ages, from teenagers down to little kids, and they’re doing a nice job.”

In 2015, a panel of experts — including Nachman — published a consensus statement in The Lancet Infectious Diseases on the lack of TB treatments for children. They reviewed published literature on this topic from January 2004 to May 2014. The panel concluded that children can be incorporated into studies at the early phases of drug development and should be a significant consideration in the development plan, rather than studied only after regulatory approval in adults is acquired. Currently, Nachman said many companies will not investigate a drug in children until it is licensed in adults.

“The pediatric research community has been standing there for a long time, saying ‘Why not start sooner?’” she said. “When you’ve gotten at least to writing that phase 3 study, when you know you’re going to see if its efficacious or not, that’s when you should drop the line to say, ‘let’s start evaluating the safety and the PK, or the dose, in children.’ The longer you wait, the more kids are going to acquire the infection or die from the disease.”

HIV: An ongoing challenge

HIV treatment has progressed substantially since the disease was first reported in 1981, and with the use of ART, patients can now expect to live a full life span.

In the U.S., Nachman said there are few cases of HIV infection in infants and babies because of diligent efforts to identify HIV-positive pregnant women and treat them with ART.

Globally, the numbers are higher, she said.

“In Stony Brook, we have about 3,500 deliveries every year. Among those deliveries, we have, give or take, 20 women with HIV infection, and we identify and treat all of them, and we have no new infected babies,” she said. “In Johannesburg, in Chris Hani Baragwanath Hospital, they have 30,000 deliveries each year. Of those, 30% are HIV-positive moms. So even if they did an excellent job and transmission was only 3% to 5%, we’re still talking a couple hundred infected babies.”

Although a 2014 study published in the journal AIDS reported that few ART drugs at that time were licensed or formulated for children, Nachman said current HIV drug development has become “a little bit kinder to pediatrics.”

“Now, in 2018, any company that is developing a drug that they think is going to move ahead in adults is saying, ‘OK, how are we going to use this in kids? What is the formulation?’” she said. “They work with NIH, they work with networks like IMPAACT” — the International Maternal Pediatric Adolescent AIDS Clinical Trials Network.

The population that is currently the most neglected in HIV drug development, Nachman said, is pregnant women.

“We need data on how to use all of these new drugs in pregnancy,” she said. “Few to no companies want to study drugs in pregnant women because they perceive that as a high-risk venture. If there’s a toxicity, they’re going to be blamed.”

The threat of antibiotic resistance

Antibiotic resistance is considered by many infectious disease experts to be one of the most significant global health threats, and children have not been spared the effects of this crisis.

According to a 2017 study of 107,610 patients at 48 children’s hospitals, the proportion of multidrug-resistant, gram-negative enteric Enterobacteriaceae has increased in pediatric patients — from 0.2% in 2007 to 1.5% in 2015.

In another study, researchers from Rush University Medical Center identified a surge in multidrug-resistant organisms in infectious disease clinics, including gram-negative bacilli, Staphylococcus aureus and Enterococcus, in children as well as in adults.

Study researcher Latania K. Logan, MD, MS, an associate professor at Rush University Medical Center and Rush Medical College, said these findings are anecdotally observed by physicians on a daily basis.

“You can ask infectious disease physicians, even some community physicians, and they will say they have noticed more resistant bacteria, whether it’s E. coli or MRSA,” she said. “MRSA has largely plateaued, but it’s now so familiar. It’s a familiar part of our everyday practices.”

Newland said that in the case of some gram-negative bacteria, such as Pseudomonas or E. coli, he and his colleagues in pediatric practice have encountered situations in which they lacked an antibiotic to treat these bacteria.

“There aren’t a lot of antibiotics, whether it’s an adult or a child, to treat multidrug-resistant infections,” he said. “We do have some. But the newer agents are not approved in children yet, but we’re forced to use them.”

Newland said he believes the issue of antimicrobial resistance in children needs to be more of a research priority. He said the first step is identifying new antibiotics that are effective against antibiotic-resistant infections in the general population. The second step is to develop clinical trials of these agents specifically in children.

“We want to have the drugs utilized and approved in children, so we know that the dosing is correct, that they’re safe and effective,” he said. “We need these clinical trials to occur in pediatrics, and frankly, we need them to occur faster than they are.”

Newland also said better strategies must be developed to optimally use antibiotics to prevent further resistance. Unfortunately, he said, antimicrobial stewardship generally limits the duration of these medications, thus making them less profitable for drug companies in the current economic model.

Need for vaccine research

One very powerful weapon in the fight against pediatric infectious disease is prevention. According to Shane, vaccines go a long way toward stamping out avoidable diseases.

“One of the things that we have had a tremendous amount of success with are vaccines,” she said. “We know that those that have been tested work well — they really are life-saving, and they need to be administered to children to protect them from infections.”

Richard F. Jacobs, MD, professor emeritus of the department of pediatrics at the University of Arkansas for Medical Sciences, said that recent mumps and measles outbreaks have underscored the need for durable vaccines.

“The recent mumps and measles outbreaks strongly support our continued vaccine implementation efforts globally, and within the U.S. for families who do not appropriately immunize their children,” Jacobs said. “The question of vaccine durability and the potential need for additional booster doses into adulthood, along with the opportunity to improve these vaccines, is important.”

Jacobs also noted that additional research is needed to improve pertussis vaccine efficacy and durability. He expressed concern that vaccine exemptions put children at risk from this deadly infection.

“There needs to be continued education, research and public policy revisions,” he said. “The question of the ‘best’ vaccine and schedule in infants and children, with continued emphasis on DTaP into adolescence and adulthood, is key to the control of this infection.”

Given the severity of the recent influenza season, Jacobs also emphasized the need for a better influenza vaccine. Early estimates published by the CDC show that the influenza vaccine was only 36% effective overall in the United States during the 2017-2018 season, and only 25% effective against the predominant circulating strain — H3N2.

“An influenza vaccine that has better protection and durability of protection is a high priority research initiative,” he said. “It would be ideal to have a future influenza vaccine that is more effective and would eliminate the need for annual immunizations.”

Newland added that S. aureus is an important target for vaccine development.

“We see so much bad Staphylococcus aureus, whether its MRSA or the susceptible version,” he said. “If we had a vaccine for that, it would be unbelievable.”

Welliver agreed, saying that although S. aureus is not currently a major cause of death in children, he is concerned about the potential damage these bacteria may do in the future, particularly in the absence of a vaccine.

“We see a lot more skin and bone infection from staph than we did years ago, and they have become resistant to some antibiotics. MRSA has become especially prominent,” he said, “In the U.S., about 40% of staph infections are MRSA, which barely existed before 2003. It’s a major cause of bone infections, pneumonias and endocarditis. So far, management with current antibiotics works, but there is going to be a limitation on that.”

Motivating progress

The slow pace of infectious disease clinical trials in children is partly due to the challenge of addressing different age groups and dosages in the studies, Nachman said.

“An adult gets the same dose, while with a child, we have to administer it as a per-weight dose,” she said. “So unless a company makes a formulation that I can give to the different age groups, you obviously can never do the study.”

According to Newland, one step that has been taken toward incentivizing pediatric trials is the pediatric provision of the Food and Drug Administration Modernization Act, which grants drug companies 6 months’ market exclusivity for conducting pediatric trials.

“They get to stay on their patents, and they get to make more money, and they get that because they are doing pediatric trials,” he said,

Jacobs said emerging infections of the future may very well drive increased prioritization of pediatric infectious disease trials through sheer necessity.

“Emerging infections, like Zika virus, will continue to make global public health and research a key element of investment for the future,” he said.

Jhavari said another important element to advancing pediatric research is the commitment of parents.

“Sleep-deprived parents with an infant child are often not interested in the burden these studies may bring,” he said. “Thankfully, some of them will still participate, and that is why we can make progress.” – by Jennifer Byrne

• References:
• CDC. Group B strep (GBS) types of infection. https://www.cdc.gov/groupbstrep/about/infection.html. Accessed April 22, 2018.
• CDC. Measles, mumps, and rubella (MMR) vaccination: What everyone should know. https://www.cdc.gov/vaccines/vpd/mmr/public/index.html. Accessed April 22, 2018.
• Flannery B, et al. MMWR Morb Mortal Wkly Rep. 2018;doi:10.15585/mmwr.mm6706a2.
• Medernach RL, et al. Infect Dis Clin North Am. 2018;doi:10.1016/j.idc.2017.11.001.
• Meropol, SB, et al. J Pediatric Infect Dis Soc. 2017;doi:10.1093/jpids/piw093.
• Nachman S. Lancet Infect Dis. 2015;doi:10.1016/S1473-3099(15)00007-9.
• Penezzato M, et al. AIDS. 2014;doi:10.1097/QAD.0000000000000240.
• Piedimonte G, Miriam KP. Pediatr Rev. 2014;doi:10.1542/pir.35-12-519.
• WHO. Tuberculosis. Key facts. http://www.who.int/en/news-room/fact-sheets/detail/tuberculosis. Accessed April 26, 2018.

• For more information:
• Richard F. Jacobs, MD, can be reached at 800 Marshall St., #653, Little Rock, AR 72202; email: rfj@uams.edu.
• Ravi Jhaveri, MD, can be reached at the Division of Infectious Diseases, University of North Carolina School of Medicine, 101 Manning Drive, Chapel Hill, NC 27599; email: ravi.jhaveri@unc.edu.
• Latania K. Logan, MD, can be reached at 1725 W. Harrison St., Chicago, IL 60612; email: latania_logan@rush.edu.
• Sharon Nachman, MD, can be reached at Stony Brook Medicine, 101 Nicolls Rd., Health Sciences Center, Department of Pediatrics, Stony Brook, NY 11794; email: sharon.nachman@stonybrookmedicine.edu.
• Jason G. Newland, MD, can be reached at 1 Childrens PL, NWT 8238 CB 8116, St. Louis, MO 61130-1002; email: jgnewland@wustl.edu.
• Andi L. Shane, MD, can be reached at 2015 Uppergate Rd., Atlanta, GA 30322; email: ashane@emory.edu.
• Robert Welliver, MD, can be reached at 1200 Childrens Ave., Oucpb 5100, Oklahoma City, OK 73104; email: april-sandefer@ouhsc.edu.

Disclosures: Jacobs, Nachman, Shane and Welliver report no relevant disclosures. Jhaveri reports participating in clinical trials with AbbVie, Alios/Janssen, Gilead Sciences and Merck, receiving research grants in the past 3 years from MedImmune and Merck, and serving on a scientific advisory board for MedImmune. Newland reports conducting industry trials with Merck.