Continuing a legacy of preventing and managing infections in children with catastrophic illnesses

In the 1960s, advances in combination chemotherapy, pioneered at St. Jude and elsewhere, led to the first large wave of children surviving acute lymphoblastic leukemia (ALL), the most common childhood cancer. Although this watershed moment saw survival rates jump from 20 to 50%, it became clear that further improving survival would require a way to prevent the often-fatal opportunistic infections that arise due to the treatment-related weakening of the immune system. 

“The late Walter Hughes discovered that the most prominent cause of death during potentially curative pediatric leukemia therapy was Pneumocystis infection,” explains Josh Wolf, MBBS, PhD, St. Jude Department of Infectious Diseases. Hughes joined St. Jude in 1969, as one of the institution’s first physicians to specialize in infectious diseases. He helped establish the hospital’s Department of Infectious Diseases and served as its chair from 1969-77 and 1981-95.

At the time, Pneumocystis jiroveci (previously carinii) pneumonitis had a 32% mortality rate in pediatric patients with ALL. Pneumocystis is a fungus that is usually easily cleared by the immune system. However, ‘’the majority of our patient population is immunocompromised by their treatment,” said Hana Hakim, MD, St. Jude Department of Infectious Diseases faculty, Office of Quality and Patient Safety member, and Infection Prevention and Control medical director. “So, they are at higher risk for infections, and if they develop an infection, usually the outcome is more severe.”

Hughes was the first to show that giving the antibiotics trimethoprim and sulfamethoxazole prevented pneumonitis in patients treated for ALL. The canonical clinical trial, published in The New England Journal of Medicine, changed the course of medicine. That pivotal point was when St. Jude began its journey at the forefront of studying infectious diseases and innovating methods to protect children with catastrophic illnesses from infections, a legacy that continues today. 

Pushing infectious disease research in pediatric oncology forward

At the crux of infectious disease control and pediatric oncology is a tension between the individual and the greater community. While antibiotic use may help save the individual patient, the cost is the potential development of ever-more antibiotic-resistant microbes. St. Jude researchers are leading the charge to balance these priorities.

“We used to think of giving prophylactic antibiotics, those given before an infection to prevent it, as increasing the risk of a patient being colonized by resistant bacteria,” said Ellie Margolis, MD, PhD, St. Jude Department of Infectious Diseases. “But surprisingly, what we’ve found is that by giving these prophylactically, we were not increasing resistance.” 
 
In a The Lancet Microbe study, Margolis and Wolf intended to identify the risks of prophylactic antibiotic use in pediatric patients with cancer. Typically, patients are only given antibiotics after developing an infection. Unexpectedly, giving prophylactic antibiotics caused less resistance than typically seen in standard treatment.

“We set out on this path to investigate the exact opposite effect,” Margolis explained. “We actually saw less total antibiotic use when patients were on the prophylactic, so the microbes had less opportunity to select for resistance genes.” Wolf remarked that, “People say there’s no such thing as a free lunch, so we were just trying to find out the price of lunch – identifying the downsides of prophylactic antibiotic use – but instead found it was a healthy lunch.”

However, greater acceptance of prophylactic antibiotic use into clinical practice remains elusive. Undeterred, St. Jude scientists continue to study better ways to use antibiotics, evaluating risks and benefits:

• Using vancomycin prophylaxis in pediatric acute myeloid leukemia (AML) to prevent common bacterial infections did not have kidney or liver toxicity, as published in Antimicrobial Agents and Chemotherapy.
  
• Giving levofloxacin prophylactically in patients with ALL during induction therapy reduced fever and neutropenia, bacterial and bloodstream infections and exposure to other antibiotics. It also reduced Clostridioides (formerly Clostridium) difficile (C. diff) infection risk by more than 95%, which was published in Clinical Infectious Diseases.
  
• Administering prophylactic fluoroquinolone antibiotics did not increase neuropathy risk in patients with ALL. This was a concern because certain chemotherapeutics used in ALL treatment have neuropathy as a side effect and this class of drug could have exacerbated the issue. Findings were published in Cancer Medicine.
  

Improving infection predictions

While chemotherapy and immunotherapy are well-known to increase infection risk, all the other aspects of cancer treatment, like hospital stays, IVs and ports, antibiotics and diet changes also contribute. “The microbiome is experiencing everything our patients are experiencing,” Margolis explained. Chemotherapy often disrupts gut microbes, giving opportunities to disease-causing microbes, which researchers such as Margolis are trying to learn how to prevent. “We ultimately want the patient’s microbiome to help them heal and resist bad bacteria. We don’t know what good looks like, but we do know different ways for the microbiome to be bad during and after treatment.”

Knowledge of suboptimal microbiome makeups can help predict the patients at highest risk of infection early. Hakim’s group found that deep sequencing of bacterial genome from stool samples could predict infections before they were clinically detectable, as published in Clinical Infectious Diseases. “We looked at patients with ALL and analyzed their gut microbiome,” Hakim said. “And then we identified a gut microbe profile that predicted who would get an infection at a later time during their treatment.” 

A major worry is bloodstream infection. These infections can have serious consequences in immunocompromised patients, from long-term neurocognitive damage to death. Wolf co-led a pilot report showing that microbial DNA, floating freely in plasma, could be sequenced and used to predict subsequent risk of bloodstream infection up to 75% of the time, published in JAMA Oncology. Many of these tests are currently too expensive and slow for clinical use but serve as a proof-of-concept of how these predictive technologies may be married to prevention in the future.

Infection investigations inform future interventions

Despite efforts to predict who is at risk and prevent infections with prophylactic therapy, some patients will inevitably experience infection. Clinical care focuses on resolving the infection and continuing cancer treatment as soon as possible. “Potential delays in chemotherapy because the child’s too sick from an infection can put the cancer treatment at risk,” said Craig Gilliam, St. Jude Office of Quality and Patient Safety, Infection Prevention and Control director, who heads practical implementation of control measures under Hakim. “We want to prevent that, as there is a mortality risk associated with chemotherapy interruption.”

Gilliam investigates potential infection sources to find ways to mitigate them. To do so, his team first looks at epidemiological evidence, such as similarities in the location of infected patients in the hospital, appointment times, which medications they take, which procedures they undergo and a host of other factors. 

“In one case, we spoke with another pediatric hospital that, like us, had patients developing the same rare infection,” Gilliam said. “We were able to find the commonality was catheters. But not the catheters themselves – we were able to narrow down the culprit to the heparin chemical we would use to flush the catheters on a regular basis that was potentially contaminated with this pathogen.” 

Hakim and Gilliam are also expanding their tool kit for infection prevention. They recently found that regular genomic surveillance could identify the spread of infectious diseases that could not be detected via conventional epidemiological tools, as published in the Journal of Hospital Infection. Even in that study, spread was minimal, indicating infection control measures worked most of the time. When Hakim looked at C. diff infection, specifically using whole genome sequencing, she found that there was almost no transmission of the bacteria at St. Jude over a long period, as published in Clinical Infectious Diseases, providing further evidence that current policies and guidelines are functioning as intended.

St. Jude leads the future of pediatric infection prevention and control  

With each iteration, investigations into infections reveal new places for prevention and treatment. As methods improve, so do survival outcomes for pediatric patients. From the simplicity of improving hand washing hygiene, published in the American Journal of Infection Control, to more technical solutions, such as placing ultraviolet light devices into heating, ventilation and air conditioning (HVAC) systems, also published in the American Journal of Infection Control, St. Jude is still adding to Hughes’ legacy innovating solutions to improve infection prevention for children with cancer. 

“Hughes came and convinced the clinical community that it’s not just about treating a patient’s cancer,” Gilliam said. “Infectious disease prevention and control are what we can do in the background to help support the oncologist and, ultimately, help more kids survive.”