Infectious teamwork

Doctors and nurses raced to place two tubes, each nearly the size of a garden hose, in 4-year-old Jasie Musick’s neck and leg vessels to connect her to a life-support machine at Monroe Carell Jr. Children’s Hospital at Vanderbilt. She was drowning in her own fluid-filled lungs, overwhelmed by a bacterial lung infection.

 

Hours earlier, doctors in her hometown of McMinnville, Tenn., had diagnosed Jasie with influenza type B, a bug that was hitting children particularly hard this year. An X-ray proved Jasie had developed more than just the flu. A smoldering bacterial pneumonia was already unstoppably building in her small lungs.

This kind of worst-case scenario was the result of a rare, but very real side effect in the wake of a seemingly simple case of the flu: she had developed a bacterial infection on top of severe influenza.

Jasie was succumbing to her own body’s attack on the bacteria Staphylococcus aureus (staph), which normally cannot find a foothold within the lungs; but in the wake of an influenza illness, can quickly consume them, in even the healthiest of individuals, especially if they are unvaccinated. Jasie had not had a flu shot.

“She was on the stretcher at the emergency department at River Park (in McMinnville) and was giving some sass about what she would do to the next doctor that wanted to poke her with a needle,” recalled her father, Jason Musick. “Then just a couple of hours later she was on life support.”

Understanding infectious diseases, such as influenza, and how to diagnose, treat and prevent them is at the core of many research projects underway at institutions including Vanderbilt, home to some of the top pediatric infectious disease experts in the world. With the highest level of intensive care, a deep bench of specialists and teamwork at Children’s Hospital, these physician-scientists are busy tackling age-old mysteries to help prevent and treat illnesses.

Jasie’s case highlights the comprehensive combination of teamwork, research and prevention efforts happening at Vanderbilt to fight these aggressive diseases.

In previous decades, bacterial infections – like Jasie’s – would have been the cause of death in millions of otherwise healthy children and adults after a bout with the flu.

Today “secondary infections” are much rarer because of the influenza vaccine, but they continue to take lives. This year a nationwide spike of 110 pediatric flu-related deaths were reported by April 1, compared with 34 the previous year. But the worst year in recent history was 2009-2010, the year of the H1N1 pandemic, when 228 children died along with many more adults.

The pattern is strikingly similar. In most cases, the child is healthy, although most are unvaccinated. By all appearances, it starts as a routine case of the flu, then after about four days, instead of getting better the child suddenly gets worse. There may be breathing difficulties, chest or stomach pain, nausea and vomiting, then rapidly progressing illness.

Pediatric Infectious Disease Fellow, Kalpana Manthiram, M.D., witnessed several cases during her first year of fellowship of what could be described as a “the worst of the worst” in flu cases. Jasie’s was among them.

“Nothing can really prepare you for the speed at which these infections act. It’s kind of incredible,” said Manthiram.

‘A very sick little girl’

The Musick family opted out of the flu shot for their children. They were all strong and healthy and they had heard it was better to let healthy children deal with illnesses like the flu on their own. And year after year they experienced the flu and recovered just fine. But this time, Jasie’s parents knew it was different.

“She had already been through the flu once last year, in December,” said her mother, Brittany Musick. “But this second time the fever just kept on.”

They took her to River Park Hospital in McMinnville, Tenn., on March 5. Her father, Jason Musick, captured cell-phone video of his scrappy middle child and only daughter hours before she fell critically ill. About the same time an X-ray revealed a white shadow over a part of her lung where fluid was collecting.

River Park staff made an urgent call for Children’s Hospital’s Angel Transport ambulance to bring her to Vanderbilt. Jasie had fallen unconscious and was critically ill.

The ambulance attendant would later tell Jasie’s mother Brittany he had to use all three blood pressure drugs he had on board, for the first time ever, to keep her blood pressure at a life-sustaining level.

She arrived at Children’s Hospital blue-skinned and taking rapid shallow breaths. An X-ray showed the shadowy white had spread to both lungs and was creeping upward. Over the next two hours, the infection and inflammation spread to every space of Jasie’s lungs. Doctors put her on a heart-lung support machine called ECMO (Extracorporeal Membranous Oxygenation). The X-ray taken at the time she was placed on ECMO showed no discernible, “black-and-breezy” spaces at all where Jasie’s lungs should be.

“Everything was done right in this case,” Manthiram stresses. “From how quickly her parents brought her in, to the outside hospital starting her on appropriate antibiotics, to getting her here quickly and on ECMO. It is just the interplay of factors we don’t completely understand. But, we know that the influenza vaccine can help prevent these severe infections.”

Brian Bridges, M.D., assistant professor of Pediatric Critical Care and Medical Director of the ECMO team, recalled getting a call from the Angel ambulance team transporting Jasie on the morning of March 5. The Angel team, made up of nurses with years of critical care experience, requested from the road that the hospital prepare to assess Jasie for ECMO.

“That is very rare. She was a very sick little girl,” Bridges said.

ECMO Surgical Director, John Pietsch, M.D., associate professor of Pediatric Surgery, said secondary infections after influenza are as dangerous for the impact of the immune response as the bacterial or viral infection itself. He says the reason children like Jasie can “crash” so quickly is that the chemical responses of the immune system take over the body’s throttles. Heart rates rise, and people breathe harder, while at the same time, vessels all over the body open up, or dilate.

“They are like a radiator, opening up blood vessels, so blood pressure begins to go down at the same time as their heart rate goes up. We have good medications to help control these things, but sometimes the patients are more potent in their body’s response than even our medicines can control.” Pietsch said.

Brittany Musick said Jasie swelled with frightening speed, her tiny neck disappeared as her chin swelled down to her chest and her eyelids puffed out like a boxer’s. The swelling and fluid in her lungs were so severe, a very new technique was applied to the ECMO machine called continuous dialysis.

“It allows us to gradually pull fluid off of these very sick patients. This way she wouldn’t have the extreme ups and downs of periodic dialysis treatments,” Bridges said.

As one of the largest and most experienced ECMO centers in the country, and one of the few that offers continuous dialysis with it, Vanderbilt’s survival rates are about 10 percent higher than most other ECMO centers. An estimated 50 percent-60 percent of patients like Jasie will survive. But in the end, doctors say all that ECMO, the team of intensivists, specialists and even the pediatric infectious disease experts can do is support the body’s efforts to heal itself.

“Fifteen years ago, these kids would have died. But they were healthy before all this, so if we can bridge them through their illness and organ failure, they have a good chance to recover fully, and grow up and have a life and kids of their own. When we see this happen, it’s almost magical,” Bridges said.

For Jasie, it was after her eighth day on ECMO that her body began to show signs it could support itself again. By March 25, she was off the ventilator, breathing on her own. By April 1, she still needed a little bit of dialysis to support her kidneys, but she resumed talking and playing and watching puppy videos on her mom’s iPad.

Studying the evidence

Theories and research projects are addressing many lingering questions. One of them is why the flu is particularly well-suited to set healthy people up for secondary infections.

“The flu and staph together create this worst-case scenario,” said Buddy Creech, M.D., MPH, assistant professor of Pediatric Infectious Diseases and one of Manthiram’s mentors.

Creech explains that a bad case of influenza has a way of stripping the lining of the whole respiratory tract, from the nose to the bottom of the lungs.

“The hair-like cells that normally sweep bacteria out of the lungs are gone, and the lungs are unprotected,” he said.

The staph bacteria that usually live quietly inside our noses or on our skin, can smolder, flare and begin to get a foothold lower in the respiratory tract. In cases like Jasie’s, the infection spreads throughout the lungs, whipping up a massive reaction of the body’s immune system over the course of just a few hours or days.

“We also know that when we get influenza our immune response is slanted in such a way that it might reduce our ability to fight bacterial infections that might occur on its heels,” Creech said.

Creech’s research focuses on staph infections. He and other Vanderbilt researchers are helping build evidence that a significant amount of damage can come from an overreaction of the immune system when it detects Staph. One theory is that some individuals lack the genetic “brakes” each person should have to temper an immune response, putting some people at higher risk for these life-threatening infections.

But even in normal immune responses, bacteria and viruses each have the ability to wreak havoc on their own. Take the toxin PVL (Panton-Valentine leukocidin), produced by certain strains of Staph. Studies show it has the power to literally “eat” or melt away tissues of the lungs. And research underway now at Vanderbilt and elsewhere is finding evidence to clearly describe the devastating role viruses have in pediatric hospitalizations for pneumonia.

In additional research, Derek Williams, M.D., MPH, assistant professor of Pediatrics, is working with a team on the “Etiology of Pneumonia in the Community” or EPIC study. The multi-institutional study has enrolled 5,000 children and adults who were hospitalized with community-acquired pneumonia between 2010 and 2012. When the work is complete, Williams says it will show that most children in the study had at least one virus detected, including influenza, but also respiratory syncytial virus (RSV), Human Metapneumovirus (HMPV) and others.

EPIC closely examines what viruses and bacteria can do together.

“With studies like EPIC, we are beginning to learn more about how viruses interact with bacteria to cause bacterial-viral co-infections which are often more severe than either bug alone. However, it also highlights a problem we have right now, which is detecting possible bacterial-viral co-infections early before children become extremely ill,” said Williams.

He explains that while viruses are readily detected from nose or throat swabs, methods for reliably diagnosing bacteria are lacking. So, it’s possible bacterial co-infections are seriously underreported in children. Williams said work is underway to develop improved diagnostic testing for pneumonia- causing bacteria including a rapid urine test and a blood test.

Early detection would allow for effective therapy for those with bacterial pneumonia, and prevent unnecessary tests and treatments for those with viral disease. However, more research needs to be done before any new tests will be ready for general use.

Prevention is key

Creech and the team are also focusing on the development of better flu vaccines as well as a possible vaccine for staph to help prevent these overwhelming infections.

“We know the influenza vaccine can prevent these severe cases, but the truth is, it’s not a 100 percent guarantee,” he said.

Several versions of a Staphylococcus vaccine have been tested with steadily improving results, although a marketable vaccine is still likely several years away.

In regards to influenza, he says a “universal” flu vaccine is the holy grail of influenza prevention. Instead of requiring an annual flu shot, people might be able to get just one vaccination and be protected, even against pandemics, for a prolonged period of time, much like polio, mumps or rubella. Such a vaccine has shown promise in mouse models, and Vanderbilt is one of the sites around the nation helping test new ways that such a vaccine could be given.

Vanderbilt is also one of the major hubs for testing of so-called “synthetic” or “DNA” vaccines, created using newer technology for producing flu vaccines. Instead of growing the virus in eggs and then killing the virus, a portion of DNA from flu is put into harmless bacteria for replication. This allows the vaccine to be made more quickly, more safely (avoiding egg allergy concerns), and more reliably.

The effectiveness of the influenza vaccine is a bit of a moving target. Every year, the vaccine is designed to fight three strains of the flu likely to circulate during the season, but it’s an educated guess. The U.S. Centers for Disease

Control and Prevention indicates the 2012-2013 flu season vaccine reduced the risk of flu-associated medical visits from influenza A (H3N2) viruses by 50 percent, and from influenza B viruses by two-thirds for most of the population. That leaves one-third to one-half the vaccinated population at some degree of risk for this past flu season.

In Jasie Musick’s case, it’s hard to know for sure whether her illness might have been prevented with a flu vaccine. But the Musick family says they have learned that as tough as their children may be, the flu can be much tougher.

Jasie is back home now and should recover fully. Her mother says she’s already back to her sassy-self, throwing her arms up in frustration and saying, “I told you!” when people can’t quite understand her hoarse, post-ventilator voice. She is certainly as spirited as she was before this experience which her grateful parents take to be an excellent sign that she will be back on schedule to start kindergarten in the fall.

“I know I will be taking illness more seriously,” Brittany Musick said. “They will definitely get their flu shots every year. We never want to have to go through this again.”

–written by Carole Bartoo