Fatal Sequence: The Killer Within
Chapter 6: The Immune System in Books


by Kevin J. Tracey, M.D.

January, 2006

We begin with two excerpts from Fatal Sequence: The Killer Within by Kevin Tracey, a neurosurgeon and immunologist who describes the case of a 1-year-old burn victim, Janice.

Introduction

TUESDAY, MAY 28, 1985. It was a birthday party for a one-year-old, but the cake had no candle. Oxygen was in use nearby, and Fire Department rules prohibited open flames. The birthday girl was Janice, a patient on the burn unit of New York Hospital. Silver foil balloons twitched gently against the ceiling, proclaiming ONE YEAR OLD in blue and green pastel letters. A circulating fan on the wall moved the humid air gently as doctors, nurses, and family passed around pieces of cake. White bandages covered Janice’s arms, legs, and torso, an intravenous bottle hung from a pole, and a green-screened cardiac monitor beeped beside her crib. The guests laughed as Janice smeared chocolate frosting across her white bandages and onto the rails of her crib. Mercifully, the burn had spared her sweet face, and Janice’s bright blue eyes sparkled.

This was more than a celebration of Janice’s first year of life, because no one had really expected her to last this long. One month earlier she had been scalded by boiling water spilled from a spaghetti pot. The baby had crawled between her grandmother’s legs just as she had turned from the stove to drain the pasta water. The woman stumbled and never made it to the sink. Boiling water had poured onto Janice, burning more than 75 percent of her body. Now the people who had kept her alive were rejoicing in her survival. After weeks of long days filled with round-the-clock care, the burn unit staff had grown to love the innocent and persistently cheerful child. It had not all been for nothing. Janice was going to make it after all.

Janice’s four weeks in the burn unit had been an unimaginable nightmare for her parents. Terrifying dreams would also haunt Janice’s doctors and nurses for years. She had been to the operating room for major surgery to excise the burned areas, which were then covered with skin grafts. She had lived through daily dressing changes that lasted more than an hour each, and she had been on and off a respirator three times. She had received gallons of intravenous fluids and tube feedings, and six different antibiotics. Somehow she had made it this far, battling through one complication after another caused by her scalding. Her wounds had left her widely exposed to the harshness of the surrounding microbial world. Antibiotics, ointments, and dressing changes did not stop the microbial invasion—germs had entered her bloodstream, and her organs had shut down. Her immune system fought back—launching a vicious attack—but as in an urban battle in streets crowded with people, where killing is indiscriminate, the immune attack had not only killed invading bacteria but severely damaged her organs as well. Janice’s lungs, kidneys, liver, and heart were damaged by what is known as severe sepsis.

Severe sepsis is a modern-day pestilence, a leading cause of death worldwide. In the United States alone it kills 215,000 annually, making it the third leading cause of death, after cardiovascular disease and cancer. More people die every day from severe sepsis (589 deaths a day) than from acute heart attack. The medical cost of its treatment in the United States exceeds $17 billion annually.

Severe sepsis can occur, as in Janice’s case, after a burn injury, but it develops more commonly in other kinds of patients. Typical conditions that predispose patients to develop severe sepsis include cancer, multiple traumas from a motor vehicle accident, and pneumonia or other infections. Severe sepsis can even develop spontaneously in previously healthy patients, especially those at the extremes of life—the very young and the elderly.

I was one of Janice’s doctors in the burn unit 20 years ago, and I was frustrated by the lack of answers to fundamental questions about severe sepsis. What is it, really? How does it happen? Why do some people get it but not others? What does it feel like? And how does it kill? Consumed by the need to know what had happened to her, and hoping to find new treatments, I began a career in scientific research shortly after I treated her. Janice’s story compelled me to study sepsis. Since that time researchers have learned that severe sepsis occurs when patients’ own molecules turn against them; they suffer and die at the hands of their own immune systems. They are wounded when molecular weapons launched against microbes damage the body’s own tissues and organs. Severe sepsis is a failure of the weapons-control system. During a routine infection or injury, your immune system responds to protect you, but it is a controlled response in which the release of weapons is held in check. Just enough are fired to effectively protect you from microbes. In a patient with severe sepsis, however, this carefully orchestrated response spins wildly out of control, instigating a sequence that can kill the patient as well as the microbes.

In a surprising twist to this story, my colleagues and I recently discovered that the brain is a master command and control center for the immune system’s weapons. Messages to the immune-microbial battlefield are carried by nerves that deliver critical orders from the brain, keeping the attack on track, restraining its magnitude, and preventing it from veering off to damage bystander organs. The brain exerts a powerful constraint on the immune response, preventing it from becoming too activated. Your brain can protect you against lethal complications from commonplace infections, cuts, scrapes, and minor injuries, such as a urinary tract infection or a pimple. Neural pathways lying deep within the brain can also prevent the severe sepsis sequence.

Janice’s story encompasses not only the 25 days that she spent in the burn unit. It also describes her scientific legacy, the work of countless scientific investigators who are unraveling the mysteries that obscured severe sepsis at the time she was hurt. Janice’s real identity remains confidential. I did not review her records to write this book; it is not a journalistic account.

Instead, these are my recollections of her struggle to survive her dual assaults: from the scalding and, afterward, from her own immune system. All the medical events described here are true. I did not make recordings or take notes during Janice’s hospitalization, so the conversations recounted here are reconstructed from my memory. The dialogue and specific daily activities here are composites, re-created from discussions and clinical events and distilled from the thousands of patients I have treated. Many, like Janice, suffered combined blows from their own immune systems and doctors’ ignorance. In preparing this book I interviewed sepsis survivors, clinicians, and scientific investigators; their quotations are exact, as noted. Other names have been changed to protect confidentiality.

Today a new class of drugs can block the immune system’s molecular weapons, significantly improving the quality of life for hundreds of thousands of patients. The scientific path that led to this major advance did not follow a straight line but took a more erratic course, marked by sharp turns, accidents, and surprises. It is not possible here (or perhaps in any single text) to list all the investigators who worked on these problems, or to describe their individual contributions to the research that led to new treatments. Instead, I have chosen to highlight a few specific discoveries in order to give a glimpse into the way basic laboratory research, far from the patient’s bedside, can occasionally identify new approaches to understanding the complexity of the immune system and suggest new methods to control it. Only a small fraction of scientific experiments actually “work.” Most of the time the results are equivocal; sometimes they are even confusing. Pivotal experiments move understanding forward, on a track that everyone hopes will circle back to the patient’s bedside as a future therapy and, perhaps, a cure.

From Chapter Five

It is not plague but severe sepsis that is serving notice as the pestilence of the twenty-first century. Severe sepsis is one of the most common causes of death worldwide, killing nearly a quarter of a million people each year in the United States alone. Deaths from severe sepsis are eclipsed only by mortality from cardiovascular disease (930,000 deaths annually from heart disease and stroke) and cancer (556,500 deaths). Unlike the plague, severe sepsis is not contagious, but more than 4 million people have died from it since Janice’s hospitalization in 1985. The number of severe sepsis deaths may actually be higher: some patients with heart disease and cancer die from severe sepsis, but their deaths are attributed to the primary or underlying disease instead. In contrast with heart disease and cancer, there are no well-funded, widely known organizations or action committees that target the disease. There is no sepsis group with the visibility and fund-raising power of the American Cancer Society or the American Heart Association.

Severe sepsis has remained below the radar of public awareness, in part because it is a diagnosis often left unspoken, even by the attending physicians, to its victims and their families. Doctors may fear its pestilential qualities more than they realize. Severe sepsis is a mysterious and untreatable, modern-day fatal illness. It causes a protracted hospitalization, usually spent in an intensive care unit, where the costs can be emotionally and financially devastating. Janice developed severe sepsis after her scald injury, but nationwide, burn injury is a relatively uncommon cause. The vast majority of severe sepsis cases occur in patients who are afflicted with more “typical” and prevalent diseases, such as heart disease, cancer, pneumonia, appendicitis, pancreatitis, chronic liver or kidney disease, and infections of the gastrointestinal or urinary tract, or with serious trauma from a motor vehicle accident or other injury.

The word sepsis comes from the Greek word se¯psis, meaning “decay,” and se¯pein, meaning “to putrefy,” or to make rotten or foul-smelling. In medical terms, sepsis is defined as either “the presence of pathogenic organisms or their toxins in the blood or tissues” or “the poisoned condition resulting from the presence of pathogens or their toxins, as in septicemia.” Patients are given a diagnosis of sepsis when they develop clinical signs of infection or systemic inflammation; sepsis is not diagnosed based on the location of the infection, or by the name of the causative microbe. Physicians draw from a list of signs and symptoms in order to make a diagnosis of sepsis, including abnormalities of body temperature, heart rate, respiratory rate, and white blood cell count. Sepsis may be diagnosed in a 72-year-old man with pneumonia, fever, and a high white count, and in a 3-month-old with appendicitis, low body temperature, and a low white count.

Sepsis is defined as severe when these findings occur in association with signs of organ dysfunction, such as hypoxemia, oliguria, lactic acidosis, elevated liver enzymes, and altered cerebral function. Like Janice, nearly all victims of severe sepsis require treatment in an intensive care unit for several days or weeks. Severe sepsis is a modern “pestilence” because, like the epidemic that killed much of Europe’s population in the fourteenth century, its cause is unknown. Lacking effective treatment for the current pestilence, doctors at the beginning of the twenty-first century stand stiffly at the bedside in their white coats, and in the waiting room, speaking to the family in hushed tones while maintaining a pose of thoughtfulness and woe. Except for the modern clothing, these scenes might have come straight out of the past, as if lifted from the weathered paintings depicting professionals with concerned faces gazing sorrowfully at the victim dying of plague.

Today’s doctors treat specific complications from severe sepsis as they arise. Comfort is given to patients and families; hope offered at the bedside lingers quietly, as if awaiting a promised future treatment that can effectively cure the disease. The modern pestilence of sepsis does not evoke the sheer horror of the fourteenth-century pandemic, primarily because it is not spread from house to house or town to town on the backs of rodents. Perhaps it is a less dramatic killer, but it is a common cause of death that we cannot effectively treat and are just beginning to understand.

Janice had just survived her battle with acute septic shock, a fulminant and rapidly progressing syndrome that is clinically similar to the septicemic form of the ancient pestilence. Next she would have to battle severe sepsis, similar to the bubonic form of plague. It would be a struggle that could last for days or weeks before she would either recover or die.

SUNDAY, MAY 12, 1985, 9 A.M. The pestilence of severe sepsis came upon Janice gradually in the second week of her hospitalization, not with the frantic activity of septic shock but with a grinding and prolonged assault—the kind that weakens resolve and tires the soul of patients old enough to be aware of it—a slowly burning consumption of her tissues. She spiked a 104°F fever, and the microbiology laboratory report indicated that there were microbes growing in her bloodstream. Today we understand that her fever was caused by cytokines, molecules produced by her immune cells to coordinate the inflammatory response to infection. These cytokines function as “endogenous pyrogens” to turn up the temperature set point in the body’s thermostat, located deep in the hypothalamus, at the base of the brain. A moderate fever from low-level cytokine release can be beneficial, aiding the immune system’s ability to kill and clear the bacteria. If cytokine accumulation in the brain becomes excessive, however, then body temperature can become dangerously high, to the point that it damages organs, including the brain itself. We gave Janice intravenous an antibiotics and placed her on a cooling blanket; hoping for the best but fearing the worst, we resumed watching and waiting.