One of the profound mysteries of medicine is why in the midst of an epidemic some people become severely ill and die while others remain unscathed.
During the great plagues of past centuries, like the Black Death, smallpox and yellow fever, the answer was often cast in religious terms: survival was a miracle and succumbing was a punishment. During this influenza pandemic of H1N1, doctors and health officials invoke “underlying conditions.” This phrase, now so ubiquitous in news reports, is rightly understood to mean concurrent medical problems like diabetes and lung disease. But such underlying conditions are only part of the mystery of why this flu is so mild for some and so serious for others.
When faced with a new infectious outbreak, clinicians treat the sick while epidemiologists collect data on their characteristics: their age, gender, ethnic background, medical history, current medications and social factors like where they traveled and whom they contacted. Early in the H1N1 epidemic, health experts had an advantage in identifying risk factors for severe disease because past cases of seasonal influenza proved, in part, to be prologue. Familiar predisposing conditions like chronic lung disease, diabetes, heart trouble, immunosuppressive disorders and pregnancy were present in many early deaths.
With that knowledge, health officials tried to help the public find the midpoint between complacency and panic. But they were somewhat hamstrung in providing details about individual deaths in order to protect the confidentiality of patients and families; so in many instances, officials resorted to using that general phrase underlying conditions as an explanation. The result was that people who had such conditions appropriately felt increased concern while those without them felt a greater level of comfort.
But over the past weeks, the first scientific papers have been published in prominent medical journals detailing the demographics and medical histories of hundreds of patients who required hospitalization and, in many instances, died. These reports came not only from the United States but also Mexico, Canada, Australia and New Zealand, and expanded on the initial data released by the Centers for Disease Control and the World Health Organization over the summer.
According to these reports, many of the patients who became very ill with H1N1 did, in fact, have the same underlying conditions as those who often develop severe seasonal flu. But these reports pointed to some important differences between the viruses.
First, the early impression of many clinicians was confirmed: seasonal flu is typically harder on the elderly; H1N1 severely hits children and young adults. What’s more, the W.H.O. suggests that H1N1 may be more contagious than seasonal flu, infecting as many as 22 percent to 33 percent of contacts as opposed to 5 percent to 15 percent for seasonal flu.
Epidemiologists also found unexpected correlations between severe H1N1 flu and problems like obesity, hypertension and increased blood lipids. In Australia and New Zealand, aboriginal and Maori peoples were disproportionately stricken — as were Native American and Inuit populations in Canada. These associations had not been prominent in past flu outbreaks.
We also learned that in the United States, more than 25 percent of all those hospitalized seem to have had no major underlying conditions. According to a C.D.C. report in September, 12 of the 36 American children who died of H1N1 by early August appear to have been completely healthy before contracting the flu.
How, then, can we explain the striking differences in outcome after exposure of apparently healthy people to the H1N1 virus, ranging from no infection to a mild respiratory illness to death?
Insight may be gained from another recent and deadly outbreak, the H.I.V. epidemic. We learned important lessons from AIDS by moving from bedside observation to laboratory investigation, as epidemiologists and clinicians worked closely with basic scientists. As the virus spread, individuals were identified who did not become infected despite significant exposure to H.I.V. Even more curious were so-called elite controllers, those who became infected but remained healthy for decades with no evidence of decline in immunity.
H.I.V., like many other viruses, has proteins and sugars on its surface that allow it to attach to human cells at specific docking sites called receptors. Harnessing the power of modern molecular biology, researchers found that some people who were amply exposed to H.I.V. yet did not become infected had a genetic difference in their receptors that prevented the virus from effectively attaching and entering their cells.
This discovery led to a new drug to treat those with AIDS who did not have this genetic advantage, protecting yet uninfected cells from the virus. And those who have carried H.I.V. for years with no apparent effects are still being intensively studied by scientists; these elite controllers may have cadres of certain immune cells that restrain the deadly pathogen. Unraveling the mysteries of the unscathed could lead to still more novel therapies.
A similar strategy of studying the genetics, receptors and immune response of people who appear to resist infection versus those who rapidly succumb is being applied to other deadly pathogens like hepatitis C, and is clearly applicable to influenza as well. There are, in fact, initial findings from researchers in Europe and Japan showing that the new virus can attach not only to receptors that bind seasonal flu, but also to other receptors deep in the lungs. Genetic differences in these other receptors could account for severe respiratory illness in some H1N1 cases.
In an epidemic, each one of us wants to know our personal risk for illness. The current definition of underlying conditions communicates only a level of increased risk, not individual susceptibility. For the first time in history, though, scientists are poised to redefine underlying conditions in a more profound way based on individual immune response. Deep in our genes, there may very well be another underlying condition that determines in part whether a virus will cause us mild or no disease, or severe illness and death.
Jerome Groopman, a staff writer for The New Yorker, and Pamela Hartzband. Both are attending physicians at Beth Israel Deaconess Medical Center and professors at Harvard Medical School.