As the annual flu season looms, some scientists have this question on their minds: Why now?
For more than a century, physicians have recognized that influenza sweeps the Northern Hemisphere during the winter months, typically peaking between late December and March.
Over the years they've floated numerous theories to explain the seasonal flu spike -- blaming everything from frigid air to the wintertime tendency to huddle indoors.
Yet these explanations "remain astonishingly superficial and full of inconsistencies," says Dr. Scott Dowell, director of the Global Disease Protection Program at the Centers for Disease Control and Prevention in Atlanta.
Dowell and other researchers are focusing on a provocative new hypothesis that blames annual flu epidemics on something most people don't get enough of this time of year: sunshine.
In a paper scheduled for publication this month in the journal Epidemiology and Infection, a Harvard University-led team proposes that a vitamin D deficiency caused by inadequate winter sun exposure may predispose people to infection.
If this theory proves correct, it would solve a longstanding mystery and have major public health consequences.
Influenza kills an average 36,000 people in the U.S. each winter, mostly among the very old and the very young. If scientists could pinpoint the secret behind its seasonal recurrence and somehow alter it, "the potential impact would be far greater than the current influenza vaccine," says Dowell.
Hippocrates, the Greek physician widely regarded as the father of medicine, was the first to recognize that certain diseases ebb and flow with the calendar. "Whoever wishes to investigate medicine properly," he wrote around 400 B.C., "should consider the seasons of the year."
Epidemiologists, however, have found that this is easier said than done.
"You look at the environment around you and say, 'What's the difference between winter and summer?' " says Dr. David Fisman of the Ontario Provincial Public Health Laboratory in Canada. "There are so many things that are seasonal, it's really hard to tease them apart."
One obvious answer is that it's colder in winter. And for as long as parents have bundled up their babies, there's been an unshakable belief that catching a chill makes a person more susceptible to cold or flu.
Since World War II, scientists have devised numerous teeth-chattering tests of this stubborn wives' tale, dunking volunteers in cold baths or confining them to refrigerated meat lockers while squirting virus-spiked mucus up their noses.
"All attempts at demonstrating some relationship between cold exposure and susceptibility to infection have proved negative," Ron Eccles, director of the Common Cold Centre at Cardiff University in Wales, concluded in a review of such studies.
Experiments on the influenza virus have hinted that the flu bug is more stable in the cool, dry air of winter. But that doesn't solve the mystery, says Fisman, whose summary of efforts to understand seasonal influenza is scheduled for publication next year in the Annual Review of Public Health.
One reason: Influenza surveillance efforts in Southeast Asia and other steamy tropical locales reveal that flu is not only common there but also exhibits seasonal patterns akin to those in colder climates.
"If you go back to the hypothesis about cold temperature and flu, it doesn't hold for the tropics," says epidemiologist Cecile Viboud of the National Institutes of Health's Fogarty International Center in Bethesda, Md.
Then there's the crowding theory. Because scientists think that the flu spreads only from person to person, most have assumed that the disease ravages in winter because people are cooped up in close quarters.
But even Sir Christopher Andrewes, the British virologist who co-discovered the influenza virus in 1933, once observed, "I have always had my doubts about this."
Andrewes, who died in 1988, said the winter crowding explanation defied common sense, since office and factory workers were indoors year-round. And summertime flu epidemics remain rare despite the prevalence of cruise ships, airplanes and subways packed with international travelers, other skeptics of the theory note.
"There are plenty of things that don't fit," says the CDC's Dowell.
The latest theory to generate a buzz centers on sunlight.
In 1981, a British general practitioner named R. Edgar Hope-Simpson published the first paper documenting a link between influenza epidemics in the Northern Hemisphere and the winter solstice.
The solstice -- which arrives on Dec. 22 this year -- is the shortest day of the year.
Hope-Simpson, who had no formal training in epidemiology, realized that influenza infections tended to jump just before and after the solstice. Solar radiation, he surmised, triggered some sort of "seasonal stimulus" that affected the flu virus, its human host or both.
"His work was basically ignored," says Dr. John Cannell, a psychiatrist at the Atascadero State Hospital in California.
In their forthcoming paper in Epidemiology and Infection, Cannell and colleagues from Harvard University, the National Institutes of Health and Boston University propose that Hope-Simpson's seasonal stimulus could be vitamin D.
The tip-off, says Cannell, came in April 2005, when influenza swept through Atascadero, a maximum-security facility for the criminally insane 200 miles south of San Francisco.
"The ward below me got it, then the ward to my right, to my left and the one across the hall," he recalls.
Cannell's 32 patients, however, were spared. As far as he could tell, there was only one difference between his patients and those who came down with flu: Cannell's patients were taking high doses of vitamin D.
Manufactured by the skin in response to solar ultraviolet B radiation (UVB), vitamin D is the only vitamin made naturally in the body.
On sunny days, a fair-skinned person can manufacture the equivalent of 20,000 international units (IU) of the vitamin in 15 minutes, says Cannell. One cup of fortified milk, by contrast, contains fewer than 100 IU.
But vitamin D production plummets during winter because people spend less time outdoors and because UVB radiation has a harder time penetrating the atmosphere in that season, especially at middle to high latitudes.
As a result, health experts in recent years have warned that many Americans may not be getting as much vitamin D as they need. One ominous sign: a recent resurgence in cases of rickets, a bone disorder caused by a lack of the vitamin.
In their paper, which draws together strands from more than seven decades of vitamin and flu research, Cannell and his colleagues argue that vitamin D stimulates production of a natural infection-fighting substance in the body called cathelicidin.
Although cathelicidin has yet to be studied directly on influenza, recent research has shown that it attacks a variety of fungi, viruses, and bacteria -- including the bug that causes tuberculosis, researchers reported last March in Science.
There's also indirect evidence of the sun's role in seasonal flu, Cannell and colleagues argue.
In the late 1970s, Soviet scientists inoculated about 835 young men in St. Petersburg with a weakened form of the influenza virus during different seasons.
The men, they discovered, were eight times more likely to develop fever and other signs of flu infection in winter than in summer. Repeating the experiment in another city yielded similar results.
And what of the sun-drenched tropics? Cannell and his colleagues point to a scattering of studies showing vitamin D deficiencies even in Hong Kong and other equatorial spots.
Another important clue: A 2003 review of tropical influenza infections found the virus strikes mainly during the rainy season, presumably a time of reduced sun exposure.
Some researchers find the vitamin D theory tantalizing.
"It's a wonderful story, and I think there's considerable substance behind it," says immunologist Dr. Michael A. Zasloff, a professor at Georgetown University.
Others wonder whether this is just another vitamin fad -- just as vitamin C was once promoted by Nobel laureate Linus Pauling as a cure for the common cold.
"They have manipulated the literature (some of it very bad literature) to prove their points," Dr. James Cherry, a pediatric infectious disease specialist at UCLA's David Geffen School of Medicine, wrote in an e-mail.
However, "the hypothesis should be easy to prove or disprove with a controlled, blinded study," he added.
Vitamin D isn't the only substance being kicked around as a seasonal stimulus candidate.
The CDC's Scott Dowell favors melatonin, a naturally occurring hormone whose production is tied to the daily light-dark cycle. Preliminary research suggests that the hormone might help regulate the body's immune response.