May 2008 Archives

This Germ Could Save your Life ...
       Or at Least Keep Your Teeth Cavity Free

Copyright Jessica Snyder Sachs, first published in Popular Science magazine

It's a drizzly morning on New York's Upper East Side, and Rockefeller University microbiologist David Thaler is sipping a double espresso amid the retro-hippie pillows and dangling paper stars of Java Girl, a favorite haunt of the neighborhood's brainiac Nobel laureates, aging poets and famous entertainers. Thaler somehow manages to embody all three-a long, graying ponytail curling down the middle of his back, wire-frame glasses askew over expansive brown eyes, and a schnozz to rival an Einstein, Ginsberg or Allen. Thaler is one of the leading cheerleaders for a new field of biotechnology aimed at engineering the bacteria inside us to deliver drugs, destroy tumors, actively fight infection, and even vaccinate against their disease-causing kin.

Our ancestors, Thaler explains, emerged from the Stone Age by genetically engineering plants and animals through selective breeding, transforming the wolves that preyed on their flocks into the domestic dogs that would guard them. "Except for wild-caught fish, virtually everything we eat today has been engineered," he says. "Meanwhile, we're walking through this ocean of bacteria and only looking at them as something that can make us sick, rather than something to cultivate." He believes that it's time to move humanity from being microbe exterminators to microbe farmers.

Thaler thinks we need what he calls a "second Neolithic revolution." Although his day job as a microbiologist at Rockefeller revolves around such abstract research as testing life's speed limit (current record for replication: eight minutes), he sees himself as an idea man, someone who might help advance an entirely different mind-set in medical microbiology: Instead of using antibiotics to kill harmful bacteria in our bodies and our environment, why not coax bacteria to do our bidding?

"The technology to harness these bacteria exists," Thaler says. Biotechnology firms already use bacteria like E. coli as tiny factories. Just slip the DNA instructions for, say, a new protein-based drug into E. coli and, in its endless quest to replicate itself, the bacterium will replicate the drug as well.

But it's one thing to employ genetically engineered bacteria to produce pharmaceuticals inside a sealed vat. It's quite another to deploy what some call "Frankenbugs" inside a patient. The same characteristics that make bacteria so amenable to genetic engineering-their malleability, their incredible replication speed, their genetic promiscuity-allow their newly acquired DNA to spread to other microbes, including potentially dangerous ones.

Such concerns have largely kept the first generation of engineered superbugs confined to biohazard-containment labs. But the few microbes that have made it into limited human trials-a cavity stopper, a tumor destroyer, a bowel soother-have been enticingly successful. And so the first standoff over body-ready bugs is taking place before the review boards of medical centers and government regulatory agencies, the people who will decide if the world is ready for engineered superbugs.

"I honestly think people are more comfortable with the idea of nano-robots scurrying through their bodies than they are of deploying bacteria," Thaler muses. "But when you think about it, you cultivate your lawn. You'd probably like to cultivate your internal landscape."

THE CAVITY KILLER

Jeffrey Hillman, an oral biologist for-merly of the University of Florida, is a poster child for the kind of biotherapeutic future that Thaler envisions. Hillman has spent a decade lobbying the FDA to let him test a transgenic tooth bug in volunteers. "Fortunately, we had no idea what was ahead," says Hillman of the gantlet of regulatory requirements he has had to tackle since 1996. That was the year Hillman founded Oragenics, a biotech firm dedicated to commercializing his patented cavity-preventing Streptococcus mutans, a genetically modified organism (GMO) that's the product of nearly 30 years of research.

Inside the mouth of most every person on the planet, colonies of S. mutans bacteria thrive on leftover sugars. The by-product of their digestion is the acid that eats away at tooth enamel and causes cavities. But there are many different strains of S. mutans, and some cause more trouble than others. In the summer of 1976, Hillman was trying to replace cavity-prone strains with those that secrete less enamel-eroding acid. Unfortunately, it seemed almost impossible to permanently eradicate a person's "native" S. mutans once his or her teeth became colonized in early childhood.

"We were trying all sorts of crazy things," Hillman recalls. "One time, we were painting volunteers' teeth with iodine. Then we tried fitting their teeth with trays filled with antibiotics." Yet no matter how thoroughly Hillman banished his volunteers' native S. mutans or how quickly he re-colonized their teeth with a benign strain, the switch-out never stuck. "Slowly but surely, a person's indigenous strain always came back," Hillman says.

In 1982 Hillman hit on the idea of first finding a strain aggressive enough to elbow out a person's native tooth tenants and then knocking out its genes for acid production. He conducted the microbial equivalent of cockfights, setting various strains of S. mutans against each other in crowded petri dishes. He knew he had found his ideal candidate when he saw that one "pinprick" colony had cleared a perfect circle in the lawn of other bacteria around it. When Hillman and two of his labmates introduced the strain into their own mouths, it quickly took over, banishing their native S. mutans in the process.

Next, Hillman deleted the microbe's gene for acid production, but the superbugs didn't survive the genetic tinkering. Most strains of S. mutans, including this one, use lactic acid to dispose of metabolic waste. Without acid excretion, the waste builds to toxic levels, killing the microbe.

Hillman solved the problem by making his bug produce alcohol instead of acid. To do so, he borrowed a gene for alcohol production from Zymomonas mobilis, which is used to make pulque, or Mexican beer. The resulting bug didn't produce enough alcohol to make its host at all tipsy. But in studies with lab rats, it replaced the animals' existing S. mutans and kept the rats mostly cavity-free on a high-sugar diet that would normally destroy their teeth.

The trouble was that Hillman now had a true transgenic-an organism that expressed the genes of two different species. The prospect of tests in humans meant that he had to go to the FDA for approval. The FDA eventually referred his case to the National Institutes of Health's Recombinant DNA Advisory Committee, created in 1974 in response to public concern over the safety of interspecies gene transfer. The committee, which includes ethicists and patients as well as scientists and physicians, reviews any application for a transgenic intended to be used outside a sealed laboratory.

In 2004, the committee gave Hillman the green light. Usually, this is enough for full FDA approval. But not this time. FDA regulators asked Hillman to cripple his bug to guarantee that it could be removed should it ever cause problems. "When we asked them what kind of problems, they had no idea," he recalls. "I guess we were setting a precedent."

The regulators saw a genetically modified bacteria that was robust enough to take over any person's mouth, and they were worried about its unchecked spread. Their decision reflected a common criticism of GMO biotherapeutics. "The main problem . . . is that [GMOs] are usually poorly contained," argues geneticist Joe Cummins. Recently retired from the University of Western Ontario, Cummins is a leading spokesman for the London-based Institute for Science in Society, an anti-GMO lobbying group. "They're bound to escape and to pollute the systems of people who don't require therapy."

So Hillman knocked out more genes, this time rendering his microbe unable to survive without an amino acid that test subjects would need to supply, twice daily, by rinsing with a specially formulated mouthwash. In addition, the agency required that Hillman test on patients wearing full dentures that could be dropped into bleach at the end of a week. The volunteers could not have children in their homes, and their spouses had to wear full dentures as well. And both the volunteers and their spouses had to be robustly healthy and under age 55. "We screened more than 1,000 potential volunteers," Hillman says, "and we found two."

The miniature, two-person trial proceeded without a hitch at the end of 2006, with no adverse side effects and complete elimination of the organism at the end of seven days. Last November, past the 10th anniversary of his original FDA application, Hillman received approval to use his crippled transgenic in a larger clinical trial. "Real people with real teeth!" he exults. For safety, the volunteers will spend the weeklong trial in a biocontainment ward.

Should his superbug prove as harmless as it appears, Hillman hopes the FDA will eventually allow him to skip the step where he renders it a nutritional cripple. Users could then dispense with the daily amino-acid mouthwash.

Might the bug then begin spreading from one person's mouth to the next? It's unlikely, Hillman says. When he and his labmates colonized their teeth with their GMO's ancestor, it did not spread to wives and girlfriends, even while remaining in their own mouths for decades.

Proponents like Thaler ask whether such an "uncontrolled release," if it were to occur, would be a bad thing. "What would it be like for us to have benign versions of Typhoid Mary walking around," he asks, "spreading their health-enhancing germs?" In some cases, though, uncontrolled release of genetically modified bacteria could lead to disaster, even if the intended effects were nothing but beneficial.

ATTACKING CROHN'S

On day three of the study at the Academic Medical Centre in Amsterdam, the 43-year-old Dutch farmer felt so good that he was packing his bags to leave the hospital. The nurses caught him just as he was headed out the door of the center's new biocontainment ward for gene therapy. Its rooms are kept under negative pressure so that even if a window breaks, bacteria-laden air will flow in, not out. The man had been spending his days confined to little more than a glorified hospital room, with doctors and nurses coming and going in head-to-toe surgical garb. The bug that was healing his body had to remain isolated, by government order. "We had to explain to him that he was not free to leave, no matter how wonderful he felt," recalls study leader Maikel Peppelenbosch.

Over the previous eight months, Peppelenbosch had managed to win government approval for a clinical trial that deployed a genetically modified cheese-making bacterium, Lactococcus lactis-Thy12, to relieve Crohn's disease [launch the gallery

here, to see how it works]. This excruciating bowel disorder is caused by the immune system mistakenly attacking the intestines' normal complement of digestive microbes. The result is a vicious cycle of painful inflammation and gaping ulcers that can progress to life-threatening perforations of the colon.

Dutch approval of the trial-and the willingness of patients to cycle through 11 days of biological isolation-was a testament to both the seriousness of the disease and the lack of reliable cures, Peppelenbosch says. "These were patients for whom taking out the bowels was their last remaining option." Funding for the study came from the U.S., by way of a private research grant from billionaires Eli and Edythe Broad, whose son suffers from Crohn's.

The way to treat the disease is to turn off the immune system's attack on the intestines' native bacteria. Researchers have long known that lab animals whose bodies fail to produce the immune-calming molecule interleukin-10 develop severe inflammatory bowel disorders similar to Crohn's. But efforts to administer IL-10 are fraught with problems. Stomach acid destroys the protein, so it can't be taken by mouth. And introducing it into the bloodstream risks paralyzing a patient's immune system.

Any solution must deliver the immune-calming molecule exactly where it's needed-inside the intestinal tract-but nowhere else. That's where Lothar Steidler's creation comes in. In 1999 Steidler was pursuing postdoctoral studies into Crohn's-disease treatments at Ghent University in Belgium. In an impressive molecular sleight of hand, Steidler took the gene for IL-10 and slipped it into L. lactis.

But he didn't stick it just anywhere in the cheese bug's genome. Steidler understood how important it was to prevent his bug from escaping into, say, the sewer system, where any number of nasty, disease-causing bacteria might pick up the IL-10 gene. The result could be pandemic disaster: a pathogen out in the wild with the ability to cripple the body's disease-fighting response.

"I knew I had to build in some sort of suicidal mechanism," he explains. He also had to prevent gene swapping between his "good bug" and a potential bad guy. So Steidler made sure that the incoming IL-10 gene always replaces another gene needed to produce the nutrient thymidine. That way, his new bugs can't make thymidine, and so they die of nutrient starvation within a few days. That fleeting life span is enough to complete their mission but not long enough to survive in the waste that flushes down the toilet.

Even better, if the inserted gene jumps into another organism, it replaces that microbe's thymidine gene. So any bug that receives the gene likewise becomes a doomed nutritional cripple. "Fortunately, Lothar designed this bacterium very well," says Peppelenbosch, who collaborated with Steidler to usher the transgenic through regulatory approval in the Netherlands. Their proposal received no objections from either regulators or the public-an unexpected feat in rabidly anti-GMO Europe, he notes.

The team faced no lack of volunteers for the trial. The doctors at the Academic Medical Centre saw scores of patients with severe Crohn's that failed to respond to standard anti-inflammatory drugs. The researchers ushered 10 patients into their containment ward, one by one, for their seven-day treatment and 11-day isolation.

Eight of the 10 Crohn's patients experienced relief from pain and diarrhea, five dramatically so. One withdrew early for unrelated reasons, and none experienced any worsening of symptoms or problematic side effects. Most important for the prospect of larger studies, Steidler demonstrated that his transgenic microbe completely disappeared from the volunteers' stool within a day of swallowing their last capsules of live bacteria.

As expected, the patients' symptoms reappeared a few weeks after they returned home, and several came back to plead for continued treatment. "We couldn't, of course," Peppelenbosch says, because the trial was over. Steidler and Peppelenbosch are seeking Dutch approval for a larger, placebo-controlled trial, this time without the onerous restrictions of isolating patients on a biohazard ward.

Built-in suicide mechanisms such as Steidler's may prove key to the widespread use of GMO biotherapeutics. "Now that the biocontainment issues are being fully recognized and achieved, I think it's all going to move very quickly," predicts North Carolina State University micro-biologist Todd Klaenhammer.

THE TUMOR BUGS

In January 2002, doctors at the Mary Crowley Medical Research Center in Dallas began injecting a genetically modified breed of salmonella into three cancer patients with large, inoperable tumors that had failed to respond to radiation or chemotherapy. For reasons still poorly understood, salmonella proliferates inside malignancies, perhaps because cancerous tumors tend to remain beyond the reach of the immune system. This salmonella was special, though. A Yale University team led by microbiologist David Bermudes inserted an E. coli gene into the bacteria. The gene produced an enzyme that activates a highly noxious, tissue-destroying drug. "The beauty is that neither the enzyme nor the drug that it activates does anything toxic except in places where they end up together," Bermudes explains. In other words, the system is engineered to be harmless outside a tumor but deadly inside it.

The 2002 pilot trial proved a success, in that the bioengineered salmonella delivered its enzyme payload, produced a modest shrinkage in tumor size, and did no harm to the three patients, but the trial was too small to make any claims of a cure. To move into larger, meaningful trials would require following in Hillman's footsteps through a battery of federal regulatory review boards. That costs money. Even if the researchers received approval to go ahead, they would need to come up with the many millions of dollars needed to usher any potential cancer treatment through large-scale patient trials.

That investment would most likely come from Vion Pharmaceuticals, the Connecticut biotech firm that currently holds Bermudes's patent on the tumor-busting salmonella. Vion has no plans to tackle the regulatory process in the near future, however, says Ivan King, Vion's vice president for research and development. "As a small company, we cannot move many things forward at any one time," he says. What's needed, he believes, is interest from a larger pharmaceutical company with much deeper pockets-just the kind of company that has yet to show interest in highly experimental bioengineered bacteria.

THE NATURAL WAY

Meanwhile, some researchers are focusing on unmodified microbes that could benefit the body. These "probiotics" are sold in grocery and health-food stores, yet few of the numerous available products have been rigorously tested. One of the exceptions is Lactobacillus GG, or "Culturelle," isolated in the 1980s by Sherwood Gorbach and Barry Goldin of Tufts University. Over the past two decades, Gorbach, Goldin and others have published 250 scientific papers on this strain's disease-fighting effects. Studies suggest that the bug has an immune-calming effect that may ease some food allergies. But its one clear and proven benefit is to reduce a person's risk of picking up one of the many nasty intestinal bugs that cause food poisoning, traveler's diarrhea and antibiotic-induced gastroenteritis, which results when antibiotics kill off a person's normal intestinal bacteria and a disease-causing invader moves in.

In Europe, where probiotics have long been popular, they have also been used to prevent chronic respiratory and ear infections. In the early 1990s, Swedish ear-nose-and-throat specialist Kristian Roos developed a throat spray containing a medley of throat bacteria that dramatically reduced the recurrence of chronic strep infections. A few years later, Roos developed a similar concoction that protected toddlers and preschoolers who were predisposed to ear infections.

Roos's probiotics demonstrated their worth in small clinical trials. But they also illustrate the challenge of developing a natural probiotic into a medical therapeutic. A small clinical trial may be enough to put a health claim on a nutritional supplement sold over the counter. But Roos wants to see such cures in the hands of doctors, who would judiciously prescribe them to patients. To do that, he must prove that his probiotics work in the same kind of large, multimillion-dollar trials that have stymied Bermudes's cancer-fighting GMO.

For that kind of money, Roos admits, investors are right to expect an ironclad patent to protect their investment. But that's difficult to do with bacteria that occur naturally on and in the human body. "Even though we can patent our particular mixture of organisms, it would be easy for someone else to come along and put together something slightly different from the hundreds of protective strains found in people's throats," he explains. Without the assurance of some meaningful patent protection on his product, he has been unable to attract financial investors, and his treatments languish in a storage freezer.

THE GOOD-MOOD BUG

Microbiologist John Stanford of University College London and his wife, Cynthia, discovered Mycobacterium vaccae while searching for a tuberculosis vaccine booster in Uganda in the early 1970s. Experts had long proposed that the widely variable efficacy of the TB vaccine stemmed from bacteria in a region's soil that provided a natural booster effect. The Stanfords, crisscrossing the African nation in search of this bacterium, isolated M. vaccae, a benign genetic cousin of Mycobacterium tuberculosis, from the muddy shores of Lake Kyoga, an area where the TB vaccine proved unusually effective against both tuberculosis and leprosy. The Stanfords hoped that injections of M. vaccae would help prevent or cure TB, but at best their vaccine proved only mildly beneficial. More curious were anecdotal reports of unexpected benefits-regressions of allergies, asthma and even cancer.

In 1992 John Stanford and his colleague Graham Rook went on to form a publicly traded company, SR Pharma, to test these immune-boosting benefits in clinical trials with late-stage lung-cancer patients. But in 2001, under a spotlight of media attention, the trial failed to appreciably increase patients' survival time. SR Pharma's stock crashed, and following a dispute over the company's future focus, the company removed Rook and Stanford from its board of directors.

Yet the trial did produce one bona fide benefit: a significant increase in "quality of life" among patients who got M. vaccae injections versus those who received a placebo. That dovetails with the work of University of Colorado neuroscientist Christopher Lowry, who last May published a study where he used M. vaccae in psychotropic experiments with rats. Lowry discovered that the bug increased brain levels of the mood-enhancing hormone serotonin and decreased depressive behavior. Even more promising, Lowry showed that M. vaccae appeared to be more discriminating than antidepressant drugs in the kinds of brain neurons it activates. It switches on the serotonin neurons associated with enhancing mood, without stimulating those that increase hyperalertness-that is, anxiety and sleeplessness. "Prozac without the side effects," he calls it. In addition, recent studies have shown that M. vaccae may be effective against TB-the Stanfords' original studies didn't supply enough doses-and may increase the survival times of some late-stage cancer patients.

It's just this sort of surprising potential that inspires researchers. "We're always saying things like, 'I feel lousy today. I must have caught a bug,' " Thaler says. "We never say, 'I feel great. I must have picked up an endorphin-producing one.' What would it mean to cultivate yourself to be contagiously healthy?"

Jessica Snyder Sachs is a contributing editor at Popular Science. Her most recent book is Good Germs, Bad Germs: Health and Survival in a Bacterial World.

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illustration by Gary Taxali

As first appeared in The New York Times, Op-Ed page, 10 Oct 2007

Copyright JESSICA SNYDER SACHS

IT'S flu season, and health agencies have expanded their flu shot recommendations to include all children ages 6 months to 5 years in addition to adults over age 50, and anyone, child or adult, with a chronic condition like severe allergies, asthma or diabetes.

More parents than ever before - nearly 65 percent - intend to vaccinate their young children this year, according to a poll by the University of Michigan. But that leaves more than a third unenthusiastic about doing so. Their reluctance may reflect not only weariness with the increasing number of childhood immunizations but also the widespread sentiment that colds and flus are a "natural" part of childhood, even vital for toughening up a developing immune system.

Some parents have come to embrace colds and flus, and in recent years we've seen a resurgence of the chickenpox party, where parents deliberately expose their preschoolers to infected playmates on the theory that it's better to get the disease than to have the vaccine.
But the idea that illness is good for children - or anyone else - is wrong. In part, the idea of "good sickness" is a throwback to a now disproved version of the "hygiene hypothesis."

In 1989, an epidemiologist in Britain, David Strachan, observed that babies born into households with lots of siblings were less likely than other babies to develop allergies and asthma. The same proved true of babies who spent significant time in day care. Dr. Strachan hypothesized that the protection came from experiencing an abundance of childhood illnesses.

Dr. Strachan's original hygiene hypothesis got a lot of press, not only in the news media but in serious medical journals. Less publicized was the decade-long string of follow-up studies that disproved a link between illnesses and protection from inflammatory disorders like allergies and asthma. If anything, studies showed, early illness made matters worse.
Moreover, studies now show that the more infections a person has during childhood, the greater his or her chance of premature death from scourges of old age like heart disease and cancer. The link appears to be chronic inflammation, a kind of lingering collateral damage from the body's disease-fighting response.

Still, Dr. Strachan's original observation was confirmed - as a group, babies in large families and day care are less likely to develop allergies and asthma than are children born into smaller families and kept at home. The same protective effect can be seen in children born on farms and in areas without public sanitation.

But the link isn't disease-causing germs. It's early and ample exposure to harmless bacteria - especially the kinds encountered living close to the land and around livestock and other young children. In other words, dirt, dung and diapers. Just as disease-causing microbes clearly bring on inflammation, harmless microorganisms appear to exert a calming effect on the immune system.

A second misconception common among vaccine-shunning parents is that there's something "natural" about the 6 to 10 respiratory infections the typical American child gets every year (or even the two to four we adults experience). Common, yes; natural no, not if "natural" represents the forces that shaped the human immune system during all but the last sliver of our 250,000 years as Homo sapiens. Colds, flus and most other contagious diseases found a central place in our lives only after we and our domestic animals began crowding together in large settlements some 5,000 years ago.

Yet the most compelling reason to get a flu shot this year is a new and deadly threat - methicillin-resistant Staphylococcus aureus, or MRSA, a dangerous kind of staph that has been causing outbreaks of deadly pneumonia among the otherwise young and healthy, typically on the heels of the flu.

Unfortunately, we have no practical way to eradicate MRSA. About a third of us silently carry staph at any given time, and trying to eradicate MRSA or any other staph strain from a community of symptom-free carriers is difficult to impossible. Worse, the experts conclude, any widespread effort to do so is certain to breed greater drug resistance.
Flu shots don't guarantee protection from MRSA pneumonia. It can piggyback on other kinds of viral respiratory infections. But protecting yourself and your children from the flu may be the best way to reduce your family's risk.

Whether dealing with the flu, other "routine" infections or even the chickenpox, the message is the same: In a world abounding in harmless, even beneficial microbes, don't embrace the tiny fraction that can make you ill.

Jessica Snyder Sachs, the former managing editor of Science Digest, is the author of the forthcoming book "Good Germs, Bad Germs: Health and Survival in a Bacterial World."

For every cell in your body, you support 10 bacterial cells that make vitamins, trigger hormones, and may even influence how fat you are. Guess what happens to them when you pop penicillin?

Copyright Jessica Snyder Sachs, as first published in DISCOVER magazine

ALAN HUDSON likes to tell a story about a soldier and his high school sweetheart. The young man returns from an overseas assignment for their wedding with a clean bill of health, having dutifully cleared up an infection of sexually transmitted chlamydia.

Image of Chlamydia by Judith Whittum Hudson

"Three weeks later, the wife has a screaming genital infection," Hudson recounts, "and I get a call from the small-town doctor who's trying to save their marriage." The soldier, with obvious double standard, has decided his wife must have been seeing other men, which she denies.

Hudson pauses for effect, stretching back in his seat and propping his feet on an open file drawer in a crowded corner of his microbiology laboratory at Wayne State Medical School in Detroit. "The doctor is convinced she's telling the truth," he continues, folding his hands behind a sweep of white, collar-length hair. "So I tell him, 'Send me a specimen from him and a cervical swab from her.' " This is done after the couple has completed a full course of antibiotic treatment and tested free of infection.

"I PCR 'em both," Hudson says, "and he is red hot."

PCR stands for polymerase chain reaction-a technique developed about 20 years ago that allows many copies of a DNA sequence to be made. It is often used at crime scenes, where very little DNA may be available. Hudson's use of the technique allowed him to find traces of chlamydia DNA in the soldier and his wife that traditional tests miss because the amount left after antibiotic treatment is small and asymptomatic.

Nonetheless, if a small number of inactive chlamydia cells passed from groom to bride, the infection could have became active in its new host.

Hudson tells the tale to illustrate how microbes that scientists once thought were easily eliminated by antibiotics can still thrive in the body. His findings and those of other researchers raise disturbing questions about the behavior of microbes in the human body and how they should be treated.

For example, Hudson has found that quiescent varieties of chlamydia may play a role in chronic ailments not traditionally thought to be related to this infectious agent. In the early 1990s, he found two types of chlamydia-Chlamydia trachomatis and Chlamydia pneumonia-in the joint tissue of patients with inflammatory arthritis. More famously, in 1996, he began fishing C. pneumonia out of the brain cells of Alzheimer's victims. Since then, other researchers have made headlines after reporting the genetic fingerprints of C. pneumonia, as well as several kinds of common mouth bacteria, in the arterial plaque of heart attack patients. Hidden infections are now thought to be the basis of still other stubbornly elusive ills like chronic fatigue syndrome, Gulf War syndrome, multiple sclerosis, lupus, Parkinson's disease, and types of cancer.

To counteract these killers, some physicians have turned to lengthy or lifelong courses of antibiotics. At the same time, other researchers are counterintuitively finding that bacteria we think are bad for us also ward off other diseases and keep us healthy. Using antibiotics to tamper with this complicated and little-understood population could irrevocably alter the microbial ecology in an individual and accelerate the spread of drug-resistant genes to the public at large.

THE TWO-FACED PUZZLE regarding the role of bacteria is as old as the study of microbiology itself. Even as Louis Pasteur became the first to show that bacteria can cause disease, he assumed that bacteria normally found in the body are essential to life. Yet his protege, Elie Metchnikoff, openly scoffed at the idea. Metchnikoff blamed indigenous bacteria for senility, atherosclerosis, and an altogether shortened life span-going even so far as to predict the day when surgeons would routinely remove the human colon simply to rid us of the "chronic poisoning" from its abundant flora.

Today we know that trillions of bacteria carpet not only our intestines but also our skin and much of our respiratory and urinary tracts. The vast majority of them seem to be innocuous, if not beneficial. And bacteria are everywhere, in abundance-they outnumber other cells in the human body by 10 to one. David Relman and his team at Stanford University and the VA Medical Center in Palo Alto, California, recently found the genetic fingerprints of several hundred new bacterial species in the mouths, stomachs, and intestines of healthy volunteers.

"What I hope," Relman says, "is that by starting with specimens from healthy people, the assumption would be that these microbes have probably been with us for some time relative to our stay on this planet and may, in fact, be important to our health."

Meanwhile, the behavior of even well-known bacterial inhabitants is challenging the old, straightforward view of infectious disease. In the 19th century, Robert Koch laid the foundation for medical microbiology, postulating: Any microorganism that causes a disease should be found in every case of the disease and always cause the disease when introduced into a new host. That view prevailed until the middle of this past century. Now we are more confused than ever. Take Helicobacter pylori. In the 1980s infection by the bacterium, not stress, was found to be the cause of most ulcers. Overnight, antibiotics became the standard treatment. Yet in the undeveloped world ulcers are rare, and H. pylori is pervasive.

"This stuff drives the old-time microbiologists mad," says Hudson, "because Koch's postulates simply don't apply." With new technologies like PCR, researchers are turning up stealth infections everywhere, yet they cause problems only in some people sometimes, often many years after the infection.

Helicobacter pylori

These mysteries have nonetheless not stopped a free flow of prescriptions. Many rheumatologists, for example, now prescribe long-term-even lifelong-courses of antibiotics for inflammatory arthritis, even though it isn't known if the antibiotics actually clear away bacteria or reduce inflammatory arthritis in some other unknown manner.

Even more far-reaching is the use of antibiotics to treat heart disease, a trend that began in the early 1990s after studies associated C. pneumonia with the accumulation of plaque in arteries. In April of 2007, two large-scale studies reported that use of antibiotics does not reduce the incidence of heart attacks or eliminate C. pneumonia. But researchers left antibiotic-dosing cardiologists a strange option by admitting they do not know if stronger, longer courses of antibiotics or combined therapies would succeed.

MEANWHILE, MANY RESEARCHERS ARE ALARMED. Infectious-diseases specialist Curtis Donskey, of Case Western Reserve University in Cleveland, says: "Unfortunately, far too many physicians are still thinking of antibiotics as benign. We're just now beginning to understand how our normal microflora does such a good job of preventing our colonization by disease-causing microbes. And from an ecological point of view, we're just starting to understand the medical consequences of disturbing that with antibiotics."

Donskey has seen the problem firsthand at the Cleveland VA Medical Center, where he heads infection control. "Hospital patients get the broadest spectrum, most powerful antibiotics," he says, but they are also "in an environment where they get exposed to some of the nastiest, most drug-resistant pathogens." Powerful antibiotics can be dangerous in such a setting because they kill off harmless bacteria that create competition for drug-resistant colonizers, which can then proliferate. The result: Hospital-acquired infections have become a leading cause of death in critical-care units.

"We also see serious problems in the outside community," Donskey says, because of inappropriate antibiotic use.

The consequences of disrupting the body's bacterial ecosystem can be minor, such as a yeast infection, or they can be major, such as the overgrowth of a relatively common gut bacterium called Clostridium difficile. A particularly nasty strain of C. difficile has killed hundreds of hospital patients in Canada over the past two years. Some had checked in for simple, routine procedures. The same strain is moving into hospitals in the United States and the United Kingdom.

JEFFREY GORDON, a gastroenterologist turned full-time microbiologist, heads the spanking new Center for Genomic Studies at Washington University in Saint Louis. The expansive, sun-streaked laboratory sits above the university's renowned gene-sequencing center, which proved a major player in powering the Human Genome Project. "Now it's time to take a broader view of the human genome," says Gordon, "one that recognizes that the human body probably contains 100 times more microbial genes than human ones."

Gordon supervises a lab of some 20 graduate students and postdocs with expertise in disciplines ranging from ecology to crystallography. Their collaborations revolve around studies of unusually successful colonies of genetically engineered germ-free mice and zebra fish.

Gordon's veteran mouse wranglers, Marie Karlsson and her husband David O'Donnell, manage the rearing of germ-free animals for comparison with genetically identical animals that are colonized with one or two select strains of normal flora. In a cavernous facility packed with rows of crib-size bubble chambers, Karlsson and O'Donnell handle their germ-free charges via bulbous black gloves that serve as airtight portals into the pressurized isolettes. They generously supplement sterilized mouse chow with vitamins and extra calories to replace or complement what is normally supplied by intestinal bacteria. "Except for their being on the skinny side, we've got them to the point where they live near-normal lives," says O'Donnell. Yet the animals' intestines remain thin and underdeveloped in places, bizarrely bloated in others. They also prove vulnerable to any stray pathogen that slips into their food, water, or air.

All Gordon's proteges share an interest in following the molecular cross talk among resident microbes and their host when they add back a component of an animal's normal microbiota. One of the most interesting players is Bacteroides thetaiotaomicron, or B. theta, the predominant bacterium of the human colon and a particularly bossy symbiont.

The bacterium is known for its role in breaking down otherwise indigestible plant matter, providing up to 15 percent of its host's calories. But Gordon's team has identified a suite of other, more surprising skills. Three years ago, they sequenced B. theta's entire genome, which enabled them to work with a gene chip that detects what proteins are being made at any given time. By tracking changes in the activity of these genes, the team has shown that B. theta helps guide the normal development and functioning of the intestines-including the growth of blood vessels, the proper turnover of epithelial cells, and the marshaling of components of the immune system needed to keep less well behaved bacteria at bay. B. theta also exerts hormonelike, long-range effects that may help the host weather times when food is scarce and ensure the bacterium's own survival.

Fredrik Backhed, a young postdoc who came to Gordon's laboratory from the Karolinska Institute in Stockholm, has caught B. theta sending biochemical messages to host cells in the abdomen, directing them to store fat. When he gave germ-free mice an infusion of gut bacteria from a conventionally raised mouse, they immediately put on an average of 50 percent more fat although they were consuming 30 percent less food than when they were germ-free. "It's as if B. theta is telling its host, 'save this-we may need it later,' " Gordon says.

Justin Sonnenburg, another postdoctoral fellow, has documented that B. theta turns to the host's body for food when the animal stops eating. He has found that when a lab mouse misses its daily ration, B. theta consumes the globs of sugary mucus made every day by some cells in the intestinal lining. The bacteria graze on these platforms, which the laboratory has dubbed Whovilles (after the dust-speck metropolis of Dr. Seuss's Horton Hears a Who!). When the host resumes eating, B. theta returns to feeding on the incoming material.

Gordon's team is also looking at the ecological dynamics that take place when combinations of normal intestinal bacteria are introduced into germ-free animals. And he plans to study the dynamics in people by analyzing bacteria in fecal samples.

Among the questions driving him: Can we begin to use our microbiota as a marker of health and disease? Does this "bacterial nation" shift in makeup when we become obese, try to lose weight, experience prolonged stress, or simply age? Do people in Asia or Siberia harbor the same organisms in the same proportions as those in North America or the Andes?

"We know that our environment affects our health to an enormous degree," Gordon says. "And our microbiota are our most intimate environment by far."

A COUPLE HUNDRED miles northeast of Gordon's laboratory, microbiologist Abigail Salyers at the University of Illinois at Urbana-Champaign has been exploring a more sinister feature of our bacteria and their role in antibiotic resistance. At the center of her research stands a room-size, walk-in artificial "gut" with the thermostat set at the human intestinal temperature of 100.2 degrees Fahrenheit. Racks of bacteria-laced test tubes line three walls, the sealed vials purged of oxygen to simulate the anaerobic conditions inside a colon. Her study results are alarming.

Salyers says her research shows that decades of antibiotic use have bred a frightening degree of drug resistance into our intestinal flora. The resistance is harmless as long as the bacteria remain confined to their normal habitat. But it can prove deadly when those bacteria contaminate an open wound or cause an infection after surgery.

"Having a highly antibiotic-resistant bacterial population makes a person a ticking time bomb," says Salyers, who studies the genus Bacteroides, a group that includes not only B. theta but also about a quarter of the bacteria in the human gut. She has tracked dramatic increases in the prevalence of several genes and suites of genes coding for drug resistance. She's particularly interested in tetQ, a DNA sequence that conveys resistance to tetracycline drugs.

When her team tested fecal samples taken in the 1970s, they found that less than 25 percent of human-based Bacteroides carried tetQ. By the 1990s, that rate had passed the 85 percent mark, even among strains isolated from healthy people who hadn't used antibiotics in years. The dramatic uptick quashed hopes of reducing widespread antibiotic resistance by simply withdrawing or reducing the use of a given drug.

Salyers's team also documented the spread of several Bacteroides genes conveying resistance to other antibiotics such as macrolides, which are widely used to treat skin, respiratory, genital, and blood infections.

As drug-resistant genes become common in bacteria in the gut, they are more likely to pass on their information to truly dangerous bugs that only move periodically through our bodies, says Salyers. Even distantly related bacteria can swap genes with one another using a variety of techniques, from direct cell-to-cell transfer, called conjugation, to transformation, in which a bacterium releases snippets of DNA that other bacteria pick up and use.

"Viewed in this way, the human colon is the bacterial equivalent of eBay," says Salyers. "Instead of creating a new gene the hard way-through mutation and natural selection-you can just stop by and obtain a resistance gene that has been created by some other bacterium."

Salyers has shown that Bacteroides probably picked up erythromycin-resistant genes from distantly related species of staphylococcus and streptococcus. Although neither bug colonizes the intestine, they are routinely inhaled and swallowed, providing a window of 24 to 48 hours in which they can commingle with intestinal flora before exiting. "That's more than long enough to pick up something interesting in the swinging singles bar of the human colon," she quips.

Most disturbing is Salyers's discovery that antibiotics like tetracycline actually stimulate Bacteroides to begin swapping its resistance genes. "If you think of the conjugative transfer of resistance genes as bacterial sex, you have to think of tetracycline as the aphrodisiac," she says. When Salyers exposes Bacteroides to other bacteria such as Escherichia coli under the disinhibiting influence of antibiotics, she has witnessed the step-by-step process by which the bacteria excise and transfer the tetQ gene from one species to another.

Nor is Bacteroides the only intestinal resident with such talents. "In June 2002, we passed a particularly frightening milestone," Salyers says. That summer, epidemiologists discovered hospital-bred strains of the gut bacterium enterococcus harboring a gene that made them impervious to vancomycin. The bacterium may have since passed the gene to the far more dangerous Staphylococcus aureus, the most common cause of fatal surgical and wound infections.

"I am completely mystified by the lack of public concern about this problem," she says.

With no simple solution in sight, Salyers continues to advise government agencies such as the Food and Drug Administration and the Department of Agriculture to reduce the use of antibiotics in livestock feed, a practice banned throughout the European Union. She supports the prescient efforts of Tufts University microbiologist Stuart Levy, founder of the Alliance for the Prudent Use of Antibiotics, which has been hectoring doctors to use antibiotics more judiciously.

Yet just when the message appears to be getting through-judging by a small but real reduction in antibiotic prescriptions-others are calling for an unprecedented increase in antibiotic use to clear the body of infections we never knew we had. Among them is William Mitchell, a Vanderbilt University chlamydia specialist. If antibiotics ever do prove effective for treating coronary artery disease, he says, the results would be "staggering. We're talking about the majority of the population being on long-term antibiotics, possibly multiple antibiotics."

Hudson cautions that before we set out to eradicate our bacterial fellow travelers, "we'd damn well better understand what they're doing in there." His interest centers on chlamydia, with its maddening ability to exist in inactive infections that flare into problems only for an unlucky few. Does the inactive form cause damage by secreting toxins or killing cells? Or is the real problem a disturbed immune response to them?

Lately Hudson has resorted to a device he once shunned in favor of DNA probes: a microscope, albeit an exotic $250,000 model. This instrument, which can magnify organisms an unprecedented 15,000 times, sits in the laboratory of Hudson's spouse, Judith Whittum-Hudson, a Wayne State immunologist who is working on a chlamydia vaccine. On a recent afternoon, Hudson marveled as a shimmering chlamydia cell was beginning to morph from its infectious stage into its mysterious and bizarre-looking persistent form. "One minute you have this perfectly normal, spherical bacterium and the next you have this big, goofy-looking doofus of a microbe," he says. He leans closer, focusing on a roiling spot of activity. "It's doing something. It's making something. It's saying something to its host.

|Science writer Jessica Snyder Sachs is the author of Good Germs, Bad Germs: Health and Survival in a Bacterial World (FSG/Hill&Wang) and Corpse: Nature, Forensics, and the Struggle to Pinpoint Time of Death (Perseus Books).

"Jessica Snyder Sachs successfully weaves story--telling, history, microbiology and evolution into an exciting account of the two aspects of microbes for humankind -- the good and the bad. The book is a wonderful read." --Stuart B. Levy, M.D., author of The Antibiotic Paradox: How the Misuse of Antibiotics Destroys their Curative Powers

 

It's hard not to get anxious about the superbugs in the news, from drug-resistant staph to the new strain of avian flu  -- especially when young children are so vulnerable to infections. But how can parents keep from getting paranoid?

Copyright Jessica Snyder Sachs, as first published in Parenting magazine

While experts don't have all the information, they do have some clear and practical advice  -- some of it surprising. Here are their answers to parents' top questions about germs:

Q:  I've read about children who've died from drug-resistant supergerms. How can I protect my family?

ANSWER: The drug-resistant germs you've heard about are methicillin-resistant Staphylococcus aureus (MRSA) and Clostridium difficile (often referred to as C. diff). We do encounter these bacteria on a regular basis, but the good news: Only rarely do they cause major harm.

MRSA generally produces hard-to-treat skin infections. Less often, it can cause severe pneumonia, typically on the heels of a chest cold or the flu, says John Bradley, M.D., director of infectious diseases at the Children's Hospital and Health Center in San Diego. Infection with the other bacterium, C. diff, is usually triggered by antibiotics and generally causes intestinal problems, such as diarrhea. But in rare cases C. diff can cause dangerous intestinal inflammation.

To protect against MRSA: Wash cuts and scratches thoroughly with soap and water, and keep them covered with a bandage until they've healed. Check the bandage every day or so, and don't ignore redness, swelling, or pus, as these can signal an infection. If the wound gets worse after a day, see a doctor and ask her about the possibility of MRSA. The same advice goes for a chest infection that takes a sudden turn for the worse.

For C. diff, the best prevention is to avoid taking antibiotics needlessly. Remember, they work only against bacterial infections, not viruses like colds and flu. When you or your child must take antibiotics, talk with your doctor about choosing the least gut-disruptive drug available and consider taking probiotics (beneficial bacteria that may help protect against drug-resistant germs). Sources of this good bacteria include Saccharomyces yeasts (in supplements), as well as yogurt and supplements containing lactobacillus. You can take probiotics after a course of antibiotics, or you can take probiotics regularly. Ask your doctor what's best for you.}]

Q:  My kids love snacking on fresh fruit and veggies on the way home from the market. Is this safe?

A: It's probably okay  -- and it's great that your kids are eager to snack on produce  -- but in very rare instances contaminated fruits and vegetables can lead to serious, even life-threatening food-borne illness. (Bad spinach, anyone?) The most common culprits include sprouts, lettuce, unpasteurized juice, melons, and tomatoes. But with the exception of sprouts (which can't be cleaned well and should never be served raw to children), a thorough rinsing under tap water decreases the risk for most fruits and vegetables  -- no soap or special sprays needed. So even though your kids may like to munch on grapes or apples on the way home from the grocery store, it's better to rinse off the produce before digging in.

Using public restrooms; the 5-second rule

Q  What can I do to make sure my kids don't pick up disease-causing germs in public rest rooms?

A: Let's start with the toilet: Unless the seat is wet or dirty (yuck), it probably harbors few germs. So you don't need to worry about layering it with tissue paper. What's more important is to turn your face away when you flush, says University of Arizona microbiologist Charles Gerba, Ph.D. (a.k.a. Dr. Germ, for his unprecedented studies of which germs lurk where). This is because the droplets that fly when you flush can be full of bacteria and viruses. ("That's another reason to put the lid down at home," says Gerba, whose research shows that in a typical home bathroom, toilet spray contaminates just about everything.)

Of course, be sure your kids wash their hands with soap and water when they're done. And during cold and flu season, it's a good idea to use a paper towel on the doorknob as they leave, since one-third of public-bathroom visitors don't wash their hands.}]

Q:  What about the "five-second rule"  -- that it's okay to pick up and eat a dropped cookie, say, if you get it off the floor quickly. Is there any harm in it?

A: That depends on where you drop the cookie. "Compared to your kitchen sink, a bare floor is quite safe," says Gerba, who practically shudders at all the germs he's catalogued in drain traps, dishcloths, and sponges. "So long as you clean the floor now and again, I wouldn't worry."

As for food that drops outside, Gerba suggests erring on the side of caution. "Toss it," he says, whether it's been on the ground for five seconds or five minutes. You don't know what got deposited on that spot before you arrived. Beach sand, for instance, is notorious for being contaminated with bird droppings, which can spread intestinal bugs. "Knowing what I know, I never eat off a bare picnic table," says Gerba. "Birds use it as their rest room while they're cleaning up the crumbs the last picnicker left behind."

Eating rare meat; avoiding avian flu

Q:  My husband likes to cook our burgers medium-rare and our eggs "sunny and runny," but what about the bacteria in these raw foods? Am I being a germophobe?

A: No. Much of the meat and eggs on our supermarket shelves is contaminated with disease-causing bacteria, and these bugs are more drug resistant than ever. Most of the time, the infections people get are run-of-the-mill food poisoning, but in a small fraction of cases, gastrointestinal infections can become a life-threatening problem. Infected babies and toddlers are among those at highest risk of death and serious complications.

To kill these germs, public-health experts recommend that you hard-cook eggs and use an instant-read thermometer to make sure burgers and egg dishes reach an internal temperature of at least 160 degrees Fahrenheit. Also, don't let raw meat or eggs contaminate other food in your kitchen; wash any plate, cutting board, counter, or silverware that's come in contact with the raw food before it touches any other food. For people who really want their eggs sunny-side up and runny, a growing number of supermarkets now carry pasteurized-in-the-shell eggs (such as Davidson's Safest Choice).

Q:  I heard that avian flu could arrive any time with migrating birds. Is it safe to let my child feed ducks at the park or seagulls at the beach?

A: Even if the dangerous avian-influenza virus (technically referred to as highly pathogenic H5N1) turns up in North American birds, the chance of transmission from birds to humans is low. In Asia, the people who have gotten this flu were almost exclusively those who regularly handle chickens and ducks. The greater risk, then, is that this virus will mutate, or change, so that it can be transmitted easily from one person to another. Thankfully, that hasn't happened yet.

Still, you and your child shouldn't get too close to wild birds, says Paul Slota, branch chief of the U.S.G.S. National Wildlife Health Center. Feeding wild birds encourages their crowding  -- which is bad for the birds as well as for people (bird droppings can spread germs).

If your child does touch a wild bird or its droppings, be sure to wash her hands with soap and water before letting her touch her face, eat, or drink. If you're not near a sink, a dollop of alcohol hand gel will do the trick.

Antibacterial soaps; puppy kisses

Q:  The supermarket is filled with soaps and household cleaning products labeled "antibacterial." Are they better than regular cleaning products?

A: No. Antibacterial soaps and cleaning products aren't any more effective in preventing the spread of disease-causing germs. (Alcohol-based hand gels, on the other hand, have been shown to cut down on the spread of infections.) What's more, the chemicals in antibacterial products work like antibiotics  -- by interfering with bacterial growth  -- and you've no doubt heard there's concern (not yet proven) that these chemicals may promote the rise of drug-resistant bacteria. "If they don't provide any benefit, why take the risk?" says Tufts University microbiologist Stuart Levy, M.D. When you want to disinfect surfaces, he and other experts recommend cleaning products that contain bleach or alcohol.

Q:  Our new puppy loves to give playful kisses. Is it okay to let him lick our child's face?

A: "The odds are in your favor that the occasional face lick is okay," says Gerba. "Just ask yourself, what was the last thing your dog licked?" Dogs can pick up intestinal parasites from infected canine buddies or if they drink from streams and lakes frequented by wildlife  -- and these infections show up in stool. So if your dog has just licked himself down there, that may not be the best time for a kiss. But if your dog doesn't show signs of illness, you should generally feel safe letting him give your child friendly licks from time to time.

Parenting contributing editor Jessica Snyder Sachs is the author of Good Germs, Bad Germs: Health and Survival in a Bacterial World (Hill&Wang/FSG).

Winter is the season of the cough, the wheeze, the whoop, the bark, and the rattle, sniffle, and honk.

Copyright Jessica Snyder Sachs, as first published in PARENTING magazine

We spend so much more time indoors, where it's easier for respiratory infections to spread from person to person. Children, with more immature immune systems, get colds and the flu more often than grown-ups. And they have their very own diseases, like croup.

That's why millions of moms (and dads) will be awake tonight, trying to figure out how to relieve their kids' coughing and congestion and fretting over whether to call the doctor or even make a midnight run to the emergency room.

Most of the time, all our kids need is a little symptom relief and comforting -- even when they sound terrible. Sometimes, a parent's wisdom lies in not giving her child medication. But some symptoms do warrant immediate medical attention, while others linger long enough to make you wonder if they signal asthma.

Art by Courtney

What you need to know:

The very common cold
Babies and kids get six to eight colds a year, but sometimes they sound sicker than they are. "What parents usually hear are the random snorts and sniffles of air passing through mucus and secretions in the nose and throat," says pediatric pulmonologist Peter Scott, M.D., of Children's Healthcare of Atlanta. There's no need to worry as long as your child seems reasonably comfortable and active, continues to eat and drink, and starts to get better after a few days. In the meantime:

Try saline drops to loosen nasal congestion. They're especially helpful for babies too young to blow their noses. Use three or four times a day.

To relieve a nighttime cough, elevate your child's head with a wedge beneath the mattress.

Offer liquids to lubricate an irritated, cough-prone throat. For babies, nurse or bottle-feed more frequently. For children, give water or diluted juice (semi-frozen if you want, for its pain-soothing chill). "But there's no need to push fluids -- normal intake is fine," says Dr. Scott.

Go easy on cold preparations. Never give babies under 6 months decongestants or cough suppressants, says Dr. Scott. Some decongestants can act as stimulants and keep an older child (and you) awake if taken within four hours of bedtime. Some moms find that over-the-counter cough suppressants help their kids, although studies haven't shown them to be effective. If coughing interferes with your child's sleep for four or five nights, talk to your doctor, who may prescribe a stronger prescription cough suppressant.

See the doctor if your baby is under 3 months and has a fever over 100.5 degrees. And call if a child of any age has symptoms -- cough, congestion, mild sore throat -- that linger for longer than a week.

 

RSV: a risk for infants

Respiratory syncytial virus (RSV) is either a minor nuisance or an emergency. Most kids get it by age 1, but parents usually think it's just a cold. But around 2 percent of the time, the virus causes bronchiolitis, an inflammation of the small tubes of the lungs. Even this condition is not usually life-threatening, but it can be in some babies under 6 months, and in preemies up to 1 year.

Maribelle Lewis, a medical technologist in Palisades Park, New Jersey, suspected RSV when her 3-month-old daughter, Aiyannah, developed a persistent wheezy cough but no fever. "Her extreme lethargy tipped me off," says Lewis.

Aiyannah's pediatrician gave her an inhaler with medication to open her airways. But over the next two days, Aiyannah stopped nursing and became even more listless. When Lewis took her baby back, the pediatrician sent her to the hospital, where Aiyannah received intravenous fluids and intensive respiratory therapy (inhaled steroids). Today Aiyannah is a healthy, happy 3-year-old.

Some babies with severe RSV do spike a high fever, but others never get hot at all. Always call your pediatrician if your child's wheezing or coughing makes it difficult to breathe, or if there's a loss of appetite and unusual lethargy.

Flu fears

Anxiety over avian flu may be dominating the news, but even the old-fashioned kind can prove severe, with symptoms that often begin like a cold but become more debilitating and long-lasting.

It often hits more abruptly, with a sudden high fever, dry cough, and a headache. There can also be muscle aches, sore throat, and a runny nose. Kids -- but rarely adults -- sometimes also have stomach problems, like diarrhea or belly pain.

For most babies (6 months and up) and children, treat flu-related cough and congestion much like those of a cold (with acetaminophen or ibuprofen, but never aspirin). Just expect more lethargy and feverishness. One exception: If you suspect flu in an infant under 2 months, go to the doctor right away; from 3 to 6 months, call.

And for a child of any age, watch out for that sore throat. If it's severe, there's a fever over 101, and it lasts more than a day, see the doctor to rule out strep. Also bring your kid in if his ear hurts (flu can cause ear infections), if a fever doesn't go away in three or four days, or if a cough persists more than a week. But it's fine to call earlier.

Sinusitis and pneumonia

Sinusitis
Around 10 percent of the time, a child's cold or flu will progress to sinus inflammation, or sinusitis, which may include a wet, or phlegmy, cough, bad breath, and thick yellow or green mucus. Sinusitis may also bring headache and fever.

The underlying cause is a bacterial infection, so it always warrants a trip to the doctor, who will likely prescribe antibiotics to clear it. Once you're back home, you can help your child breathe better by letting her inhale steam over a hot (but no longer boiling) pot or cup of water.

Pneumonia
"We were a bit too sanguine," admits Marina Budhos, a mom in Maplewood, New Jersey. Last February, her son Sasha, 4, had been coughing for nearly two weeks, though he never had a fever. Then, in the middle of one night, he woke up crying inconsolably. His breathing was labored, and he looked exhausted. "We brought him in the next morning, and the nurse took one look at him and said, 'He's a mess.'"

Sasha had pneumonia, which occurs when a respiratory virus settles into the chest and causes an inflammation of the lung's air sacs. Sometimes the cause is bacterial, typically as a secondary infection after a cold or flu.

Unfortunately, figuring out whether a child's congestion is in the lungs is maddeningly difficult, even for doctors. "That's why we spend so much time with our stethoscopes on your child's chest," says Joshua Needleman, M.D., a pediatric pulmonologist at Children's Hospital at Montefiore, in New York City. Three red flags:

Coughing that lasts two weeks or more

Coughing plus fast breathing and a high, persistent fever

Coughing that returns a few days after a cold appears to go away

Pneumonia can come on quickly, with fever, shaking, and chest pain, or slowly, with fatigue, weakness, and headache. See your pediatrician, who'll examine your child and most likely have her chest x-rayed. If he sends you home, treat symptoms with rest, fluids, and children's pain relievers (but not cough suppressants, which may interfere with your child's ability to clear congestion out of the lungs). But don't be surprised if the doctor hospitalizes your child to make sure she's getting enough oxygen and to bring the infection under control.

Croup

Croup, an infection of the larynx (the voice box) is a rite of early childhood for millions of families. When Jennifer Lopez's son Noah, 3, woke up barking one night, she turned on the hot shower and sat with him upright on her lap in the steamy bathroom. "He was coughing so deep in his chest, we could just feel his pain," says the Gainesville, Florida, mom. When Noah's breathing became more labored -- his nostrils flaring and his belly and chest heaving -- his parents called the pediatrician, who sent them to the emergency room. There, Noah got an injection of steroids -- a standard treatment that's safe in kids as young as 3 months -- and was given an inhaler with medication to help open his airways. He went home three hours later.

"The family did everything right," says pediatrician Ari Brown, M.D., author of Baby 411. They elevated their child's head and headed for a steamy bathroom. (The opposite -- going out into the cool night air -- can also ease croup for many children.) Even more important, the Lopezes sought immediate medical care when they saw signs that Noah was struggling for breath.

Another sign of extreme airway narrowing is when croup's classic bark turns into a high-pitched squeal, called "stridor." If a steamy bathroom or a whiff of chilly air doesn't make the squeal disappear in 20 minutes, head to the emergency room, says Dr. Brown.

 

Whooping cough

Sandy Knight thought she knew what to expect when her 3-month-old son Luke got his third cold: "It always started the same, with a runny nose. Then toward the end, he'd get a nighttime cough."

But this cough sounded different. Instead of a little "cough-cough," Luke would hack on and on and then pause, as if gagging. "My husband and I would sit there on edge, just waiting for Luke to take a breath." Somewhat sheepishly, Knight, of Austin, Texas, took Luke to his pediatrician the next morning. "I'm probably being a silly mom," she began. Far from it, given what Knight described -- prolonged coughing followed by a gag or gasp. The doctor swabbed Luke's nose and throat for analysis. The diagnosis: pertussis, a.k.a. whooping cough, a serious bacterial infection that can lead to pneumonia, seizures, even death. Luke and both of his parents got a five-day course of antibiotics, and everyone was fine.

This highly contagious disease has been making a disturbing comeback across North America. It's the only vaccine-preventable disease that's on the increase, with more than 18,000 reported cases in 2004, up from around 10,000 in 2003. Babies are especially vulnerable until they get the third of four diphtheria-tetanus-pertussis (DtP) vaccinations, usually at 6 months. Those under 3 months are at special risk of pertussis-related apnea, in which they stop breathing altogether and need emergency help.

Pertussis starts like a common cold, with a runny nose, sneezing, and cough, with or without fever. After a week or two, the cough tends to worsen, with severe and prolonged coughing jags punctuated by gags and gasps and, occasionally, vomiting. In spite of its name, babies under 1 rarely "whoop." Nor do adults (kids do). Any suspected case of pertussis warrants a trip to the doctor, as antibiotics may be needed.

The best prevention: Stay on schedule with baby shots and remain vigilant for signs of pertussis until full protection kicks in around 6 months. Though your baby's first DtP shot may produce a spike in temperature, studies have shown it does not cause lasting harm -- and certainly nothing to compare with the disease's dangerous symptoms.

By the time your child becomes a teenager, though, his immunity will start to wane. That's why the Centers for Disease Control and Prevention now recommends that all kids at age 11 or 12 get the new Food and Drug Administration- approved Tdap vaccine (Boostrix), which adds pertussis to the tetanus-diphtheria booster -- and that adults get it every ten years (sooner if you're around an infant). This should help curb the spread of whooping cough to young children.

Coughs and congestion may always be a part of early childhood. They'll become less frequent as our kids strengthen their immunity through regular vaccinations and, inevitably, a touch of actual sickness. In the meantime, your watchful vigilance protects them from serious dangers, and your TLC eases these rites of passage.

When to call 911
Pneumonia, croup, whooping cough (pertussis), RSV, and asthma can each make a baby or child struggle to breathe. This is an emergency. Call 911 if your child:

pauses more than 10 seconds between breaths

breathes very rapidly for more than a minute

turns gray or blue

Or if:

his nostrils are flaring

the muscles between or below the ribs (or the chin) are moving inward, a phenomenon called retraction

PARENTING contributing editor Jessica Snyder Sachs is the author of Good Germs, Bad Germs: Health and Survival in a Bacterial World (Hill&Wang/FSG)