The Coming Plague

by Laurie Garrett

  Schlievert’s model named the menstrual cycle as the ideal vehicle for such a bacterial mechanism. A woman would undergo a sensitizing round of Staphylococcus exposure during one menstrual period and would recover, but the bacteria would remain in her vagina. With the following menstrual flow the bacterial population would surge—aided, no doubt, by the provision of an ideal tampon growth surface. And the improperly sensitized immune system would autodestruct.

  In Schlievert’s hands the model was so clearly demonstrable that he could accurately predict the precise range of symptoms he would produce in a rabbit, based on the quantity of toxin he used and on what dose schedule he injected the animals.

  “Tampons are just a passive co-factor in this disease,” Schlievert said. “The disease can be produced by your garden variety staph. But five years ago [1975] we got a new staph variety in the U.S.”

  In addition to being resistant to the penicillin-class antibiotics, the new staph strain was very bad at doing some things classic Staphylococcus did, such as kill red blood cells, produce skin boils, and break up fatty acids in the human body. But it seemed that the new strain grew particularly rapidly—100 to 2,500 times faster than normal staph bacteria.

  “There was nothing the [tampon] industry could do to put out a safe product once this strain surfaced,” Schlievert said. “The disease won’t go away without tampons. It just needs a nutrient-rich environment. If you stopped all tampon use in the country today, the organism would adapt. It’s just going to pop up somewhere else.”

  Lending support to his theory of immune system disruption, Schlievert and Osterholm discovered autoimmune diseases in some TSS survivors. Osterholm had a patient in Minnesota who suffered acute Toxic Shock for five weeks; a few weeks after her recovery the patient developed lupus, a classic autoimmune disease. At UCLA another TSS survivor developed such severe lupus that her spleen—the organ that produces B cells—was removed. A survey of twelve other Los Angeles TSS survivors revealed that 75 percent of them were making antibodies against their own cells.

  Based on dose studies in rabbits, Schlievert calculated that a single milligram of the pyrogenic exotoxin was enough to kill a 220-pound person. From the blood of one woman who died of TSS, Schlievert extracted over ten milligrams of the toxin.

  By the close of 1980 Schlievert was deeply frustrated. He had been sending his data to the CDC, he’d cooperated with public health officials in four states, and he had shared data with Todd’s group in Denver, yet the federal scientists continued to discount his findings. Todd accused Schlievert of grandstanding, and told inquiring reporters that “Patrick needs to calm down and publish his findings. Otherwise nobody will take him seriously.”

  Schlievert was trying to publish his studies, but Science, the New England Journal of Medicine, and the Journal of Infectious Diseases had by November 1980 all either rejected his paper or told Schlievert that they weren’t publishing any TSS studies.

  “Something really needs to be done about this situation,” Schlievert said. “I find it very disgusting. I have to defend what I’m doing. It shouldn’t be this way. They [CDC] won’t tell me what they’re doing, but they demand that I tell them every single thing I do.”

  In January 1981, Todd called for a national scientific forum to settle the dispute. As time went by, the Denver physician was increasingly persuaded by Schlievert’s data. He became a convert.

  The Institute of Medicine (a division of the prestigious National Academy of Sciences in Washington, D.C.) subsequently convened a special meeting on TSS, and delineated areas of consensus, dispute, and needed additional research.31 Schlievert and the CDC’s Dan finally agreed to a laboratory research protocol that could settle the dispute. Schlievert sent a “cookbook,” as he called it, describing the methods he used to isolate the toxin and prove its role in TSS. The CDC, in turn, sent Schlievert a set of coded blood samples, and various Staphylococcus strains, not telling him in advance which came from TSS patients. By March it had all checked out, and the CDC team co-published with Schlievert the discovery of TSST-1 —Toxic Shock Syndrome Toxin-1.32

  Though the CDC team and Schlievert were now “on the same side of the fence,” as the UCLA scientist put it, there was bitterness. Schlievert, Todd, and Osterholm all felt that they had suffered for publicly disagreeing with the agency, and resented the CDC’s tendency to quash contrary ideas.

  Toxic Shock Syndrome gradually fell off the front pages of the nation’s newspapers and television news, but the problem did not disappear. The CDC continued to report Toxic Shock Syndrome cases in 1982,33 1983,34 and 1984.35 The numbers of cases declined, and the epidemiological pattern steadily shifted from the 1980 paradigm that was overwhelmingly an ailment of menstruating women to a more generalized disease that struck a broad spectrum of society, male and female alike.

  By April 1984 a total of 2,509 Toxic Shock Syndrome cases had been reported to the CDC; 110 (or 5 percent) were fatal. Of the 2,295 cases in women, 89 percent were menstruating when they fell ill. And 93 percent of the total cases (male and female) that occurred in 1980 involved menstruating women; that dropped to 71 percent in 1983.

  Over the years it would become apparent that the highest incidence of TSS was among people of Scandinavian and German extraction, presumably because of a unique genetic susceptibility to staphylococcal infection. That explained the geographic clustering inside the United States in areas such as Wisconsin and Minnesota, to which generations earlier Scandinavians and Germans had immigrated.36 Outside the United States, the highest incidences of TSS would be seen in Sweden, Denmark, and Germany. TSS cases had by 1984, however, also occurred in every state in the United States, as well as Canada, most Western European countries, Japan, Australia, New Zealand, Israel, and South Africa.

  Close CDC examination of the tampon use patterns of 285 women who contracted the disease during 1983–84 revealed that tampon absorbency was strongly correlated with the risk of contracting TSS, though the chemical content of the tampons was not.37

  And when the VLI corporation of Irvine, California, introduced a contraceptive vaginal sponge to the U.S. market in July 1983 (called Today), the FDA almost immediately received reports of TSS cases associated with the product. With Today, most cases occurred in nonmenstrual days, and the risk of a woman contracting the disease while wearing the sponge was forty times greater than the odds for a nonmenstruating woman who didn’t use the product. The sponge was designed to be worn for twenty-four hours, during which it presumably served as a Staphylococcus growth site much as did superabsorbent tampons used for shorter durations of time.38

  The Institute of Medicine report had recommended that women avoid using superabsorbent tampons. And Wolfe’s group petitioned the FDA in 1982 to have tampon manufacturers legally required to state product absorbency according to a standardized scale. Wolfe’s group wanted the recently developed Syngyna absorbency assay to be used as the gold standard.39

  The following year the FDA did work out an agreement with industry. On tampon boxes appeared two TSS messages. The first stated: “ATTENTION: Tampons are associated with Toxic Shock Syndrome (TSS). TSS is a rare but serious disease that may cause death.” In addition, the terms “Junior absorbency,” “Regular absorbency,” “Super absorbency,” and “Super Plus absorbency” were standardized, and charts listing their relationship to blood absorption were put on all boxes.40

  Toxic Shock Syndrome continued to be a problem in the industrialized world well into the 1990s. Infection was, by 1990, clearly associated with surgery, tampon use, and skin injuries.41

  Clinically, evidence continued to accumulate in support of Schlievert’s original hypothesis of toxin-driven immune system misfunction. For example, during the 1985–86 flu season in Minnesota nine people developed TSS
as a complication of flu; five died. The victims ranged from five to fifty-six years of age, and none of the cases were associated with tampons or menstruation.

  Physicians were able to culture S. aureus from the throats and nasal passages of the TSS sufferers, and the bacterial strain was a prolific manufacturer of both TSST-1 and another staph poison, enterotoxin B. The scientists hypothesized that influenza infection caused throat and nasal irritation. The patients probably became infected with staph by wiping their contaminated hands over their noses or holding their hands over their mouths while coughing. Those who developed acute TSS probably had been exposed to the organism before, which sensitized their immune systems. Or the influenza had already laid havoc to the immune system, and the staph toxins simply took advantage of an already dangerous situation.42 Physicians in Virginia reported a similar case, involving an athletic, healthy eighteen-year-old boy who died of TSS following a bout of flu. They warned that “a newly recognized syndrome of postinfluenza toxic shock syndrome may be emerging.”43

  Jim Todd, having come around to a complete acceptance of Schlievert’s TSS hypothesis, examined the use of corticosteroids in the treatment of Toxic Shock. If Schlievert was correct, giving steroids to TSS victims would be a good idea because the chemicals dampened the immune response. Todd compared twenty-five TSS patients who received steroids during their illnesses with twenty who did not. The steroid recipients fared far better, recovering more quickly from TSS and suffering shorter periods of feverish hypertension.44

  Tomisaku Kawasaki, who had been working since 1967 on the syndrome that bore his name, was not at all convinced that adult Toxic Shock Syndrome was the same thing as the illness he originally observed in Japanese children. By the mid-1980s Kawasaki syndrome was diagnosed in thousands of children worldwide every year,45 primarily among infants. For most children the ailment was relatively harmless, but in a minority of cases the syndrome was extremely dangerous, as aneurysms developed in their coronary arteries, causing death due to a heart attack.

  Individuals who became infected with Staphylococcus through using contaminated needles to inject recreational drugs ran a high risk of endocarditis heart attacks. And while aneurysms of the coronary artery were not seen among such adult patients, brain aneurysms (cerebral or systemic) were observed.46

  Schlievert and his supporters were nearly certain that Kawasaki syndrome was nothing more than the response of immune-naïve infants to the same, or similar, bacterial toxins that caused TSS in adults. He persuaded Kawasaki to send coded samples of blood from children who suffered Kawasaki syndrome or other ailments, and Schlievert used his assays for TSST-1 to try to determine which samples came from children with the mysterious disease. Schlievert’s TSST-1 antibody assays correctly identified half the Kawasaki syndrome cases and did not mistakenly identify any of the controls.

  In order to prove Koch’s Postulate, however, Schlievert needed to show that injections of TSST-1 could produce Kawasaki syndrome in animals—a feat that, by 1994, he had yet to accomplish.

  In collaboration with researchers from the National Jewish Center for Immunology and Respiratory Medicine in Denver and Boston’s New England Medical Center, Schlievert demonstrated in 1993 that Kawasaki syndrome in at least some children was related to the TSST-1 toxin. Sixteen children with Kawasaki were compared with fifteen youngsters who were suffering fevers and rashes due to other causes. Bacteria that secreted TSST-1 were found in the blood or mucus swabs of thirteen of sixteen Kawasaki patients, compared with only one of the controls. And the toxin produced proliferation of a specific population of T cells in the kids with Kawasaki (VB2 + T cells); there was no such cellular population expansion seen in the controls. 47

  The 1993 Kawasaki study had provided further evidence for another Schlievert observation: namely, that the strain of S. aureus that produced TSST-1 was genetically unique, and had not played a significant role in human disease prior to 1975.

  A survey of dozens of samples of TSS-producing bacteria from diverse geographic locales showed that they were all descendants of a single clone of Staphylococcus.48 In addition to producing the killer toxin, the apparently new strain of staph was dependent on its hosts for supplies of the amino acid tryptophan. (Normal Staphylococcus make their own tryptophan.) In laboratory cell cultures the new strain actually looked different to the naked eye: normal staph colonies thrived on red blood cells and appeared golden in color, but the new strain seemed unable to digest beef or human blood cells and colonies were white or blanched.

  The new strain grew up to 10,000 times faster than normal staphylococcal colonies, churning out massive quantities of the TSST-1 poison, as well as enzymes that rendered it immune to penicillin, ampicillin, and other members of the penicillin-class of antibiotics.

  In laboratory tests, TSST-1 and five other toxins extracted from various staph strains proved to be the most potent T-cell stimulators ever found.49 In the short run, the immune chaos it produced could lead to huge expansions in the CD4 T-cell population (the same population that is destroyed by the AIDS virus). That, in turn, caused secretions of CD4-related chemicals that produced the symptoms of high fevers, shock, and rashes. If lab animals or people were continually reexposed to the toxin, as was the case for many menstruating women who suffered increasingly severe monthly bouts with the bacteria, this CD4 T-cell overstimulation could lead to a wasting syndrome, anorexia, and chronic overproduction of key immune system chemicals. 50

  This dramatic immunological effect resulted in TSST-1’s designation as a “superantigen”—an extraordinarily potent immune system stimulator capable of inducing a cascade of activities within the system.

  Using sophisticated molecular biology techniques developed in the late 1980s, various scientists were able to show that the unique genetic characteristics for the virulence of the toxic shock staph strain, as well as those responsible for its inability to consume red blood cells and produce septicemia, all clustered together as a continuous segment of bacterial DNA. Furthermore, that segment of DNA was mobile—it could move around along the bacterial chromosome.51 In most cases, it took up residence alongside either the gene for production of tryptophan or, less frequently, that responsible for making another key amino acid that was occasionally deficient in TSST-1 strains, tyrosine. 52

  The strain’s ability to withstand penicillin was due to another transposable DNA segment that caused production of an enzyme, beta-lactamase, which rendered penicillin harmless to the bacteria. This penicillin-resistant genetic segment was first observed in staphylococci shortly after the introduction of penicillin into clinical medicine in North America and Europe, and was known to move about in the microbial world as a plasmid.53

  The two transposons (TSST-1 and beta-lactamase) appeared to be linked in the new staph strain; TSST-1 was never present in a Staphylococcus bacterium without beta-lactamase, and their expression seemed to be simultaneous.

  So a tempting conclusion was revealed: perhaps the Toxic Shock Syndrome outbreak followed a unique genetic event in which a plasmid that carried both gene sets was absorbed into an S. aureus bacterium sometime in the 1970s under ecologic circumstances that were ideal for that organism’s growth and rapid multiplication.

  It was tempting to conclude that misuse of penicillin antibiotics was responsible for the event. Because the poison genes and those for antibiotic resistance appeared to be carried together on a plasmid, selection pressure imposed by penicillin use could have caused the mutation event. That was, of course, pure speculation. Proving such an event took place—much less where and when it happened—was impossible.

  However the new strain originally emerged, its debut elicited a strong human response. A multimillion-dollar industry was shaken, menstruating women were terrified, scientists feuded, and the credibility of two U.S. federal agencies—the FDA and the CDC—was challenged.

  As was the case with HIV and so many other mic
robes, the new poisonous microbe was victorious. Despite the frenetic (though ineffective) efforts of Homo sapiens, the microbe succeeded in carving out a biological niche in the human world and taking permanent hold.

  By 1994 Toxic Shock Syndrome was an enduring addition to the list of human pathogens, and though it no longer attracted lawsuits and front-page news, the novel S. aureus strain was causing nearly as many infections, ailments, and deaths in the 1990s as it had in 1983. Though Rely had been off the market for over a decade, and tampon boxes were covered with a variety of warnings, menstruating women continued to come down with TSS, particularly those who used superabsorbent products.

  One could only take comfort in the fact that the disease, if quickly diagnosed and treated, was curable. Though the TSST-1 bacterium was resistant to penicillin antibiotics, it was vulnerable to other classes of the drugs.

  At least, so far.

  13

  The Revenge of the Germs, or Just Keep Inventing New Drugs

  DRUG-RESISTANT BACTERIA, VIRUSES, AND PARASITES

  Consider the difference in size between some of the very tiniest and the very largest creatures on Earth. A small bacterium weights as little as 0.00000000001 gram. A blue whale weighs about 100,000,000 grams. Yet a bacterium can kill a whale … . Such is the adaptability and versatility of microorganisms as compared with humans and other so-called “higher” organisms, that they will doubtless continue to colonise and alter the face of the Earth long after we and the rest of our cohabitants have left the stage forever. Microbes, not macrobes, rule the world.