The Coming Plague (72 page)
Authors: Laurie Garrett
Schlievert isolated toxin from TSS patients and injected it into rabbits. Within a matter of hours the rabbits developed classic Toxic Shock Syndrome, complete with high fevers, markedly low blood pressure, and mucosal secretion of S.
aureus
. He was then able to re-isolate the toxin from the rabbits' infected mucosa. Two weeks later Schlievert gave the by then recovered rabbits a subcutaneous second injection of the toxin. Half the animals developed scarlet fever-like rashes.
aureus
. He was then able to re-isolate the toxin from the rabbits' infected mucosa. Two weeks later Schlievert gave the by then recovered rabbits a subcutaneous second injection of the toxin. Half the animals developed scarlet fever-like rashes.
When Schlievert measured various components of the immune systems of the rabbits, he found that T-cell levels jumped following the first toxin injections. Four days after the injection, with the animals still ailing, their antibody production levels (particularly of IgM) were way down, while their
total white blood cell counts were two and a half times above normal. It seemed that suppressor T cells, which were in astonishing abundance, were stifling the rabbits' antibody responses.
total white blood cell counts were two and a half times above normal. It seemed that suppressor T cells, which were in astonishing abundance, were stifling the rabbits' antibody responses.
By day ten, the toxin had killed off most of the rabbits' T cells, and Schlievert saw a surge in the antibody-producing B-cell population. In particular, IgG antibodies filled the bloodstream, where they sought out their toxin targets. By day twelve the rabbits' blood was full of tightly bound complexes of these antibodies coupled with the toxin moleculesâsome of which were still attached to the T cells they had invaded.
The immune system then became confused, Schlievert said. It saw the T cells, as well as the toxin, as its enemy and began to autodestruct. The result was autoimmune disease.
On the basis of what he saw in rabbits and mice, Schlievert put forward the following hypothesis of the human disease: a new form of S.
aureus
was in the United States (and, based on case reports, by 1981 in Sweden and Canada); the strain possessed a set of genes that coded for pyrogenic exotoxin A; first-time infection resulted in a mild form of flu-like disease that did not meet the CDC definition of either TSS or Kawasaki syndrome; that first exposure did, however, set in motion a chain of events in the immune system that sensitized the patient; following a second or third round of exposure to the
Staphylococcus
toxin the individual's immune system went into a self-destruct mode, and the unchallenged toxin produced Toxic Shock Syndrome.
aureus
was in the United States (and, based on case reports, by 1981 in Sweden and Canada); the strain possessed a set of genes that coded for pyrogenic exotoxin A; first-time infection resulted in a mild form of flu-like disease that did not meet the CDC definition of either TSS or Kawasaki syndrome; that first exposure did, however, set in motion a chain of events in the immune system that sensitized the patient; following a second or third round of exposure to the
Staphylococcus
toxin the individual's immune system went into a self-destruct mode, and the unchallenged toxin produced Toxic Shock Syndrome.
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 surgeâaided, no doubt, by the provision of an ideal tampon growth surface. And the improperly sensitized immune system would autodestruct.
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 surgeâaided, 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 rapidlyâ100 to 2,500 times faster than normal staph bacteria.
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 rapidlyâ100 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.”
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 spleenâthe organ that produces B cellsâwas 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.
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 âToxic Shock Syndrome Toxin-1.
32
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 âToxic 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.
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.
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.
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 1983â84 revealed that tampon absorbency was strongly correlated with the risk of contracting TSS, though the chemical content of the tampons was not.
37
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
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
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
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
41
Clinically, evidence continued to accumulate in support of Schlievert's original hypothesis of toxin-driven immune system misfunction. For example, during the 1985â86 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
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
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.
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
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.
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