TOXIC SHOCK SYNDROME

Review article

TOXIC SHOCK SYNDROME

M. S. BERGDOLL

1 Food Research Institute, University of Wisconsin, 1925 Willow Drive, Madison, WI 53706, United States.

ABSTRACT. Toxic shock syndrome is a staphylococcal disease caused by toxins produced by the staphylococci, toxic shock syndrome toxin-1 and enterotoxin B. The disease results from staphylococci growing in the vagina with the use of tampons during menstruation, primarily in young women. However, any staphylococcal infection can result in toxic shock syndrome if the staphylococci produce the appropriate toxins and the individual has no antibodies to the toxins. The symptoms can be quite severe, with high fever, low blood pressure, diffuse macular erythroderma, orthostatic dizziness, vomiting and or diarrhea at the onset, severe myalgia, peeling of the skin of the palms of the hands and the soles of the feet after seven to ten days, and death in some cases. The disease is not contagious as it is necessary for the toxin producing organisms to infect a cut or incision or be inserted into the vagina with a tampon. A high percentage of individuals have protective antibody titers to the toxins, with the percentage of individuals with titers increasing with age. Anyone colonized with a toxin-producing staphylococci will have a protective antibody titer. The source of the disease causing staphylococci is difficult to determine although it can be transferred from other family members or from a surgeon during operations. The disease is more or less accidental. The toxins are classed as superantigens because they react with many more T-cells than do conventional antigens. They stimulate the production of cytokines which may be directly involved in toxic shock syndrome.

KEY WORDS: toxic shock syndrome, toxic shock syndrome toxin, staphylococci, enterotoxins, antibodies.

INTRODUCTION

Toxic shock syndrome had undoubtedly been around long before it was recognized as a specific disease. This may have been because the disease was associated with staphylococcal infections originating in different sites of the human body. The signs and symptoms of TSS were reported in 1978 by Todd et al. (19) when they observed an illness in seven young people who had identical symptoms. The major findings noted were high temperature, vomiting, diarrhea, a rash, low blood pressure, and peeling of the skin from the palms of the hands and soles of the feet 7 to 10 days after onset of the illness, and multisystem involvement.

Not much attention was paid to the disease until 1980 when a dramatic increase in illnesses with TSS symptoms occurred in young women menstruating and using tampons (7,17). Even though Todd et al. (19) had associated TSS with staphylococcal infections of various types, all of the cases of TSS reported in 1980 were associated with the use of tampons during menstruation. It was only when the symptoms became well established that TSS cases related to other types of staphylococcal infections began to be recognized (6). It was found that any type of staphylococcal infection could result in TSS if the staphylococci causing the infection produced toxic shock syndrome toxin-1 (TSST-1) and the individual had no antibodies to this toxin. Now at least half of the TSS cases in the United States are a result of staphylococcal infections other than those related to the use of tampons.

SYMPTOMS OF THE DISEASE: One of the most striking aspects of TSS is the rapidity with which the symptoms appear and progress in a previously healthy individual of any age or sex (4). Most patients remember the exact time at which they experienced the first symptoms, usually chills, fever, headache, and myalgias. As with most toxin-mediated diseases the sequence of appearance and the progression of symptoms are predictable.

A second striking aspect of the clinical symptoms of TSS is the presence, early in the course, of a decrease in vasomotor tone as measured by a low systemic vascular resistance. This decrease in tone results in the pooling of blood in the peripheral vasculature with vascular congestion in organs and tissues, probable relaxation of the microcirculation, and poor venous return. This leaked fluid is high in protein as indicated by measuring the colloid oncotic pressure of the fluid. The clinical correlate of these hemodynamic changes is a profound depletion of intravascular volume with second spacing manifested in the patient as orthostatic syncope, hypotension, and nonpitting edema.

The organ congestion, interstitial edema compressing small vessels, and decrease in circulating blood volume result in the third striking symptoms of this disease, ischemia, and multisystem organ involvement and ultimately failure. It is as yet unclear as to whether this multisystem organ involvement is a function exclusively of ischemia or represents direct toxin or mediator-induced damage as well.

The usually sudden onset of the symptoms occurs as early as eight hours after surgical procedures in which the incision became contaminated with a toxin-producing staphylococci. However, the occurrence of symptoms takes much longer in the menstrual cases, usually on the second or third day after the beginning of menstruation. This is primarily because it takes this amount of time for sufficient growth of staphylococci to occur in the vagina to produce TSST-1. The initial symptoms are both gastrointestinal and systemic. The early symptoms may include vomiting and/or diarrhea, although TSST-1 does not produce an emetic reaction in monkeys as does the enterotoxins.

One of the major early symptoms of TSS is fever with a temperature of at least 38.9ºC, which is one of the four major criterion of the strict definition of TSS for diagnosing the illness as TSS (Table 1) (3). Fever along with vomiting, and diarrhea are similar to those of influenza and sometimes the illness is mistakenly diagnosed. The gastrointestinal symptoms are similar to those of staphylococcal food poisoning, however, the fever and severe myalgias are not associated with food poisoning. Although diarrhea is characteristic of food poisoning, the diarrhea accompanying TSS is a profuse secretory diarrhea and of several days duration. In TSS, the patient abruptly experiences chills and fever, headache, sore and tender mouth and throat, nausea, possibly vomiting, generalized myalgias, muscle tenderness and weakness, abdominal pain, malaise, and profuse diarrhea.

TABLE 1.
Toxic shock syndrome case definition.*

Fever: Temperature > 38.9ºC

Rash: Diffuse macular erythroderma

Desquamation: 1 to 2 weeks after onset of illness, particularly of palms, soles, fingers, and toes.

Hypotension: Systolic blood pressure < 90 mm Hg for adults, or children, < 5th percentile for age <16 years of age:orthostatic syncope or orthostatic dizziness

Involvement of three or more of the following organ systems:

A. Gastrointestinal: vomiting or diarrhea at onset of illness

B. Muscular: severe myalgia or creatinine phosphokinase level greater than twice the upper limit of normal

C. Mucous membranes:vaginal, oropharyngeal, orconjunctival hyperemia

D. Renal: BUN or serum creatinine greater than twice the upper limit of normal: or > 5 white blood cells per high power field in the absence of a urinary tract infection

E. Hepatic: total bilirubin, SGOT, or SGPT greater than trace the upper limit of normal

F. Hematologic: platelets < 100,000/mm

G. Central nervous system: disorientation or alterations consciousness without focal neurologic signs when fever and hypotension are absent

Negative results on the following tests, if obtained:

A.Blood, throat, or cerebrospinal fluid cultures. Blood cultures may be positive for S. aureus.

B. Serologic tests for Rocky Mountain spotted fever, leptospirosis, or measles.

* From Centers for Disease Control (3).

Over the course of the next 24 to 48 h, generalized edema of face, hands and feet, arthralgias, particularly of the wrists, knees, ankles, fingers, and toes, the erythroderma, conjunctival injection, cough, dizziness and syncope, incontinence, and oliguria frequently develop in addition to the initial symptoms. If the natural history of severe disease is unimpeded, within 48 to 72 h of the first symptoms, a diffuse encephalopathy is observed with confusion, agitation, disorientation, irritability and combativeness, lethargy, hallucinations, and in some cases unresponsiveness.

Observation of a moderately to severely ill patient reveals a confused, disorientated, often agitated individual or one often lying motionless in bed due to the extreme muscle tenderness. Localized or generalized erythroderma with intensely injected conjunctivae and often mottling of the peripheral extremities with chanotic nailbeds are superimposed on edematous facies, fingers, toes, wrists, and ankles. Dehydration is not always noted due to the interstitial edema and anscara.

Tachycardia, markedly elevated temperatures, and hypotension which is initially orthostatic are present. On closer examination, the erythroderma, if not generalized, may be most intense over the perineum, edematous labia, and inner thighs in a menstruating patient, or adjacent to the focus of infection in nonmenstruating patients. There may be a petechial or maculopapular component to the erythroderma.

In addition to the injected conjunctive, and frequent subscleral hemorrhage, all of the oral mucous membranes including the tongue will be intensely erythematous. Punctate ulcerations and red cracked lips but no exudate will be present. About 25% of patients will have a strawberry tongue. In menstruating patients, the cervicovaginal mucous membranes will also be intensely red. A purulent menstrual discharge is present in half of the patients and on colposcopy small vaginal ulcerations may be present.

Examination of the abdomen is most impressive for the generalized muscle tenderness with no peritoneal signs. Examination of the locomotor system may reveal nuchal rigidity, severe generalized or localized muscle pain and tenderness, and periarticular edema of the wrists, ankles, fingers, and toes as well as a nonpitting, brawny edema of the palms, soles, and extremities. The central nervous system examination is impressive for the confusion, agitation, or lethargy without focal findings.

In postoperative cases of TSS, the wound invariably appears normal and uninflamed despite the presence of toxin producing bacteria. Traditional findings of swelling, erythema, tenderness, and pus are rarely present. In nonmenstrual, and nonpostoperative patients, a rigorous search should be made for the source of the infection with attendant toxin production.

EPIDEMIOLOGY: Toxic shock syndrome is not a contagious disease in that it is not normal for one person to acquire it from an infected person. The conditions for contracting the disease are more or less accidental. In the case of menstrual TSS it is necessary to insert the toxin-producing staphylococci with the tampon and for the woman to have no or a very low antibody titer to TSST-1. Very little information is available about the source of the disease causing organism as the staphylococci are ubiquitous and are carried by many individuals. It is possible for one person to acquire them from another person, for example, someone in the family. This was demonstrated by a nurse who developed TSS from a staphylococcal strain that was present in her mother's throat, but did not cause her mother any problems. She had a high antibody titer to TSST-1. In nonmenstrual TSS, it is difficult to trace the source of the disease-causing organism. However, if the disease results following an operation it is possible to trace the source of the organism, because in all probability one of the operating personnel is a carrier. This has been possible in two or three cases where more than one person developed TSS after having operations by the same surgeon. TSS following all types of surgical operations have been reported, without information of the source of the organism except in some cases to suggest that the patient carried the toxin-producing organism in the nasal passages before the operation. This may be a possible source except that anyone who is colonized with a toxin-producing organism will have antibodies to the toxin unless the organism was newly acquired.

In the case of general infections leading to TSS, it is not possible to trace the source of the organism causing the infections. It can be concluded that the disease is accidental, and happens rather infrequently.

ASSOCIATION WITH STAPHYLOCOCCI: The association of TSS with staphylococci was first reported by Todd et al. (19) when they noted similar illnesses in seven young people. Three of the children were teenage girls who were menstruating using tampons at the time of their illness. Although S. aureus was isolated from a vaginal culture from the one menstruating patient from whom a vaginal culture was taken, the significance of this was not recognized. S. aureus was isolated from the site of infection in two other patients, a buttock abscess and empyema, and from the mucous membranes of three other patients. All of the isolates had similar characteristics, including five were lysed by group I phages. They assumed that the cause of the illnesses was due to staphylococci.

It was not until late 1979 and early 1980 that particular note was made of young women developing symptoms similar to those described by Todd et al. (19) and that staphylococci could be isolated from the vaginas of each of the patients (7,17). Final proof was the association of a specific toxin (TSST-1) with the staphylococci involved (2,16).

The classification of staphylococci into species is not straight forward as not all strains of a particular species have all of the properties generally used to identify it. For example, the fermentation of mannitol anaerobically is an identifying characteristic of S. aureus, but an occasional S. aureus strain does not ferment mannitol. More than half (60%) of TSS strains belong to phage group I and many of them are weakly hemolytic.

The majority of TSS strains produced TSST-1, but several of the strains produced enterotoxin B (SEB) (Table 2) (6), more isolated from nonmenstrual than menstrual cases. The symptoms produced in rhesus monkeys given relative large doses of SEB produced symptoms very similar to those observed in TSS (1). This was noted in the early diagnosis of TSS and Bergdoll et al. (2) wanted to include in their original paper this observation, but Lancet required a shortening of the paper for publication and this part was removed. It is of interest that after the advent of TSS that SEB was produced by the strains that were responsible for pneumonia in elderly individuals following the flu (15 ). The illnesses were classified as TSS. This is of interest because shortly after the identification of SEB in the 1950's there were many cases of staphylococcal pneumonia following the flu in the New England area. When these strains were examined for enterotoxin production, many of them produced SEB. It is likely that the illness was TSS, but this disease was not known then.

TABLE 2.
Production of toxins by S. aureus from 380 TSS patients.

TSST-1 ANTIBODIES: Essentially all of the initial cases of TSS were in young women and in Todd's (19) case young people. One might have concluded that it was a young person's disease because seldom was an older person involved. This was clarified only when it was discovered that it was not uncommon for individuals to have antibodies to TSST-1. Crass in Bergdoll's laboratory was the first to check the sera from TSS patients and from normal individuals. It was discovered that essentially none of the TSS patients had antibodies to the toxin (Table 3), whereas a high percentage of healthy individuals had protective antibody titers (>100) (6). It was discovered that the percentage of individuals with protective antibody titers increased with age, which explained why most TSS cases were among teen-agers, with a decreasing number of those in their twenties (Table 4) (20).

TABLE 3.
Antibody titers to TSST-1 in TSS patients.

TABLE 4.
Antibody titers of > 1:100 to TSST-1 in humans of different ages.

It is a good question as to how individuals obtained titers to the toxin. Two studies were made on the relationship of the carriage of TSST-producing staphylococci and the presence of a protective antibody titer (8,14). All individuals colonized with TSST-producing staphylococci had protective antibody titers except one (61/62), but this individual developed a protective titer. This may not be the entire explanation for the titers, as it would seem unlikely that almost everyone sometime in his life would be colonized with TSST-1-producing staphylococci. This is one reason why those who develop TSS are not likely carriers of TSST-1-producing staphylococci unless the colonization was relatively recent.

It is of interest that TSS has not been reported from the developing countries such as Brazil. Although many cases in the developed countries such as the United States, occur in young women using tampons during menstruation, this is not a common practice in the developing countries. For example, only 9 of 215 women involved in a special project used tampons (10). The other possibility was that a higher percentage of individuals in the developing countries have protective antibody titers to TSST-1. The above study showed that only two individuals of the 49 whose sera were examined for the presence of antibodies to TSST-1 had no or low antibody titers (Table 5).

TABLE 5.
Antibody titers of > 1:100 to TSST-1 in Brazilian women of different ages.

Normally if the disease is caused by a toxin, patients will develop antibodies to the toxin during convalescence. This was not the case with at least 60% of TSS patients, particularly those with the menstrual related disease (Table 2) (6). This is not understood, but it may be because the toxin is immunosuppressive.

TOXIC SHOCK SYNDROME TOXIN 1 (TSST-1): TSST-1 was originally identified as an enterotoxin and given the name enterotoxin F (SEF) (2). This was because originally it produced an emetic reaction in monkeys and was thought to have two half-cysteine residues, an identifying characteristic of an enterotoxin. After the toxin was purified it no longer produced an emetic reaction in monkeys and did not have any half-cysteine residues, thus the name was changed to TSST-1, although sometimes the designation SEF is occasionally encountered.

Although the original evidence was convincing that TSST-1 was the major toxin responsible for TSS, our original paper was rejected because the reviewers did not believe this was the toxin. The rapidity with which the toxin was purified and identified, seven months from the time we started working with the TSS strains, may have been one reason. This was possible because my group had long experience with the staphylococcal enterotoxins which are similar toxins. We were constantly purifying the enterotoxins and to insert another toxin into the purification line was no problem. Another possibility is that our work was related to foods, not to the medical field. Staphylococcal food poisoning and the enterotoxins were never taken seriously by the medical field, primarily because staphylococcal food poisoning was a relatively mild illness. Therefore, the enterotoxins could not be very potent toxins.

The Bergdoll group was the leading group to which the medical field came for analysis of the staphylococcal strains and serum from TSS patients. In the course of examining the staphylococcal strains we discovered that some strains produced only SEB, not TSST-1 (Table 2) (6). This was not a surprise to me, because we knew the real potency of the enterotoxins. Others were not easily convinced that the enterotoxins were involved, but eventually accepted them as possible causes of TSS. It is of interest that no strain was found to produce both TSST-1 and SEB, which was additional proof that SEB was involved. Although enterotoxin A (SEA) was commonly produced by TSST-1 strains, we never found a strain involved in TSS that produced SEA alone (Table 2). It is possible that it contributed to the signs and symptoms of TSS, however, its production apparently was insufficient to produce the symptoms alone. Enterotoxin C (SEC) was produced in conjunction with TSST-1 by some strains, but seldom was it produced without TSST-1. This may have been because many people had a relatively high antibody titer to SEC and people were protected against these strains. It appeared that the combination of TSST-1 and SEC was potent because in six cases of respiratory TSS in which this combination was produced, all six patients died (5).

TSST-1 AS A SUPERANTIGEN: It is well known that the staphylococcal enterotoxins are among the most mitogenic of known compounds (9). Other products of the staphylococci are also mitogenic, with TSST-1 being similar to the enterotoxins in its lymphocyte mitogenicity (12). This activity was observed when the toxin stimulated rabbit splenocytes to proliferate, as measured by incorporation of [ H] thymidine into DNA. Lymphocytes isolated from both murine and rabbit spleens and human peripheral and cord blood proliferated nonspecifically in vitro. Proliferation in the mouse and human systems depended on the presence of macrophages in the lymphocyte populations. Proliferation was achieved with 0.1 ng TSST-1 for human mononuclear cells (Table 6). The activity resided solely in the T-cell populations.

TABLE 6.
Proliferation of lymphocytes by TSST-1 in mononuclear cells from human PBMs, murine, and rabbit splenocytes.

The fact that the enterotoxins and TSST-1 reacted with many more T-cells than did conventional mitogens, such as the plant lectins, phytohemagglutin (PHA) and concanavalin (Con A), resulted in their designation as superantigens (21). Further study revealed that unlike other antigens, the attachment to T-cells did not require processing of the protein molecules for them to be presented to the T-cells by major histocompatibility complex (MHC) class II molecules (11). Neither do they attach to the T-cell receptor (TCR) in the same manner as conventional antigens, which attach in the groove between the alpha and beta chains of the TCR. Instead the superantigens attach to variable (V) portions of the ß chain (Vß) at the side of the receptor, with each superantigen attaching to specific Vß elements of the TCR. Conventional antigen attachment to T cells is highly specific and very limited, whereas the superantigens attach essentially to all T cells that present the Vß elements specific for the superantigen in question. Further, the superantigens stimulate both CD4+ and CD8+ T cells, whereas conventional antigens stimulate only CD4+ T cells.

The binding to CD8+ cells is of particular importance because the functional activation of these cells inhibits immunoglobulin production. Apparently, the CD8+ cells are responsible for TSST-1-induced suppression of the response of immunoglobulin-secreting cells to polkweed mitogen (13). This may be one explanation why a high percentage of TSS patients do not develop antibodies to TSST-1 during convalescence (4). Also SEB can induce multiple T-suppressor cell populations that inhibit both primary and secondary plaque-forming cell responses (18).

CYTOKINE PRODUCTION STIMULATED BY TSST-1: The cause of TSS is not completely understood, primarily because no animal model has been found that elicits all of the signs and symptoms observed in humans. Although TSST-1 appears to be a very potent toxin, it is doubtful that it is directly responsible for the signs and symptoms observed in TSS. It is more likely that the cytokines it stimulates production and/or release of in animals and humans, such as interleukin 1 and 2 (IL-1,IL-2), tumor necrosis factor (TNF), interferon gamma (INF-gamma) and others, produce the signs and symptoms observed in TSS. These are very active compounds and produce many of the TSS signs and symptoms observed in humans.

CONCLUSION: The staphylococci are very common microorganisms and can be found almost everywhere. The genus is composed of more than 30 species, most of which are coagulase-negative and less likely to be involved in disease. Although the major species, S. aureus, is the most virulent of the species, it is a common inhabitant of the human body without causing any problems. Only when it finds a suitable environment such as a cut, wound, or incision in which to grow and produce toxic substances does it cause problems. Its adaptability to antibiotics has made it one of the most difficult organisms to control, particularly in a hospital environment.

REFERENCES

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16 SCHLIEVERT PM., SCHANDS KN., DAN BB., SCHMID GP., NISHIMURA RD. Identification and characterization of an exotoxin from Staphylococcus aureus associated with toxic shock syndrome.J. Infect. Dis., 1981, 143, 509-16.

17 SHANDS KN., SCHMID GP., DAN BB., BLUM B., GUIDOTTI RJ., HARGRETT NT., ANDERSON RL., JILL DL., BROOME CV., BAND JD., FRASER DW. Toxic-shock syndrome in menstruating women: Association with tampon use and Staphylococcus aureus and clinical features in 52 cases. N. Engl. J. Med., 1980, 303, 1436-42.

18 TAUB DD., LINN YS., ROGERS TJ. Characterization and genetic restriction of suppressor effector cells induced by staphylococcal enterotoxin B. J. Immunol., 1990, 144, 456-62.

19 TODD J., FISHAUT M., KAPRAL F., WELCH T. Toxic shock syndrome associated with phage group I staphylococci.Lancet, 1978, 2, 116-8.

20 VERGERONT JM., STOLZ SJ., CRASS BA., NELSON DB., DAVIS JP., BERGDOLL MS. Prevalence of serum antibody to staphylococcal enterotoxin F among Wisconsin residents: implications for toxic-shock syndrome. J. Infect. Dis., 1983, 148, 692-8.

21 WHITE H., HERMAN A., PULLEN AM., KUBO R., KAPPLER JW., MARRACK P. The Vß- specific superantigen staphylococcal enterotoxin B; Stimulation of mature T cells and clonal deletion in neonatal mice. Cell, 1989, 56, 27-35.

Received 23 April 1996.

Accepted 24 May 1996.

CORRESPONDENCE TO:

M. S. BERGDOLL - Food Research Institute, University of Wisconsin, 1925 Willow Drive, Madison, WI 53706, United States.

Publication Dates

• Publication in this collection
  08 Jan 1999
• Date of issue
  1997

History

• Accepted
  24 May 1996
• Received
  23 Apr 1996