Toxic shock syndrome

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Mahshid Mir, M.D. [2], Syed Hassan A. Kazmi BSc, MD [3]

Toxic shock syndrome (TSS) is a rare, but potentially fatal disease caused by bacterial toxins. Different bacterial toxins may cause toxic shock syndrome, depending on the situation. The causative agents are the Gram-positive bacteria Staphylococcus aureus and Streptococcus pyogenes. Streptococcal TSS is sometimes referred to as toxic shock-like-syndrome (TSLS) . Some cases maybe caused by Clostridium sordellii, influenza virus and varicella zoster virus. The syndrome consists of sudden onset of fever, chills, vomiting, diarrhea, muscle aches, hypotension and a scarlantiform rash. Diagnosis of toxic Shock Syndrome (TSS) is mainly based on the clinical presentation. The initial management of toxic shock syndrome involves the removal of any foreign materials such as tampons, vaginal sponges, or nasal packing. Antimicrobial therapy is indicated in toxic shock syndrome. Supportive therapy for toxic shock syndrome includes intravenous fluids, control of blood pressure, and dialysis in cases of renal failure. Patients with multiple organ failure are admitted to the intensive care unit.

The term toxic shock syndrome was first used in 1978 by a Denver pediatrician, Dr. J.K. Todd, to describe the staphylococcal illness in three boys and four girls aged 8-17 years.^[1] Even though S. aureus was isolated from mucosal sites from the patients, bacteria could not be isolated from the blood, cerebrospinal fluid, or urine, raising suspicion that a toxin was involved. The authors of the study noted that reports of similar staphylococcal illnesses had appeared occasionally as far back as 1927. Most notably, the authors at the time failed to consider the possibility of a connection between toxic shock syndrome and tampon use, as three of the girls who were menstruating when the illness developed were using tampons.^[2]

Toxic shock syndrome may be classified based on the microbiological organisms involved in causing the disease. Commonly involved organisms are Staphylococcus aureus and Streptococcus pyogenes (GAS). Less commonly involved organisms leading to the development of toxic shock syndrome are Clostridium sordelli, Influenza and Varicella Zoster virus (the etiological agent of chickenpox).

The pathophysiology of toxic shock syndrome can be explained based on the etiological agent causing the disease. The general mechanism for all the etiological agents is the same, which involves non-specific activation of T lymphocytes by toxins acting as superantigens leading to release of cytokines. There are small differences in the mechanism of cytokine production which can be explained individually for the organisms involved.

Toxic shock syndrome is caused by a toxin produced by certain types of Staphylococcus bacteria. A similar syndrome, called toxic shock-like syndrome (TSLS), can be caused by streptococcal bacteria. Some cases of toxic shock syndrome have been known to be caused by Clostridium sordellii, influenza virus and varicella zoster virus.

Toxic shock syndrome (TSS) may have a similar presentation to some diseases which present as a rash, fever and hypotension. Some features are unique to toxic shock syndrome and can be used to differentiate it from other diseases.

Toxic shock syndrome (TSS) became a nationally notifiable disease in 1980. After the initial epidemic, the number of reported cases decreased significantly. Close observation during 1986 which was conducted in different parts of the United States, confirms the decreasing trend. Currently, the total incidence is 0.5 per 100,000 population. Incidence rates declined from 6 to 12 per 100,000 among women 12-49 years of age in 1980 to 1 per 100,000 among women 15-44 years of age in 1986.^[1] Apart from menstruation associated TSS, non-menstruating cases having a skin or soft tissue infection have also been identified.^[2]

Menstruating women, women using barrier contraceptive devices, persons who have undergone nasal surgery, and persons with postoperative staphylococcal wound infections are the most important risk factors for toxic shock syndrome.

If left untreated toxic shock syndrome after initial presentation, may rapidly lead to multi-organ system failure with serious morbidity and mortality. Appropriate treatment leads to full recovery of the patient.

Diagnosis of Toxic Shock Syndrome (TSS) is mainly based on the clinical presentation.

The most common symptoms of TSS include fever, erythroderma, and general viral infection symptoms like myalgia. Less common symptom of TSS include desquamation (which occur after 1-3 weeks of disease onset).

Patients with toxic shock syndrome (TSS) usually present with shock. Physical examination of patients with TSS is usually remarkable for hypotension, fever, and diffuse erythroderma. The presence of desquamation on physical examination is highly suggestive of TSS.

Laboratory findings consistent with the diagnosis of toxic shock syndrome (TSS) include leukocytosis, anemia and thrombocytopenia. A positive blood culture is diagnostic for Streptococcal TSS, although in other causes of TSS blood culture doesn’t have a high value.

On chest x-ray, toxic shock syndrome (TSS) is characterized by diffuse bilateral interstitial and alveolar infiltrates due to ARDS.

On brain CT-scan, toxic shock syndrome (TSS) is characterized by a midline shift, or effacement of the basilar cisterns due to cerebral edema.

There are no MRI findings associated with toxic shock syndrome (TSS).

There are no other specific imaging findings​ for toxic shock syndrome (TSS).

Although the best diagnostic tool for toxic shock syndrome (TSS) diagnosis is with clinical findings and laboratory exams, there are still some specific diagnostic ways to confirm TSS diagnosis. These techniques include frozen section biopsy and staphylococcus aureus antibody testing.

Women wearing a tampon at the onset of symptoms should remove it immediately. The severity of this disease results in hospitalization for treatment. Antibiotic treatment consists of penicillin and clindamycin.

One of the symptoms of streptococcal toxic shock syndrome is extreme infection of the skin and deeper parts is called necrotizing fasciitis. This often requires prompt surgical treatment.

Menstrual toxic shock syndrome can be prevented by avoiding the use of highly absorbent tampons. Risk can be reduced by changing tampons more frequently and using tampons only once in a while during menstruation.

Secondary prevention strategies following toxic shock syndrome (TSS) include chemoprophylaxis for invasive group A streptococcus or staphylococcuscarriers. Although it is still not certain to be helpful.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The term toxic shock syndrome was first used in 1978 by a Denver pediatrician, Dr. J.K. Todd, to describe the staphylococcal illness in three boys and four girls aged 8-17 years.^[1] In January 1980, epidemiologists in Wisconsin and Minnesota reported the appearance of TSS, mostly in menstruating women, to the CDC.^[2]

The term toxic shock syndrome was first used in 1978 by a Denver pediatrician, Dr. J.K. Todd, to describe the staphylococcal illness in three boys and four girls aged 8-17 years.^[3] Even though S. aureus was isolated from mucosal sites from the patients, bacteria could not be isolated from the blood, cerebrospinal fluid, or urine, raising suspicion that a toxin was involved. The authors of the study noted that reports of similar staphylococcal illnesses had appeared occasionally as far back as 1927. Most notably, the authors at the time failed to consider the possibility of a connection between toxic shock syndrome and tampon use, as three of the girls who were menstruating when the illness developed were using tampons.^[4]

• In January 1980, epidemiologists in Wisconsin and Minnesota reported the appearance of TSS, mostly in menstruating women, to the CDC.^[5]
• S. aureus was successfully cultured from most of the women. A CDC task force investigated the epidemic as the number of reported cases rose throughout the summer of 1980, accompanied by widespread publicity. In September 1980, the CDC reported that users of Rely were at increased risk for developing TSS.^[6]

• On September 22, 1980, Procter and Gamble recalled Rely^[7] following release of the CDC report. As part of the voluntary recall, Procter and Gamble entered into a consent agreement with the FDA “providing for a program for notification to consumers and retrieval of the product from the market”.^[8] However, it was clear to other investigators that Rely was not the only culprit. Other regions of the United States saw increases of menstrual TSS before Rely was introduced.^[9] It was shown later that higher absorbency of tampons was associated with an increased the risk for TSS, regardless of the chemical composition or the brand of the tampon. The sole exception was Rely, for which the risk for TSS was still higher when corrected for its absorbency.^[10] The ability of carboxymethylcellulose to filter the S. aureus toxin that causes TSS may account for the increased risk associated with Rely.^[11]

• By the end of 1980, the number of TSS cases reported to the CDC began to decline. The reduced incidence was attributed not only to the removal of Rely from the market, but also from the diminished use of all tampon brands. According to the Boston Women’s Health Book Collective, 942 women were diagnosed with tampon-related TSS in the USA from the March 1980 to March 1981, 40 of whom died.

• In August of 1978 Procter and Gamble introduced superabsorbent Rely tampons to the United States market^[12] in response to women’s demands for tampons that could contain an entire menstrual flow without leaking or replacement Rely used carboxymethylcellulose (CMC) and compressed beads of polyester for absorption. This tampon design could absorb nearly 20 times its own weight in fluid^[11].
• It was later found that use of Rely tampons was associated with development of toxic shock syndrome.^[13]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Toxic shock syndrome may be classified based on the microbiological organisms involved in causing the disease. Commonly involved organisms are Staphylococcus aureus and Streptococcus pyogenes (GAS); less commonly involved organisms leading to the development of toxic shock syndrome are Clostridium sordelli, Influenza virus and Varicella Zoster virus (the etiological agent of chickenpox).^{[1][2][3][4][5][6]}

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

The pathophysiology of toxic shock syndrome can be explained based on the etiological agent causing the disease. The general mechanism for all the etiological agents is the same, which involves non-specific activation of T lymphocytes by toxins acting as superantigens leading to release of cytokines.^[1] There are small differences in the mechanism of cytokine production which can be explained individually for the organisms involved.

Toxic shock syndrome (TSS) is known to be caused by the intoxication by one of the various exotoxins produced by Staphylococcus aureus, namely toxic shock syndrome toxin-1 (TSST-1). It may also be caused by some strains of Streptococcus pyogenes or Group A streptococcal (GAS) infection. There have been reports of TSS caused by Clostridium perfringens and Clostridium sordelli in women undergoing medical abortion.^{[2][3][4][5][6]}

S. aureus strains are facultative aerobes, which colonize the human mucosal surfaces like vagina and anterior nares.^[7]

• Various attachment proteins for example, fibronectin-binding proteins and collagen-binding proteins among many others, facilitate attachment to host cells, or interfere with host immune responses through the antiphagocytic action of proteins such as protein A. After attachment to host cells (particularly epithelial cells), the S. aureus produces cytolysins, which aid entry of the Toxic shock syndrome toxin-1 (TSST-1–the major toxin involved in TSS) into the system.
• TSST-1 is a protein based exotoxin, which acts as a superantigen (SAg). SAgs bind to certain regions of major histocompatibility complex (MHC) class II molecules of antigen-presenting cells (APCs) outside the traditional antigen-binding site, and at the same time bind in their native form to T cells at specific sites of the variable region of the beta chain (Vbeta) of the T cell receptor (TcR). This interaction triggers the activation (proliferation) of the targeted T lymphocytes and leads to release of high amounts of various cytokines and other effectors by immune cells. ^[1]
• The SAg with the help of cytolysins, specially α-toxin, binds by its dodecapeptide region to human epithelial cells, possibly CD40 or another unknown receptor, stimulating the production of pro-inflammatory chemokines including TNF-alpha, IL-6 and MIP-3α.^[8] The SAg must cross the mucosal barrier to cause disease, but it seems likely that submucosal SAg activities, rather than systemic activities, are sufficient for TSS production. ^[9]
• SAgs cause release of IL-1 beta and IL-6 from antigen presenting cells (APC) and have a direct action on the hypothalamic temperature control center.
• Staphylococcal toxic shock syndrome toxin 1 (TSST-1) is also the cause of menstrual toxic shock syndrome (mTSS) associated with vaginal colonization by Staphylococcus aureus; IL-8 and MIP-3α may originate from vaginal epithelial cells, which are highly chemotactic.^[10]

• The gene encoding toxic shock syndrome toxin is carried by a mobile genetic element of S. aureus in the SaPI family of pathogenicity islands.^[11]

• Streptococcus pyogenes, a beta-hemolytic bacterium that belongs to Lancefield serogroup A, also known as the group A streptococci (GAS) (particularly those harboring the M protein, specifically M1, M3 and M18) which are capable of producing the superantigens speA, speB and speC have been associated with severe cases of streptococcal toxic shock syndrome, also called Toxic shock-like syndrome (TSLS).^[12][13]
• Systemic invasion by the GAS is required for producing TSLS, which is in contrast to TSS caused by S.aureus (which only requires mucosal invasion to produce TSS). GAS associated TSS is not tampon-associated, because streptococci are anaerobic organisms and thus do not require oxygen for growth and toxin production (unlike S. aureus associated TSS).
• The pyrogenic exotoxin type A gene is associated with group A streptococcal strains isolated from patients with TSLS and may play a causative role in this illness.^[14]
• SpeA and SpeB non-specifically activate T cells causing release of pro-inflammatory cytokines like IL-6, IL-8, and MIP-3α^[15], which leads to fever, rash, capillary leak, and subsequent hypotension, the major symptoms of toxic shock syndrome. SpeB degrades immunoglobulins and cytokines, as well as through cleavage of C3b, inhibiting recruitment of phagocytic cells and the complement activation pathway.^[16]

• TSLS causing strains of streptococci have genetic sequences that code for exotoxins spe A, B and C. ^[17]

• Toxic shock syndrome after abortion can be caused by C. perfringens as well as C. sordellii, can be nonfatal, and can occur after spontaneous abortion and abortion induced by medical regimens other than mifepristone and misoprostol,^[18] although a fatal case of C. sordellii toxic shock syndrome after medical abortion with mifepristone and misoprostol was reported in 2001, in Canada.^[19]
• Clostridium sordellii strains can produce two large clostridial cytotoxins (LCCs); lethal toxin (TcsL) and hemorrhagic toxin (TcsH), similar to those produced by Clostridium difficile, Clostridium novyi and Clostridium perfringens.^[20]
• TcsL is the most important virulence factor required for producing Toxic shock syndrome (TSS).^[21] It is a major pathogenicity factor, which in addition to its in vivo effects, is cytotoxic to cultured cell lines. It causes reorganization of the cytoskeleton accompanied by morphological changes. The TcsL is a single-chain protein toxin, which comprises of three sites: receptor-binding, translocation and catalytic site. These sites reflect the self-mediated cell entry via receptor-mediated endocytosis, translocation into the cytoplasm, and execution of their cytotoxic activity by an inherent enzyme activity, respectively. Enzymatically, the toxins catalyze the transfer of a glucosyl moiety from UDP-glucose to the intracellular target proteins which are the Rho and Ras GTPases.
• Rho and Rac are the main regulators of the cell barrier integrity; Rho plays a key role in the maintenance of tight junctions, a structure existing between endothelial cells, whereas Rac is a major regulator of the integrity of VE-cadherin junctions, mainly adherens junctions.^[22]
• The covalent attachment of the glucose moiety to a conserved threonine within the effector region of the GTPases causes inactivation of Rho-GTPases.^[23]
• Glucosylation of Rac, another major target for TcsL, leads to alteration in Rac-dependent adherens junctions, vascular leakage, subsequent edema formation and the refractory shock like syndrome seen in C. sordelii infections. In conclusion, death induced by TcsL seems to be the consequence of an increase in vascular permeability, resulting from modifications of endothelial cells. Extravasation of blood fluid into the pleural cavity leads to anoxia and finally to cardiorespiratory failure, in the absence of inflammation. ^[24]

There are no specific gross pathology findings associated with toxic shock syndrome.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Toxic shock syndrome (TSS) is known to be caused due to intoxication by one of the various exotoxins produced by Staphylococcus aureus, namely toxic shock syndrome toxin-1 (TSST-1). It may also be caused by some strains of Group A streptococcal (GAS) infection. ^[1] There have been reports of TSS caused by Clostridium perfringens and Clostridium sordelli in women undergoing medical abortion, parturition and gynaecological procedures.^{[1][2][3][4][5]} Some viruses have also been implicated in the development of toxic shock syndrome.

1.Staphylococcus associated Toxic shock syndrome (TSS)

• Staphylococcus aureus, a gram positive coccus has been known to be a major cause of toxic shock syndrome via the production and intoxication by toxic shock syndrome toxin-1 (TSST-1). ^[2]
  • Staphylococcal enterotoxin F^[3]
  • S. aureus colonizes the anterior nares and vagina of humans. About 20% of people are persistent carriers, 60% are intermittent carriers, and about 20% are almost never colonized by S. aureus. ^[4]

2.Group A streptococcus associated Toxic shock syndrome (Toxic sock-like syndrome, TSLS)

• Streptococcal TSS occurs most frequently in the setting of invasive infection due to group A Streptococcus (Streptococcus pyogenes). ^[5]

• Toxic shock syndrome has been seen as a complication in patients suffering from streptococcal pharyngitis and necrotizing fasciitis.^[6]

• There have been reports of TSS in patients taking NSAIDs during infection by GAS. The possible mechanism that has been proposed, is inhibition of neutrophil function and increased cytokine production. ^[7]

1.Clostridium associated Toxic shock syndrome

• Clostridium sordellii is a part of the normal flora of the vagina and may gain entry into the uterus via the cervix during spontaneous or induced abortion, childbirth, or menstruation. C. sordellii is a cause of toxic shock syndrome associated with gynecologic procedures, parturition, and abortion (including spontaneous, surgical, and medical abortion).^{[8][9][10][11][12]}

2.Viral infection^[13]

• • Influenza virus
  • Varicella zoster virus

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Toxic shock syndrome (TSS) may have a similar presentation to some diseases which present as a rash, fever and hypotension. Some features are unique to toxic shock syndrome and can be used to differentiate it from other diseases.

Toxic shock syndrome requires all 3 manifestations of fever, hypotension and diffuse scarlatiniform rash (innumerable small red papules that are diffusely distributed plus erythema, which blanches and desquamates one or two weeks after onset of illness). It presents with various signs of infection, hemodynamic dysfunction and organ failure.

Clinical presentation of fever, hypotension and rash must be differentiated from other diseases like:

• Meningococcemia
• Steven Johnson syndrome (SJS)
• Toxic epidermal necrolysis (TEN)
• Scarlet fever
• Red man syndrome
• Drug reaction with eosinophilia and systemic symptoms (DRESS syndrome)

Clinical presentation of fever and rash must be differentiated from other diseases like:

• Viral exanthem
• Rickettsial disease
• Kawasaki disease
• Staphylococcal scalded skin syndrome
• Exfoliative erythroderma syndrome
• Erythema multiforme major

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Approximately half the cases of staphylococcal TSS reported today are associated with tampon use during menstruation, usually in young women and up till now 42% of cases have occurred in females under the age of 19 years, though TSS also occurs in children, men, and non-menstruating women.

• Toxic shock syndrome (TSS) became a nationally notifiable disease in 1983. After the initial epidemic, the number of reported cases decreased significantly. ^[1]
• Incidence rates declined from 6 to 12 per 100,000 among women 12-49 years of age in 1980 to 1 per 100,000 among women 15-44 years of age in 1986.^[2]
• Apart from menstruation associated TSS, non-menstruating cases having a skin or soft tissue infection have also been identified.^[3]
• In a study conducted during 2000-2006, the average annual incidence per 100,000 persons of all TSS cases was 0.52 cases (95% CI, 0.32–0.77), of menstrual cases was 0.69 (95% CI, 0.39–1.16), and of non-menstrual cases was 0.32 (95% CI, 0.12–0.67). ^[4]
• Women aged 13–24 years had the highest incidence with an annual rate of menstrual TSS of 1.41 cases per 100,000.  ^[5]

• MRSA strains have increased in prevalence during the last decade and MRSA have been reported as the cause of TSS.^[6]

• Approximately half the cases of staphylococcal TSS reported today are associated with tampon use during menstruation, usually in young women, though TSS also occurs in children, men, and non-menstruating women.

• Menstruating females had the highest incidence with an annual rate of menstrual TSS of 1.41 cases per 100,000 based on incidence data from 2000-2003.^[7]
• It has been estimated that each year 1 to 17 of every 100,000 menstruating females will get TSS. In the US in 1997, only five confirmed menstrual-related TSS cases were reported, compared with 814 cases in 1980, according to data from the Centers for Disease Control and Prevention (CDC).
• About 25 percent of non-menstrual cases of Toxic shock syndrome occur in males.

• Women aged 13–24 years have the highest incidence with an annual rate of menstrual TSS of 1.41 cases per 100,000.^[8]
• To date, 42% of cases have occurred in females under the age of 19 years. ^[9]

• Epidemiology studies conducted in the late 1980s showed that women who develop mTSS tended to be predominately white. ^[10]
• White population are more likely to be carriers of toxigenic S. aureus than black, Hispanic, or Asian population.^[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

Menstruating women, women using barrier contraceptive devices, persons who have undergone nasal surgery, and persons with postoperative staphylococcal wound infections are the most important risk factors for toxic shock syndrome.

• Vaginal colonization by S. aureus in mensruating women using tampons^[1]
• Infections
• Nasal packing
• Wound infection
• Recent surgery
• Compound fracture

• Absence of protective immunity
• Parturition

Although scientists have recognized an association between toxic shock syndrome (TSS) and tampon use, no firm causal link has been established. Research conducted by the CDC suggested that use of some high absorbency tampons increased the risk of TSS in menstruating women. A few specific tampon designs and high absorbency tampon materials were also found to have some association with increased risk of TSS. These products and materials are no longer used in tampons sold in the U.S. (The materials include polyester, carboxymethylcellulose and polyacrylate).^[2] Tampons made with rayon do not appear to have a higher risk of TSS than cotton tampons of similar absorbency.^[3]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Hassan A. Kazmi BSc, MD [2]

If left untreated toxic shock syndrome after initial presentation, may rapidly lead to multiorgan system failure with serious morbidity and mortality. Appropriate treatment leads to full recovery of the patient.

During the early phase of development of toxic shock syndrome (TSS), the patient will develop severe flu-like symptoms such as a high fever, vomiting, a sun-burn like rash, muscle aches and general weakness. If left untreated, these symptoms may progress to hypotension, tachycardia, high grade fever, diarrhea, vomiting, irritability, drowsiness and eventually organ failure. Early recognition and aggressive management can decrease the overall morbidity and mortality of toxic shock syndrome.

Toxic shock syndrome (TSS) may lead to the following complications:

• Severe organ dysfunction
  • Kidney failure
  • Heart failure
  • Liver failure
  • ARDS^[1]
• Patients with initial soft tissue infection due to Group A Streptococci (GAS), presenting as toxic shock syndrome may deteriorate rapidly leading to necrotizing fasciitis and myositis, which may give rise to a compartment syndrome with associated rhabdomyolysis.^[2]

• Patients with toxic shock syndrome who are diagnosed early and given appropriate treatment often have a good prognosis. Early treatment can help prevent complications such as renal failure, respiratory failure, and coagulation disorders. However, the mortality (death) rate is about 5%-15%, and patients who develop complications have a poorer prognosis than those who do not. Patients who develop TSS are at risk for reinfection

• Some of the factors which may lead to a poor outcome for a patient suffering from toxic shock syndrome are:^[3]
  • Leukocytopenia
  • Thrombocytopenia
  • Hypotension
  • Low body temperature
  • High blood creatinine levels

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