Nonmenstrual Toxic Shock Syndrome Research Articles

Fatal, non-menstrual staphylococcal toxic shock syndrome associated with dental implant

Staphylococcal toxic shock syndrome (TSS) is a life-threatening disease that characterized by rapid onset of fever, rash, hypotension, and multi-organ failure.A 58-year-old man presented to the emergency department (ED) with complaints of fatigue, myalgia, and blurred vision which had progressed over 48 hours. His medical history included hypertension and dental implant treatment that lasted 15 days. Despite aggressive medical treatment, which included multiple vasopressors, continuous renal replacement therapy in combination with CytoSorb and broad-spectrum antibiotics, he died 16 hours after admission to the intensive care unit. was detected in his blood and ETA cultures after the patient's death.Staphylococcal TSS is classified as menstrual and non-menstrual. Non-menstrual TSS cases have been documented with increasing frequency in the literature. We present a case of Staphylococcal TSS in a 58-year-old male patient who had a dental surgery history. Our patient died within a few hours after admission to the ICU with signs of multi-organ failure. We wanted to draw attention to this issue by presenting our patient.

The Association Between Onset of Staphylococcal Non-menstrual Toxic Shock Syndrome With Inducibility of Toxic Shock Syndrome Toxin-1 Production.

Non-menstrual toxic shock syndrome (non-mTSS) is a life-threatening disease caused by Staphylococcus aureus strains producing superantigens, such as staphylococcal enterotoxins A, B, C, and toxic shock syndrome toxin-1 (TSST-1). However, little is known about why the TSS cases are rare, although S. aureus strains frequently carry a tst gene, which encodes TSST-1. To answer this question, the amount of TSST-1 produced by 541 clinical isolates was measured in both the presence and absence of serum supplementation to growth media. Then a set of S. aureus strains with similar genetic backgrounds isolated from patients presenting with non-mTSS and those with clinical manifestations other than non-mTSS was compared for their TSST-1 inducibility by human serum, and their whole-genome sequences were determined. Subsequently, the association of mutations identified in the tst promoter of non-mTSS strains with TSST-1 inducibility by human serum was evaluated by constructing promoter replacement mutants and green fluorescent protein (GFP) reporter recombinants. Results showed that 39 out of 541 clinical isolates (7.2%), including strains isolated from non-mTSS patients, had enhanced production of TSST-1 in the presence of serum. TSST-1 inducibility by human serum was more clearly seen in non-mTSS strains of clonal complex (CC)-5. Moreover, the whole-genome sequence analysis identified a set of sequence variations at a putative SarA-binding site of the tst promoter. This sequence variation was proven to be partially responsible for the induction of TSST-1 production by human serum. We conclude that the onset of staphylococcal toxic shock syndrome caused by TSST-1-producing CC-5 strains seem at least partially initiated by serum induction of TSST-1, which is regulated by the mutation of putative SarA-binding site at the tst promoter.

Clinical and Molecular Epidemiology of Staphylococcal Toxic Shock Syndrome in the United Kingdom.

Staphylococcal toxic shock syndrome (TSS) was originally described in menstruating women and linked to TSS toxin 1 (TSST-1)-producing Staphylococcus aureus. Using UK national surveillance data, we ascertained clinical, molecular and superantigenic characteristics of TSS cases. Average annual TSS incidence was 0.07/100,000 population. Patients with nonmenstrual TSS were younger than those with menstrual TSS but had the same mortality rate. Children <16 years of age accounted for 39% of TSS cases, most caused by burns and skin and soft tissue infections. Nonmenstrual TSS is now more common than menstrual TSS in the UK, although both types are strongly associated with the tst+ clonal complex (CC) 30 methicillin-sensitive S. aureus lineage, which accounted for 49.4% of all TSS and produced more TSST-1 and superantigen bioactivity than did tst+ CC30 methicillin-resistant S. aureus strains. Better understanding of this MSSA lineage and infections in children could focus interventions to prevent TSS in the future.

The SaeRS Two-Component System Is a Direct and Dominant Transcriptional Activator of Toxic Shock Syndrome Toxin 1 in Staphylococcus aureus

Toxic shock syndrome toxin 1 (TSST-1) is a Staphylococcus aureus superantigen that has been implicated in both menstrual and nonmenstrual toxic shock syndrome (TSS). Despite the important role of TSST-1 in severe human disease, a comprehensive understanding of staphylococcal regulatory factors that control TSST-1 expression remains incomplete. The S. aureus exotoxin expression (Sae) operon contains a well-characterized two-component system that regulates a number of important exotoxins in S. aureus, although regulation of TSST-1 by the Sae system has not been investigated. We generated a defined deletion mutant of the Sae histidine kinase sensor (saeS) in the prototypic menstrual TSS strain S. aureus MN8. Mutation of saeS resulted in a complete loss of TSST-1 expression. Using both luciferase reporter experiments and quantitative real-time PCR, we demonstrate that the Sae system is an important transcriptional activator of TSST-1 expression. Recombinant SaeR was able to bind directly to the tst promoter to a region containing two SaeR consensus binding sites. Although the stand-alone SarA transcriptional regulator has been shown to be both a positive and a negative regulator of TSST-1, deletion of sarA in S. aureus MN8 resulted in a dramatic overexpression of TSST-1. As expected, mutation of agr also reduced TSST-1 expression, but this phenotype appeared to be independent of Sae. A double mutation of saeS and sarA resulted in the loss of TSST-1 expression. This work indicates that the Sae system is a dominant and direct transcriptional activator that is required for expression of TSST-1. The TSST-1 superantigen is an exotoxin, produced by some strains of S. aureus, that has a clear role in both menstrual and nonmenstrual TSS. Although the well-characterized agr quorum sensing system is a known positive regulator of TSST-1, the molecular mechanisms that directly control TSST-1 expression are only partially understood. Our studies demonstrate that the Sae two-component regulatory system is a positive transcriptional regulator that binds directly to the TSST-1 promoter, and furthermore, our data suggest that Sae is required for expression of TSST-1. This work highlights how major regulatory circuits can converge to fine-tune exotoxin expression and suggests that the Sae regulatory system may be an important target for antivirulence strategies.

Unusual staphylococcal toxic shock syndrome presenting as a scarlet-like fever

Diagnosis of nonmenstrual staphylococcal toxic shock syndrome (TSS) is often challenging. A female medical colleague had a rare entity, a staphylococcal pharyngitis complicated by TSS. The diagnosis was confirmed by isolation of tst-positive Staphylococcus aureus in throat culture and by identification of a specific Vβ2 expansion pattern of her T lymphocytes. Recent improvements in microbiology can be of great help for the diagnosis of nonmenstrual TSS.

Staphylococcal toxic shock syndrome: superantigen-mediated enhancement of endotoxin shock and adaptive immune suppression.

Infectious diseases caused by Staphylococcus aureus present a significant clinical and public health problem. S. aureus causes some of the most severe hospital-associated and community-acquired illnesses. Specifically, it is the leading cause of infective endocarditis and osteomyelitis, and the second leading cause of sepsis in the USA. While pathogenesis of S. aureus infections is at the center of current research, many questions remain about the mechanisms underlying staphylococcal toxic shock syndrome (TSS) and associated adaptive immune suppression. Both conditions are mediated by staphylococcal superantigens (SAgs)-secreted staphylococcal toxins that are major S. aureus virulence factors. Toxic shock syndrome toxin-1 (TSST-1) is the SAg responsible for almost all menstrual TSS cases in the USA. TSST-1, staphylococcal enterotoxin B and C are also responsible for most cases of non-menstrual TSS. While SAgs mediate all of the hallmark features of TSS, such as fever, rash, hypotension, and multi-organ dysfunction, they are also capable of enhancing the toxic effects of endogenous endotoxin. This interaction appears to be critical in mediating the severity of TSS and related mortality. In addition, interaction between SAgs and the host immune system has been recognized to result in a unique form of adaptive immune suppression, contributing to poor outcomes of S. aureus infections. Utilizing rabbit models of S. aureus infective endocarditis, pneumonia and sepsis, and molecular genetics techniques, we aim to elucidate the mechanisms of SAg and endotoxin synergism in the pathogenesis of TSS, and examine the cellular and molecular mechanisms underlying SAg-mediated immune dysfunction.

Engineering a soluble high-affinity receptor domain that neutralizes staphylococcal enterotoxin C in rabbit models of disease.

Superantigens (SAgs) are a class of immunostimulatory exotoxins that activate large numbers of T cells, leading to overproduction of cytokines and subsequent inflammatory reactions and systemic toxicity. Staphylococcal enterotoxin C (SEC), a SAg secreted by Staphylococcus aureus, has been implicated in various illnesses including non-menstrual toxic shock syndrome (TSS) and necrotizing pneumonia. SEC has been shown to cause TSS illness in rabbits and the toxin contributes to lethality associated with methicillin-resistant S.aureus (MRSA) in a rabbit model of pneumonia. With the goal of reducing morbidity and mortality associated with SEC, a high-affinity variant of the extracellular variable domain of the T-cell receptor beta-chain for SEC (~14 kDa) was generated by directed evolution using yeast display. This protein was characterized biochemically and shown to cross-react with the homologous (65% identical) SAg staphylococcal enterotoxin B (SEB). The soluble, high-affinity T-cell receptor protein neutralized SEC and SEB in vitro and also significantly reduced the bacterial burden of an SEC-positive strain of MRSA (USA400 MW2) in an infective endocarditis model. The neutralizing agent also prevented lethality due to MW2 in a necrotizing pneumonia rabbit model. These studies characterize a soluble high-affinity neutralizing agent against SEC, which is cross-reactive with SEB, and that has potential to be used intravenously with antibiotics to manage staphylococcal diseases that involve these SAgs.

Detrimental effects of T regulatory cell-promoting IL-2-anti-IL-2 complexes in staphylococcal toxic shock syndrome. (164.13)

Abstract Menstrual or non-menstrual toxic shock syndrome (TSS), caused by the superantigen exotoxins of Staphylococcus aureus or Streptococcus pyogenes, is characterized by a robust activation of the immune system, systemic cytokine/chemokine storm, multiple organ failure and possibly death, if not treated promptly. We tested whether increasing the numbers of Treg in vivo by administration of IL-2-anti-IL-2 complexes (IL2C) could be beneficial in TSS. Administration of IL2C [prepared by incubating 1µg of IL-2 (Peprotech) and 5µg anti-IL-2 (eBioscience, clone-JES6-1A12) in a total 200 µl at 37oC for 30 min] on days 0, 1 and 2, caused a 3 to 4-fold increase in CD4+CD25+FoxP3+ Treg numbers in the spleens of HLA-DR3 transgenic mice by day 5. However, upon challenge with staphylococcal enterotoxin B (SEB, 50µg), compared to untreated HLA-DR3 transgenic mice, IL2C-treated mice produced significantly higher levels of IFN-γ (1714±1365 versus 6642±2253 pg/ml), MIP-1α (782±23 versus 2305±376 pg/ml,), MIP-1β, RANTES and TNF-α. SEB-induced mortality was also significantly increased in the IL2C treated group. While only 1/5 mice died in untreated group, 6/11 mice died in the IL2C treated group. In conclusion, even though administration of IL2C significantly increased the Treg numbers, such a treatment also increased their susceptibility to TSS. Hence, the benefits of T reg-promoting IL-2-anti-IL-2 complexes in TSS or related conditions need more stringent evaluation.

Staphylococcal Toxic Shock Syndrome 2000–2006: Epidemiology, Clinical Features, and Molecular Characteristics

IntroductionCirculating strains of Staphylococcus aureus (SA) have changed in the last 30 years including the emergence of community-associated methicillin-resistant SA (MRSA). A report suggested staphylococcal toxic shock syndrome (TSS) was increasing over 2000–2003. The last population-based assessment of TSS was 1986.MethodsPopulation-based active surveillance for TSS meeting the CDC definition using ICD-9 codes was conducted in the Minneapolis-St. Paul area (population 2,642,056) from 2000–2006. Medical records of potential cases were reviewed for case criteria, antimicrobial susceptibility, risk factors, and outcome. Superantigen PCR testing and PFGE were performed on available isolates from probable and confirmed cases.ResultsOf 7,491 hospitalizations that received one of the ICD-9 study codes, 61 TSS cases (33 menstrual, 28 non-menstrual) were identified. The average annual incidence per 100,000 of all, menstrual, and non-menstrual TSS was 0.52 (95% CI, 0.32–0.77), 0.69 (0.39–1.16), and 0.32 (0.12–0.67), respectively. Women 13–24 years had the highest incidence at 1.41 (0.63–2.61). No increase in incidence was observed from 2000–2006. MRSA was isolated in 1 menstrual and 3 non-menstrual cases (7% of TSS cases); 1 isolate was USA400. The superantigen gene tst-1 was identified in 20 (80%) of isolates and was more common in menstrual compared to non-menstrual isolates (89% vs. 50%, p = 0.07). Superantigen genes sea, seb and sec were found more frequently among non-menstrual compared to menstrual isolates [100% vs 25% (p = 0.4), 60% vs 0% (p<0.01), and 25% vs 13% (p = 0.5), respectively].DiscussionTSS incidence remained stable across our surveillance period of 2000–2006 and compared to past population-based estimates in the 1980s. MRSA accounted for a small percentage of TSS cases. tst-1 continues to be the superantigen associated with the majority of menstrual cases. The CDC case definition identifies the most severe cases and has been consistently used but likely results in a substantial underestimation of the total TSS disease burden.

Non-menstrual toxic shock and the in vivo roles of seb and ivig

Introduction: Non-menstrual toxic shock syndrome (TSS) has a higher mortality than menstrual toxic shock syndrome, and SEB is a well recognised causative superantigen. Although IVIG is advocated by some as a treatment for TSS, recent UK guidelines do not mention TSS as an indication for use. This study set out to investigate the role of SEB in non-menstrual staphylococcal TSS and the potential treatment value of IVIG.

Analysis of superantigenic toxin Vβ T-cell signatures produced during cases of staphylococcal toxic shock syndrome and septic shock

Most clinical isolates of Staphylococcus aureus harbour genes encoding superantigenic toxins that bind the Vbeta domain of T-cells, but little information is available concerning superantigenic toxin production during staphylococcal toxic shock syndrome (TSS) and septic shock. This prospective study investigated 14 patients with staphylococcal TSS or septic shock; the toxin gene profile of each isolate was determined and flow-cytometry was used to identify the discriminant Vbeta signature (DVbetaS) of each superantigenic toxin in vitro. Attempts were also made to identify in-vivo production of superantigenic toxin DVbetaS in patients' blood. The DVbetaS identified in vitro were: toxic shock syndrome toxin (TSST)-1, Vbeta 2; staphylococcal enterotoxin (SE), Vbeta 9, Vbeta 22; SEB, Vbeta 3, Vbeta 14, Vbeta 17; SED, Vbeta 1, Vbeta 8; egc, Vbeta 5.3, Vbeta 7.1, Vbeta 9, Vbeta 23; and SElK, Vbeta 5.1. The DVbetaS of TSST-1 and SEB were detected in patients with menstrual and non-menstrual TSS, respectively, whereas no Vbeta signature was detected during septic shock. All patients with septic shock (but only one patient with TSS) had lymphopenia and/or impaired cellular immunity. Detection of a superantigenic toxin DVbetaS may help to show which toxin is produced during staphylococcal TSS, thus confirming the diagnosis and hastening the administration of anti-toxin therapy. In contrast, this approach failed to demonstrate superantigenic toxin involvement in cases of septic shock. In this latter condition, a superantigenic toxin may not be produced by S. aureus, or its production may occur without expansion of targeted T-cells because of T-cell apoptosis and/or anergy.

One in five mortality in non-menstrual toxic shock syndrome versus no mortality in menstrual cases in a balanced French series of 55 cases

Staphylococcus aureus superantigenic toxins are responsible for menstrual and non-menstrual toxic shock syndrome (TSS). We compared the clinical and biological characteristics of 21 cases of menstrual TSS (MTSS) with 34 cases of non-menstrual TSS (NMTSS) diagnosed in France from December 2003 to June 2006. All 55 S. aureus isolates had been spontaneously referred to the French National Staphylococcal Reference Center, where they were screened for superantigenic toxin gene sequences. Most of the patients had previously been in good health. The most striking differences between MTSS and NMTSS were the higher frequency in NMTSS of neurological disorders (p=0.028), of S. aureus isolation by blood culture (50% versus 0% in MTSS), and the higher mortality rate in NMTSS (22% versus 0% in MTSS). The tst and sea genes were less frequent in isolates causing NMTSS than in those causing MTSS (p<0.001 and 0.051, respectively). Higher mortality was significantly associated with the presence of the sed gene (p=0.041), but when considering NMTSS survivors and non-survivors, no clinical or bacteriological factors predictive of vital outcome were identified. Specific antitoxinic therapy was rarely prescribed, and never in fatal cases. Higher mortality was observed in NMTSS than in MTSS, and no definite factors could explain the higher severity of NMTSS. NMTSS would require more aggressive therapy, comprising systematic rapid wound debridement, antistaphylococcal agents, including an antitoxin antibiotics, and intravenous immunoglobulin.

Drotrecogin Alfa (Activated) for Nonmenstrual Toxic Shock Syndrome Associated with Methicillin Resistant Staphylococcus aureus Infection

Nonmenstrual toxic shock syndrome (TSS) due to Staphylococcus aureus can lead to significant morbidity and mortality. While drotrecogin alfa (DA) has been employed in patients with Methicillin-resistant Staphylococcus aureus (MRSA) severe sepsis and septic shock, its utility in TSS remains unclear. The authors report a case of severe sepsis in the setting of MRSA-associated TSS that responded to treatment with DA. This case illustrates a potential role for DA in the treatment of toxic shock syndromes and emphasizes the importance of aggressive diagnostic and therapeutic modalities in approaching these conditions.

Staphylococcal Infections

Staphylococcal Infections

Staphylococcal Infections

Staphylococcal Infections

Toxic Shock Syndrome in Children

Toxic shock syndrome (TSS) is an acute, toxin-mediated illness, like endotoxic shock, and is characterized by fever, rash, hypotension, multiorgan involvement, and desquamation. TSS reflects the most severe form of the disease caused by Staphylococcus aureus and Streptococcus pyogenes. A case definition for staphylococcal TSS was well established in the early 1980s and helped in defining the epidemiology. Since the late 1980s, a resurgence of highly invasive streptococcal infections, including a toxic shock-like syndrome, was noted worldwide and a consensus case definition for streptococcal TSS was subsequently proposed in 1993. Both TSS and the toxic shock-like syndrome occur at a lower incidence in children than in adults. Changes in the manufacturing and use of tampons led to a decline in staphylococcal TSS over the past decade, while the incidence of nonmenstrual staphylococcal TSS increased. Nonmenstrual TSS and menstrual TSS are now reported with almost equal frequency. The incidence of streptococcal TSS remains constant after its resurgence, but varies with geographic location. Streptococcal TSS occurs most commonly following varicella or during the use of NSAIDs. Sites of infection in streptococcal TSS are much deeper than in staphylococcal TSS, such as infection caused by blunt trauma, and necrotizing fasciitis. Bacteremia is more common in streptococcal TSS than in staphylococcal TSS. Mortality associated with streptococcal TSS is 5-10% in children, much lower than in adults (30-80%), and is 3-5% for staphylococcal TSS in children.TSS is thought to be a superantigen-mediated disease. Toxins produced by staphylococci and streptococci act as superantigens that can activate the immune system by bypassing the usual antigen-mediated immune-response sequence. The host-pathogen interaction, virulence factors, and the absence or presence of host immunity determines the epidemiology, clinical syndrome, and outcome. Early recognition of this disease is important, because the clinical course is fulminant and the outcome depends on the prompt institution of therapy. Management of a child with TSS includes hemodynamic stabilization and appropriate antimicrobial therapy to eradicate the bacteria. Supportive therapy, aggressive fluid resuscitation, and vasopressors remain the main elements. An adjuvant therapeutic strategy may include agents that can block superantigens, such as intravenous immunoglobulin that contains superantigen neutralizing antibodies.

Toxic Shock Syndrome in Two CAPD Patients with Staphylococcus Aureus Exit-Site Infection

Toxic shock syndrome (TSS) is an illness defined by the occurrence of fever, rash, hypotension, multiple organ system dysfunction, and desquamation. Nonmenstrual TSS is often associated with surgical or nonsurgical cutaneous infections, which are rarely purulent or inflamed (Reingold AL, et al. Nonmenstrual toxic shock syndrome: a review of 130 cases. Ann Intern Med 1982; 96:871-4). Toxic shock syndrome associated with peritoneal exit-site infection but without peritonitis is extremely unusual (Sherbotie JR, et al. Toxic shock syndrome with Staphylococcus aureus exit-site infection in a patient on peritoneal dialysis. Am J Kidney Dis 1990; 15:80-3). We describe 2 patients that met the Centers for Disease Control case definition of TSS secondary to a peritoneal dialysis catheter exit-site infection with signs of mild inflammation and growth of Staphylococcus aureus, but with no evidence of peritonitis.

Comparative molecular analysis of community- or hospital-acquired methicillin-resistant Staphylococcus aureus.

Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is a growing public health concern that has been associated with pediatric fatalities. It is hypothesized that the evolution of CA-MRSA is a recent event due to the acquisition of mec DNA by previously methicillin-susceptible strains that circulated in the community. This study investigated the genetic relatedness between CA-MRSA, hospital-associated MRSA (HA-MRSA), and nonmenstrual toxic shock syndrome (nmTSS) isolates. Thirty-one of 32 CA-MRSA isolates were highly related as determined by pulsed-field gel electrophoresis and spa typing yet were distinguishable from 32 HA-MRSA strains. The 31 related CA-MRSA isolates produced either staphylococcal enterotoxin B (n = 5) or C (n = 26), and none made TSS toxin 1. All CA-MRSA isolates tested contained a type IV staphylococcal cassette chromosome mec (SCCmec) element. In comparison, none of the HA-MRSA isolates (n = 32) expressed the three superantigens. Antibiotic susceptibility patterns were different between the CA-MRSA and HA-MRSA isolates; CA-MRSA was typically resistant only to beta-lactam antibiotics. Six of twenty-one nmTSS isolates were indistinguishable or highly related to the CA-MRSA isolates. MnCop, an nmTSS isolate obtained in Alabama in 1986, was highly related to the CA-MRSA isolates except that it did not contain an SCCmec element. These data suggest that CA-MRSA strains may represent a new acquisition of SCCmec DNA in a previously susceptible genetic background that was capable of causing nmTSS. CA-MRSA poses a serious health risk not only because it is resistant to the antibiotics of choice for community-acquired staphylococcal infections but also because of its ability to cause nmTSS via superantigen production.

Toxic shock syndrome originating from the foot

The most familiar etiology of toxic shock syndrome (TSS) is that of menstruation and tampon use. Nonmenstrual TSS has been described in all types of wounds including postsurgical, respiratory infection, mucous membrane disruption, burns, and vesicular lesions caused by varicella and shingles. A case of TSS occurring in a diabetic male patient with foot blisters is presented. Early recognition by an infectious disease specialist and appropriate medical management led to complete recovery. There have been no reported cases of Staphylococcus aureus TSS originating in the foot to date.

Prolonged course of toxic shock syndrome associated with methicillin-resistant Staphylococcus aureus enterotoxins G and I

Toxic shock syndrome (TSS), which may be hfe-threatening, is defined by clinical and laboratory evidence of fever, rash, hypotension, and multisystem abnormalities in the absence of other causes. Most cases are nonmenstrual in origin. I-* Whereas Staphylococcus aureus TSS toxin-l causes the vast majority of menstrual cases, it causes only about half of other cases.” Staphylococcal enterotoxins (SEs) were implicated in nonmenstrual TSS cases shortly after the role of TSS toxin-l was elucidated, and currently, SEs that are reported to be associated with TSS are SEs A, B, C, D, G, H, and I, with SE-B most commonly reported and SE-G and SE-I most recently reported, albeit the latter two with scant clinical details.2s4-8 The following case associated with SE-G and SE-I illustrates the consequences of these immunomodulatory pyrogenic toxin superantigens over a prolonged course, as well as pitfalls in their diagnosis and management.