Pediatric Toxic Shock Syndrome

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Overview of Pediatric TSS

Toxic shock syndrome (TSS) is a multisystem disease manifested by sudden onset of fever, chills, hypotension, and rash. Multisystem involvement may cause vomiting, diarrhea, myalgia, mucous membrane hyperemia, mental confusion, renal dysfunction, hepatic abnormalities, and thrombocytopenia.

TSS is caused by toxin-producing strains of staphylococci (staphylococcal TSS) and streptococci (streptococcal TSS). Both causes are discussed in this article. Todd et al first described staphylococcal toxic shock syndrome in 1978.[1] The association of TSS with menstruation and tampon use was established in 1980. Cases of TSS caused by streptococci were first reported in the mid-1980s.

The following table summarizes key distinctions between staphylococcal and streptococcal TSS.

Table. Features of Staphylococcal and Streptococcal Toxic Shock Syndrome



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See Table

The goal of medical therapy is to eradicate infection and to prevent complications. Seriously ill patients may require care in the intensive care unit (ICU). Surgical removal of tampons or other foreign bodies or surgical debridement of necrotic tissue may be required.

Go to Toxic Shock Syndrome, Septic Shock, and Pediatric Sepsis for complete information on these topics.

For patient education resources, see the Women’s Health Center, as well as Toxic Shock Syndrome.

Pathophysiology and Etiology

Staphylococcal TSS

Staphylococcal toxic shock syndrome (TSS) is caused by certain toxin-producing strains. Toxic shock syndrome toxin-1 (TSST-1) is implicated in 75% of patients with TSS, enterotoxin B is implicated in 23% of patients with TSS, and enterotoxin C is implicated in 2% of patients with TSS. Evidence implicating Staphylococcus aureus in TSS is as follows:

TSST-1 and the enterotoxins are superantigens. They result in nonspecific T-lymphocyte stimulation without normal antigenic recognition. This massive activation of lymphocytes leads to release of cytokines that contribute to the development of toxic shock syndrome.[3]

Staphylococcal TSS has been associated with menstruation and the following nonmenstrual conditions:

Use of hyperabsorbent tampons creates conditions conducive to the production of staphylococcal TSS. Tampons increase the vaginal partial pressure of oxygen, stimulating toxin synthesis. They supply surfactants that can increase toxin production. Tampons also bind magnesium and shift the growth kinetics of S aureus to increase toxin production.

Toxic shock syndrome (TSS) caused by methicillin-resistant Staphylococcus aureus (MRSA) nosocomial infection is a growing concern in both adult and pediatric patients. A recent study suggested a potential role of testing for TSST-1 antibody in the clinical setting might help to predict and prevent the appearance of TSS caused by nosocomial MRSA infection[5]

Streptococcal TSS

Streptococcal Toxic Shock syndrome (STSS) is a serious complication caused by exotoxins of Group A Streptococcus (GAS). It presents with fulminant shock and rash, is rapidly progressive with Multi-Organ Dysfunction Syndrome.[6]  Streptococcal TSS is caused by streptococci that produce streptococcal pyrogenic exotoxin A (SPEA) (which has a 50% amino acid homology to staphylococcal enterotoxins B and C), streptococcal pyrogenic exotoxin B (SPEB), or both. SPEA-producing organisms are more common in the United States, whereas SPEB-producing streptococci are recovered more frequently from patients with streptococcal TSS in Sweden and the United Kingdom.

The predominant streptococcal serotype that produces TSS is M-1 (80% of strains in Sweden), although other serotypes, such as M-2, M-3, M-12, and M-28, may also produce this syndrome.

SPEA and SPEB trigger a cascade of inflammatory cytokines, such as tumor necrosis factor-alpha, interleukin (IL)-2, and IL-6, leading to multiorgan injury and shock. Inflammatory cytokines may also be produced by other streptococcal components, such as peptidoglycan and lipoteichoic acid. Recently, streptococcal superantigen (SSA), a novel pyrogenic exotoxin, was isolated from an M-3 strain.

Streptococcal TSS has been associated with the following conditions:

Most patients with streptococcal TSS do not have any underlying disease. Person-to-person spread of streptococcal TSS has been described.

Epidemiology of Pediatric TSS

The annual incidence of staphylococcal toxic shock syndrome (TSS) in the United States is 1-5 cases per 100,000 menstruating women. An estimated 77-93% of cases occur in women (41% occur in females aged 13-19 y). The incidence of menstrual TSS has decreased since the discontinuation of hyperabsorbent tampon marketing. The annual incidence of streptococcal TSS is 5-10 cases per 100,000 population.

Staphylococcal TSS is common in people aged 15-35 years. More than 90% of cases in women occur in those aged 15-19 years. Streptococcal TSS is seen in all age groups; however, most cases occur in people aged 20-50 years.

Staphylococcal TSS is more common in females during menstruation. Nonmenstrual TSS is 3 times more common in females than in males. Streptococcal TSS affects males and females equally.

There are significant racial/ethnic, socioeconomic, and comorbid disparities in the incidence and mortality of TSS in adults and children in the USA.

In a recent analysis of 4491 hospitalizations with a diagnosis of TSS from the 2003-2012 Nationwide Inpatient Sample, TSS was associated with female sex (adjusted odds ratio [95% confidence interval], 1.54 [1.48-1.60]), younger age (0-17 years, 2.17 [2.06-2.29]; 40-59: 0.53 [0.50-0.56]; 60-79: 0.28 [0.26-0.30]; 80+: 0.13 [0.11-0.14] compared with 18-39) and race/ethnicity (black, 0.63 [0.59-0.67]; Hispanic: 0.60 [0.56-0.64]; Asian, 1.11 [1.00-1.11]; and other, 0.83 [0.75-0.92] compared with white)[8] .

Clinical Presentation of Pediatric TSS

Patient history

Staphylococcal toxic shock syndrome (TSS) is frequently seen in women during menstruation. More recently, with the decline in use of hyperabsorbent tampons, recognition of nonmenstrual TSS has been increasing. Sources of TSS include postsurgical wounds, postpartum, postabortion, burns, soft tissue injuries, pharyngitis, and focal infections. Several type of wounds, many appearing relatively benign, may harbor toxin-producing staphylococci. Thus, herniorrhaphy, mammoplasty, arthroscopy, and other surgical wound infections may be complicated by the development of TSS. Manifestations of the syndrome usually begin 2 days after surgery.

The onset of staphylococcal TSS is usually abrupt. Symptoms include fever, chills, myalgia, malaise, headache, sore throat, muscle tenderness, fatigue, vomiting, watery diarrhea, and abdominal discomfort. In a review of staphylococcal TSS by Davis and colleagues (1982), clinical findings included the following[9] :

Staphylococcal TSS associated with menstruation occurs more frequently in communities without a history of prior antibiotic exposure and is caused primarily by organisms that produce toxic shock syndrome toxin-1 (TSST-1). By contrast, nonmenstrual staphylococcal TSS is more common in hospitalized patients who have received prior antibiotic therapy; TSST-1 production is noted in only 50% of the patients. Enterotoxin B and C production is associated with the remainder of nonmenstrual staphylococcal TSS cases.

The onset of streptococcal TSS is typically abrupt as well. An influenzalike syndrome, consisting of fever, chills, myalgia, nausea, vomiting, and diarrhea, may be noted in 20% of patients.

Physical examination

In patients with staphylococcal TSS, rash, hypotension, and hyperemic conjunctival, pharyngeal, and vaginal mucosae are seen. Diffuse erythroderma, cyanosis, and edema of extremities may be noted. Desquamation, especially of the palms and soles, may follow (see the images below). Alteration in mental status may result in somnolence, agitation, disorientation, and obtundation.



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Desquamative erythroderma. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Cl....



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Strawberry tongue. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc.....

In patients with streptococcal TSS, fever is the most common early sign, although hypothermia may be present in patients with shock. Almost 50% of patients may have normal blood pressure (systolic pressure >110 mm Hg) upon admission but develop hypotension within the subsequent 4 hours. In virtually all patients, shock is apparent at the time of admission or within 4-8 hours. A diffuse scarlatina-like erythema occurs in only 10% of patients.

Soft tissue infection occurs in 80% of patients and may progress from localized swelling and erythema to necrotizing fasciitis (see the image below) or myositis in 70% of these patients. Pain is abrupt at onset and is usually preceded by tenderness or other localized physical findings.



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Necrotizing fasciitis. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin P....

Non–soft tissue infections occur in 20% of patients and may include endophthalmitis, myositis, perihepatitis, peritonitis, and myocarditis. Confusion (55% of patients), coma, or combativeness may be noted.

Complications

Complications of staphylococcal TSS include the following:

Complications of streptococcal TSS include the following:

Rarely, other complications may be noted, such as myocardial failure and pulmonary edema.

Diagnosis of Pediatric TSS

Diagnostic considerations

Staphylococcal toxic shock syndrome (TSS) is defined by the following criteria:

Clinical Criteria

  1. Fever: temperature ≥102.0°F (38.9°C)
  2. Rash: diffuse macular erythroderma
  3. Desquamation: 1-2 weeks after onset of rash
  4. Hypotension: systolic blood pressure ≤90 mm Hg for adults or less than fifth percentile by age for children aged less than 16 years
    • Gastrointestinal: vomiting or diarrhea at onset of illness
    • Muscular: severe myalgia or creatine phosphokinase level at least twice the upper limit of normal
    • Mucous membrane: vaginal, oropharyngeal, or conjunctival hyperemia
    • Renal: blood urea nitrogen or creatinine at least twice the upper limit of normal for laboratory or urinary sediment with pyuria (greater than or equal to 5 leukocytes per high-power field) in the absence of urinary tract infection
    • Hepatic: total bilirubin, alanine aminotransferase enzyme, or aspartate aminotransferase enzyme levels at least twice the upper limit of normal for laboratory
    • Hematologic: platelets less than 100,000/mm3
    • Central nervous system: disorientation or alterations in consciousness without focal neurologic signs when fever and hypotension are absent
     
     

Laboratory Criteria

The diagnosis of TSS is considered confirmed if the laboratory criteria are met and all five of the clinical criteria described above are present.

The diagnosis of TSS is considered probable if the laboratory criteria are met and four of five clinical criteria are met.

Streptococcal TSS is defined by the following criteria:

A: Isolation of group A streptococci

  1. From a sterile site, such as blood, cerebrospinal fluid (CSF), pleural fluid, peritoneal fluid, or a tissue biopsy specimen
  2. From a nonsterile body site, such as the throat, vagina, sputum, or superficial skin lesions

B: Clinical signs of severity

  1. Hypotension - In adults, systolic blood pressure lower than or equal to 90 mm Hg; in children, systolic blood pressure lower than the fifth percentile for age
  2. Clinical and abnormal laboratory test results (requires 2 or more of the following criteria):

See the list below:

The diagnosis of streptococcal TSS is definite when criteria A1, B1, and B2 are met. The diagnosis of streptococcal TSS is probable when criteria A2, B1, and B2 are met.

Note that failure to diagnose a mild case of TSS may result in legal liability.

Differentials

The differential diagnosis of pediatric TSS includes the following:

Other problems to be considered are as follows:

Laboratory Studies

Microbiologic studies should be performed to recover the organisms from appropriate samples, such as blood, surgical wounds, vagina, throat, or soft tissue aspirates.

In a review of staphylococcal toxic shock syndrome (TSS) by Davis and colleagues, the frequencies of abnormal laboratory results were as follows[9] :

Abnormal laboratory findings in patients with streptococcal TSS include the following:

Coagulation studies should be obtained, including prothrombin time, activated partial thromboplastin time, platelet count, fibrinogen split products, and D-dimer. Appropriate serologic analysis may be necessary to evaluate other possible differential diagnoses.

Other Studies

Imaging studies

Soft tissue radiography, computed tomography (CT) scanning, or magnetic resonance imaging (MRI) may help delineate the deeper tissue involvement in patients with necrotizing fasciitis and streptococcal toxic shock syndrome (TSS).

Lumbar puncture

If central nervous system infection (eg, meningitis) is possible, lumbar puncture should be performed to sample cerebrospinal fluid for analysis and culture as appropriate.

Histologic Findings

Histopathologic findings in patients with staphylococcal toxic shock syndrome (TSS) include desquamation of vaginal and cervical mucosa, periportal hepatic inflammation, acute tubular necrosis, and the abnormal pulmonary findings of acute respiratory distress syndrome (ARDS).

Treatment of Pediatric TSS

Medical care

TSS is a potentially deadly disease requiring prompt recognition and treatment. Focused history, physical examination, and laboratory testing are important for the diagnosis and management of this disease. The goal of medical therapy is to eradicate infection and to prevent complications. Seriously ill patients may require care in the intensive care unit (ICU), including dialysis for renal failure, ventilatory support for acute respiratory distress syndrome (ARDS), and correction of coagulopathy using plasma and blood products as necessary[10] .

The treatment regimen for staphylococcal toxic shock syndrome (TSS) includes the following:

The treatment regimen for streptococcal TSS includes administration of normal saline or colloids. Intractable hypotension that results from diffuse capillary leaking may require large amounts of these fluids. Albumin replacement may be necessary in patients in whom albumin levels drop lower than 2 g/dL. Vasopressor/inotrope infusion should be performed as necessary. Aggressive supportive care in an ICU is needed.

Penicillin should be given in conjunction with clindamycin for antibiotic treatment. Clindamycin therapy for streptococcal TSS produces better results than penicillin alone for the following reasons:

Some studies have suggested a salutary effect of IVIG therapy for streptococcal TSS. In one such comparative observational study of patients treated with IVIG, the mortality rate decreased to 34%, compared with a mortality rate of 67% in historical control subjects.[11] . In a Swedish surveillance study conducted between April 2002 and December 2004 concluded that IVIG contributed to a significantly improved survival in patients with streptococcal TSS[12] .A multicenter, retrospective, cohort study suggested that use of IVIG added to the cost of hospitalization but did not improve outcomes in streptococcal TSS.[13] . There is paucity of well-designed studies on the use of Intravenous immunoglobulin (IVIG) for the treatment of TSS. The use of IVIG for its treatment remains controversial[14] . In the future, double-blind trials may further clarify the role of IGIV in streptococcal TSS.[15, 16] .

Early recognition of TSS, intensive care management, which includes the use of adjunctive therapy with intravenous immunoglobulin and clindamycin[17] . The role of hyperbaric oxygen in streptococcal TSS remains uncertain in the absence of any comparative clinical trials.

Surgical care

Prompt surgical debridement of any necrotizing skin lesion, such as may be seen in patients with necrotizing fasciitis and streptococcal TSS, is mandatory. Failure to debride necrotic tissue promptly may lead to poor outcome.

Any tampons or other implicated foreign materials present in patients with staphylococcal TSS should be removed. Failure to do so may cause legal liability.

Consultations

Appropriate consultations include an infectious diseases specialist; a surgeon, if debridement is considered; and other specialists and subspecialists, as the clinical situation dictates.

Further inpatient care

Patients with TSS should be transferred to the ICU for closer observation and aggressive therapy for hypotension and other complications.[18] Patients with ARDS may require ventilatory support. Those with severe renal failure may require dialysis.

Deterrence/prevention

Scrupulous wound care and appropriate early treatment of wounds should minimize TSS as a complication of staphylococcal and streptococcal infections. Effective antistaphylococcal therapy for staphylococcal TSS decreases recurrence.

Female patients with staphylococcal TSS should be warned against the use of tampons. Use of other intravaginal devices should be avoided in patients with TSS.

Active immunization with a TSST-1 vaccine is under investigation. In a phase II trial to assess the safety, tolerability, and immunogenicity of a recombinant detoxified toxic shock syndrome toxin-1 variant (rTSST-1v) vaccine in adult volunteers the vaccin was safe, well-tolerated, and immunogenic.[19] This is an important step in vaccine development to prevent TSS. 

Prognosis of Pediatric TSS

The vast majority of patients with staphylococcal toxic shock syndrome (TSS) recover uneventfully. Since the discontinuation of hyperabsorbent tampon marketing, the mortality rate, already low, has declined from 5.6% to 3.3%. Staphylococcal toxic shock syndrome can recur, particularly in the absence of antistaphylococcal therapy and with continued use of tampons. Neuropsychiatric manifestations, such as memory loss and lack of concentration, may persist in some patients.

Compared with non-TSS septic shock, TSS has significantly lower fatality rates, disease severity, and length of hospital stay[20] . In a recent study of TSS, predictors of in-hospital mortality included respiratory failure (13.66 [11.37-16.43]), liver disease/failure (3.36 [2.59-4.34]), chickenpox (91.26 [27.74-300.25]), coagulopathy (2.14 [1.85-2.48]), and higher age[8] . Streptococcal TSS is associated with poorer outcomes than staphylococcal TSS[20] . The mortality rate  in streptococcal TSS is 30%.

Author

Vinod K Dhawan, MD, FACP, FRCPC, FIDSA, Professor, Department of Clinical Medicine, University of California, Los Angeles, David Geffen School of Medicine; Chief, Division of Infectious Diseases, Rancho Los Amigos National Rehabilitation Center

Disclosure: Nothing to disclose.

Specialty Editors

Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Larry I Lutwick, MD, FACP, Editor-in-Chief, ID Cases; Moderator, Program for Monitoring Emerging Diseases; Adjunct Professor of Medicine, State University of New York Downstate College of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation

Disclosure: Nothing to disclose.

References

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Desquamative erythroderma. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Strawberry tongue. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Necrotizing fasciitis. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Desquamative erythroderma. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Necrotizing fasciitis. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Strawberry tongue. Reproduced with permission from Drage, LE. Life-threatening rashes: dermatologic signs of four infectious diseases. Mayo Clin Proc. 1999;74:68-72.

Findings Staphylococcal Toxic Shock Syndrome Streptococcal Toxic Shock Syndrome
Age15-35 y20-50 y
SexMore common in femalesMales and females
Local invasive diseaseAbsentPresent
Generalized erythrodermaPresentAbsent
Nausea, vomiting, or diarrhea>90% of patientsUncommon
BacteremiaUncommon60% of patients
Toxins implicatedTSST-1; enterotoxins B and CStreptococcal pyrogenic exotoxins A and B
Mortality rate3.3%30%