Hospital Medicine

Toxic shock syndrome

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Toxic Shock Syndrome

I. What every physician needs to know.

Toxic shock syndrome (TSS) is a life-threatening acute illness resulting from bacterial exotoxins, which act as superantigens to produce an overwhelming cytokine release throughout the body. The ensuing inflammatory response is responsible for systemic shock and multi-organ failure.

Although classic staphylococcus TSS is known for its association with menstruation and tampon use, almost half of all staphylococcal TSS is due to non-menstrual causes. Most staphylococcal TSS, especially menstruation-related, is due to the exotoxin Toxic Shock Syndrom Toxin 1 (TSST-1) produced by Staphylococcus aureus. Although most individuals have acquired the antibody to TSST-1 by young adulthood, those who do not have the antibody are susceptible to disease.

Additional staphylococcal enterotoxins exist and are thought to be responsible for the remainder of cases of staphylococcal TSS. Non-menstrual cases are most commonly associated with postpartum and surgical wounds, but other staphylococcal infections (e.g., abscess, rhinosinusitis,, osteomyelitis, gastrointestinal and respiratory infections) and nonsurgical wounds (such as burns and insect bites) have also been implicated.

Group A streptococcal (GAS) infection may also lead to TSS, most commonly in association with a skin, vaginal, or pharyngeal site of entry. Streptococcus pyogenes produces various virulence factors that determine the pathogenesis and invasiveness of the bacteria, including those known as M-proteins, several of which are thought to be specific for GAS toxic shock syndrome. Less commonly, GAS TSS may result from invasive infections, such as pneumonia or septic arthritis.

Lastly, TSS is rarely caused by other toxin producing bacteria such as the anaerobic gram positive bacillus Clostridium sordellii(CS). Clostridium species are often associated with the female reproductive tract as non-virulent colonizers of the vagina. They may, however, lead to TSS following spontaneous or medical abortion, childbirth, or menstruation.

II. Diagnostic Confirmation: Are you sure your patient has toxic shock Syndrome?

Diagnostic confirmation is difficult to achieve early in the course of TSS; thus, a high degree of suspicion is necessary to make this clinical diagnosis. There is no confirmatory testing; rather, the diagnosis is made in the presence of the appropriate clinical features discussed in the following section

A. History Part I: Pattern Recognition

The diagnosis of TSS should be considered in a patient presenting with fevers, erythroderma, and hypotension. Patients with Staphylococcal TSS may additionally present with nonspecific complaints such as malaise, myalgias, nausea, vomiting, diarrhea, and headache. These symptoms may be mistakenly attributed to a viral syndrome; however, the disease progresses rapidly following initial presentation. The characteristic clinical feature of diffuse erythroderma should prompt consideration of potential TSS. This rash presents with an erythematous, macular, sunburn-like appearance inclusive of the palms and soles, with injection and hyperemia of mucous membranes. Skin manifestations can vary from mild to severe and may be (but are not always) more pronounced around the site of inoculation. Appropriate menstrual or surgical history may also prompt a provider to consider this diagnosis.

At least three of the following systems must be involved to meet the clinical criteria of the Centers for Disease Control and Prevention: gastrointestinal, muscular, skin and mucous membrane, renal, hepatic, hematologic, and central nervous system. Renal, hepatic, and hematologic dysfunction, if present, is apparent on laboratory testing (see section IIE below). Altered mental status without a focal neurologic finding on exam is characteristic of central nervous system manifestations. The clinical course can also be complicated by respiratory and cardiac dysfunction, though these are not disease-specific.

Menstruation-related cases usually demonstrate symptoms within the first few days of the onset of menses.Patients with post-surgical TSS, similarly, develop symptoms by the second postoperative day in most cases. Rarely, staphylococcal TSS may present several weeks following surgery. Late symptoms and complications of TSS include desquamation of the palms and soles, which occurs about 1 to 2 weeks after onset of symptoms, and temporary loss of hair and nails about 1 to 2 months after the acute illness.

The clinical presentation of Group A Strep (GAS) TSS is not unlike staphylococcal TSS. As with staphylococcal TSS, nonspecific flu-like symptoms and erythroderma can be seen. However, classically, the patient has fever and severe soft tissue pain preceding physical exam findings and out of proportion to any recent trauma that may have been sustained. Evidence of cellulitis, myositis, and even necrotizing fasciitis occur with GAS TSS.

For a definitive diagnosis of GAS TSS, positive cultures must be recovered from a normally sterile site and associated with hypotension and evidence of diffuse systemic involvement (two or more of the following: renal impairment, coagulopathy, hepatic dysfunction, acute respiratory distress syndrome, rash, or soft tissue necrosis). GAS cultured from typically nonsterile sites with associated symptoms should be managed similarly, but strictly speaking, can only be formally defined as probable cases of GAS TSS.

Patients with CS TSS present with similar nonspecific flu-like symptoms which rapidly progress to shock usually within a week after child delivery, abortion, menstruation, or gynecologic procedures.

B. History Part 2: Epidemiology

Menstrual cases of staphylococcal TSS were most prevalent in the early 1980s. Rates have decreased since that time, primarily due to the discontinuation of the super-absorbent and polyacrylate tampons and public awareness campaigns. According to the CDC, the rate of TSS in 1980 was 6-12 per 100,000 women of menstruating age. In 1979-1980, 91% of TSS cases were menstruation-related. Since that time, both the incidence and menstruation-related proportion of cases have decreased. The current incident rate of staphylococcal TSS is thought to be about 0.5-4 per 100,000 people per year.

Risk factors for staphylococcal TSS include the use of tampons (higher risk with higher absorbency and length of use), certain barrier contraceptives (e.g., sponges, cervical caps, and diaphragms), nasal packing, surgery, and gynecologic procedures.

The incidence of invasive GAS infections has been reported as high as about 5 cases per 100,000 people annually. Only a fraction of these (about 10%) met criteria for TSS.

CS TSS is extremely rare. Only a small number of cases have been reported.

C. History Part 3: Competing diagnoses that can mimic Toxic Shock Syndrome.

Heat Stroke:

Patients have a reported history of sun exposure. Symptoms include fever, erythematous “rash” (sunburn), altered mental status, hypotension, tachycardia, and renal impairment.

Kawasaki Disease:

This disease is usually seen in children less than 5 years of age. Symptoms include fever, mucositis with conjunctivitis, rash, lymphadenopathy, edema, and coronary artery aneurysms. The rash is erythematous and nonspecific, and begins about 5 days after fever onset.

Leptospirosis:

Symptoms begin 2-28 days after contact with water contaminated by infected animals and include fever, myalgias, gastrointestinal symptoms, headache, conjunctivitis, and frequently an erythematous rash.

Meningococcemia:

The related rash is petechial and purpuric in nature.

Rocky Mountain Spotted Fever:

There is a 2-14 day incubation period after an infected tick bite. Ninety percent of patients develop a rash. The rash begins as erythematous macules on the extremities 2- 5 days after fever onset, then spreads to the trunk. Palms and soles may be involved, as well. On around the sixth day of symptoms, the classic petechial rash manifests.

Scarlet Fever:

Symptoms include sore throat, “strawberry” tongue, and rash. The rash begins 12-48 hours after fever onset and is erythematous, rough (“sandpaper”-like), and diffuse in character.

Septic shock:

Infections due to nontoxin-producing gram-positive or gram-negative bacteria.

Staphylococcal food poisoning:

An associated rash is not typical.

Typhoid:

Infection is associated with travel to endemic areas in unvaccinated patients. Along with fever and gastroenteritis, an erythematous spotted rash on the trunk can be seen. There is a long course of symptoms, lasting several weeks in duration.

Various other febrile mucocutaneous diseases such as measles, systemic lupus erythematosus, and viral syndromes are also often in the initial differential diagnosis.

D. Physical Examination Findings.

In TSS, as with all distributive shock, physical exam findings consistent with increased cardiac output and decreased systemic vascular resistance are evident – warm extremities with skin mottling and slow capillary refill, prior to isotonic fluid resuscitation.

The classic erythroderma associated with staphylococcal TSS is a macular, erythematous, diffuse rash resembling a sunburn. However, symptoms can range from mild to more extreme presentations with vesicles and bullae. If there is associated disseminated intravascular coagulation, petechiae can be present as well. Wound-related staphylococcal TSS may demonstrate local inflammation or appear intact. Management with wound irrigation remains the same, however.

In menstruating women, examination should be performed to evaluate for retained tampon material.

Similarly, soft tissue infections associated with GAS TSS can vary in presentation. Physical exam findings can range from minimal to no physical exam findings, to localized erythema and edema, to severe cases with darker discolorations, bullae, crepitus, sloughing, and necrosis.

In CS TSS, the resultant generalized edema is a severe, defining feature. However, unlike other toxic shock syndromes, fever and rash are not typical.

E. What diagnostic tests should be performed?

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

In staphylococcal TSS, a complete blood count with differential may show a shift toward neutrophilia and increased production of immature band forms. There is often, but not always, a leukocytosis and thrombocytopenia. A basic metabolic panel should be checked to reveal any metabolic acidosis and renal failure. Abnormal liver function tests with elevated liver transaminases and hypoalbuminemia are common during the acute illness. Creatine phosphokinase levels should be monitored as significant muscle injury with subsequent rhabdomyolysis can occur. Blood cultures should be sent but are only rarely positive for staphylococcal bacteremia in staphylococcal TSS. Cultures of wounds and mucous membranes should be taken if a source of infection is suspected and, unlike blood cultures, are positive in up to 90% of staphylococcal TSS cases. As in all cases of distributive shock, serum lactate is a useful prognostic indicator and marker of the adequacy of volume resuscitation and infectious source control.

In GAS TSS, laboratory findings will similarly show multi-organ involvement and dysfunction. However, blood cultures are positive in more than half of cases. When myositis is present, associated rhabdomyolysis and renal failure is common.

In CS TSS, profound leukemoid reactions, with white blood cell counts greater than 100,000 cells/microliter, have been reported.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Imaging should be targedidentifying the source of infection and may include chest radiograph, ultrasound of a skin and soft tissue site, and computed tomography of the extremity, chest, or abdomen

F. Over-utilized or “wasted” diagnostic tests associated with this diagnosis.

Although over-utilized testing is not commonly associated with this diagnosis, we do place emphasis on the importance of early empiric treatment in suspected cases, as discussed later. Treatment should not be delayed while confirmatory testing is obtained, and a high clinical suspicion is paramount.

III. Default Management.

Usual care for septic shock is advised. Aggressive fluid resuscitation should be undertaken early, with 20-30 cc/kg of isotonic fluid given initially. Serial lactate measurements, central venous oxygen saturation, if available, and clinical assessment of volume status can assist with determining the adequacy of resuscitation. Appropriate cultures should be obtained prior to administration of antibiotics, although treatment should not be withheld if there is delay in obtaining cultures.

Tampons should be removed and the vagina irrigated in menstrual-related TSS. Similarly, surgical wounds should be cultured, explored, and irrigated. Surgical evaluation should be requested as appropriate. In the case of pelvic-associated TSS (tampon-associated, IUD use, PID, postpartum, postoperative, etc), an obstetric and gynecologic specialist should be involved as soon as possible.

Antibiotics should be started within the first hour of presentation and continued for 10-14 days to help decrease toxin release and, importantly, disease recurrence. If there is a concern for other etiologies of septic shock, empiric broad-spectrum antibiotics should be chosen. However, the initial antibiotic regimen chosen for suspected staphylococcal TSS is intravenous clindamycin plus vancomycin for coverage of both methicillin-resistant (MRSA) and methicillin-susceptible (MSSA) Staphylococcus aureus. Clindamycin is chosen as a first-line agent because it inhibits bacterial protein synthesis, unlike the cell-wall inhibition of beta-lactams. Clindamycin is effective against toxin-production and with large bacterial toxin burdens. Linezolid can be used in place of clindamycin if the patient is allergic. For confirmed MSSA infection, therapy with vancomycin should be switched to nafcillin, as this is the preferred therapy, and clindamycin should be continued. If the patient is penicillin-allergic but cephalosporin-tolerant, cefazolin is used in lieu of nafcillin for MSSA treatment. In difficult to manage patients where improvement is refractory to standard management, the use of intravenous immunoglobulin can be considered. An infectious diseases consultant should provide guidance.

Management of GAS TSS is similar in that cardiovascular and organ failure support, antibiotics, and early surgical debridement of any wounds or infected tissues are the cornerstones of treatment. Empirically, broad spectrum antibiotics, including a beta-lactam antibiotic, should be given intravenously to cover undifferentiated septic shock. If there is any suspicion for a GAS toxin-mediated shock syndrome, clindamycin should also be empirically prescribed for its appropriate coverage of streptococcal infections and protein-synthesis inhibiting action. Antibiotics can be narrowed to penicillin in conjunction with clindamycin once the diagnosis of GAS is confirmed. The duration of antibiotics is at least 10-14 days (depending on the primary infection), but may be longer depending on timing of culture clearance and clinical improvement. Intravenous immunoglobulin therapy should be considered as well, and an infectious diseases consultant should guide this management.

Diagnosis and treatment of Clostridium TSS is similar to other TSSs, consisting of early antibiotics, culture and debridement of infected sites, aggressive cardiovascular resuscitation, and monitoring and management of the ensuing multi-organ dysfunction. Again, empiric antibiotics with appropriate broad-spectrum coverage for septic shock should be given early. Clindamycin, as with other toxic shock syndromes, is crucial in reducing toxin production and should be included in initial choice of antibiotics. Antibiotics can be narrowed to clindamycin and penicillin once the diagnosis of CS TSS is confirmed.

Standard infection control precautions are implemented in MSSA related cases. Contact precautions should be assigned to patients with MRSA, clostridium, or wound-related cases.

A. Immediate management.

Empiric antibiotics, including clindamycin, and isotonic fluid resuscitation should be given immediately upon recognition of severe sepsis or septic shock.

B. Physical Examination Tips to Guide Management.

Standard cardiovascular goals (i.e., mean arterial blood pressure >65, urine output, central venous oxygen saturation) should guide resuscitation. Intensive care unit (ICU) level monitoring is indicated initially until vital signs, labs (end organ damage), and mental status are stabilized (See Septic Shock chapter)..

C. Laboratory Tests to Monitor Response to, and Adjustments in, Management.

Standard tests to monitor vital signs and end organ function should guide management. Dialysis and ventilator support may be required (See Septic Shock chapter).

D. Long-term management.

There is no specific long-term management.

E. Common Pitfalls and Side-Effects of Management.

  1. Even wounds that do not appear classically infected can be implicated in TSS and therefore need to be investigated.

  2. Complete the 10-14 day antibiotic course to help prevent recurrence of staph TSS.

IV. Management with Co-Morbidities.

See Septic Shock chapter.

A. Renal Insufficiency.

No change in standard management.

B. Liver Insufficiency.

No change in standard management.

C. Systolic and Diastolic Heart Failure.

No change in standard management.

D. Coronary Artery Disease or Peripheral Vascular Disease.

No change in standard management.

E. Diabetes or other Endocrine issues.

No change in standard management.

F. Malignancy.

No change in standard management.

G. Immunosuppression (HIV, chronic steroids, etc).

No change in standard management.

H. Primary Lung Disease (COPD, Asthma, ILD).

No change in standard management.

I. Gastrointestinal or Nutrition Issues.

No change in standard management.

J. Hematologic or Coagulation Issues.

No change in standard management.

K. Dementia or Psychiatric Illness/Treatment.

No change in standard management.

V. Transitions of Care.

A. Sign-out considerations While Hospitalized.

Cardiovascular monitoring guidelines should be stressed (See Septic Shock chapter).

B. Anticipated Length of Stay.

The length of stay can vary greatly depending on end-organ damage and complications that result.

C. When is the Patient Ready for Discharge.

Patients are typically ready for discharge once vital signs and mental status have been stable for over 48 hours, end-organ damage is improved and stabilized, and oral antibiotics can be tolerated. The patient should not be transitioned to oral antibiotics unless there is good gastrointestinal function and absorption, the temperature has normalized, hemodynamics are stable, and cultures are negative (See Septic Shock chapter).

D. Arranging for Clinic Follow-up.

1. When should clinic follow up be arranged and with whom?

Patients should have outpatient follow-up within a week after discharge to ensure organ function is stable, the antibiotic course is being completed in full, and to evaluate the desquamation that by definition ensues in staphylococcal TSS and may also occur in GAS TSS. Electrolytes, renal function, liver function tests, and complete blood count should be repeated. Follow-up with an infectious diseases specialist is reasonable when nearing the end of or after completion of antibiotics.

2. What tests should be conducted prior to discharge to enable best clinic first visit?

N/A

3. What tests should be ordered as an outpatient prior to, or on the day of, the clinic visit?

N/A

E. Placement Considerations.

N/A

F. Prognosis and Patient Counseling.

Mortality from menstrual TSS has improved over time with most recently reported rates of about 2%. There is about a 5% mortality rate in nonmenstrual staphylococcal TSS.

Mortality is higher in GAS TSS, reportedly ranging from 30-70%. Prognostic indicators are based on severity of disease at presentation as evidenced by lab and vital sign abnormalities.

Survivors of all ICU stays, and particularly those involving prolonged mechanical ventilation, pharmacologic sedation, and delirium, are at risk of developing post-intensive care syndrome (PICS). This syndrome is characterized by new or worsened cognitive, psychiatric, or physical disability after an ICU stay. Patients should be aware of the challenges of recovery, and education from providers prior to discharge is beneficial.

CS TSS carries an even greater mortality burden and is mostly fatal.

VI. Patient Safety and Quality Measures.

A. Core Indicator Standards and Documentation.

N/A

B. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Discuss signs and symptoms of TSS with menstruating patients. Advise women to use the lowest absorbency tampon possible and to change tampons frequently (at least every 8 hours, but preferably more often).

Patients who have had staphylococcal TSS are at risk for recurrence. They are advised not to use tampons and to complete the full course of antibiotics to help prevent recurrence. Intrauterine device use is also a risk factor for recurrence.

VII. What's the Evidence?

Lappin, E, Ferguson, AJ. "Gram-positive toxic shock syndromes". Lancet Infect Dis. vol. 9. 2009. pp. 281-90.

Aldape, MJ, Bryant, AE, Stevens, DL. "Clostridium sordelliiinfection: epidemiology, clinical findings, and current perspectives on diagnosis and treatment". Clin Infect Dis. vol. 43. 2006. pp. 1436-46.

Stevens, DL, Bisno, AL, Chambers, HF. "Executive summary: practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America". Clin Infect Dis. vol. 59. 2014. pp. 147-59.

Rivers, E, Nguyen, B, Havstad, S. "Early goal-directed therapy in the treatment of severe sepsis and septic shock". N Engl J Med. vol. 345. 2001. pp. 1368-77.

Angus, DC, Yealy, DM, Kellum, JA. "Protocol-based care for early septic shock". N Engl J Med. vol. 371. 2014. pp. 386.

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