CBRNE - Staphylococcal Enterotoxin B 

Updated: Jan 27, 2021
Author: Bruce A Gleason, MD; Chief Editor: Duane C Caneva, MD, MSc 

Overview

Background

Toxins are poisons produced by living organisms. Staphylococcal enterotoxin B (SEB) is an exotoxin excreted by the Staphylococcus aureus bacterium. Staphylococcus species thrive and produce toxins in unrefrigerated meats, dairy, and bakery products. S aureus is also a major human pathogen responsible for numerous infections, including skin and soft tissue infections and pneumonia.

The SEB this article is concerned about normally exerts its effect on the intestines and is therefore termed an enterotoxin. More recent research has identified additional superantigens that have been subclassified into enterotoxin serotypes and enterotoxin-like serotypes. Although staphylococcal enterotoxins A, B, and C (SEA, SEB, SEC) and toxic shock syndrome toxin–1 are now believed to all be responsible for clinically significant toxic shock in humans, SEB remains the prototypical superantigen.  Not all toxins result in a lethal outcome, but they may cause significant morbidity.[1, 2, 3]

SEB is the toxin most commonly associated with classic food poisoning.[1, 4, 5] It has also been demonstrated to cause a nonmenstrual toxic shock syndrome (TSS).[6]  Researchers have implicated SEB in the pathophysiology of chronic atopic dermatitis, chronic rhinitis, and ulcerative colitis.[7]

SEB has been studied as a potential biological warfare agent because it can easily be aerosolized; it is very stable; and it can cause widespread systemic damage, multiorgan system failure, and even shock and death when inhaled at very high dosages. However, SEB is classified as an incapacitating agent because in most cases aerosol exposure does not result in death but in a temporary, though profoundly incapacitating, illness lasting as long as 2 weeks.[8]

Source

SEB is 1 of 7 originally identified enterotoxins produced by certain strains of coagulase-positive S aureus, a gram-positive coccus that forms clumps. S aureus is known to colonize the nasal passages and axillae in humans. Research has elucidated the structures of numerous enterotoxin-like superantigens, with two new enterotoxins, now known as SES and SET, discovered in 2008.[9, 10, 11]

Structure

SEB consists of 239 amino acid residues and has a molecular weight of 28 kd. It is 1 of the 7 least antigenically distinct enterotoxin proteins that have been identified (A, B, C, D, E, I, and toxic shock syndrome toxin–1). SEB has 2 distinct tightly "packed" domains that have a very complex tertiary structure. This compact structure enables SEB to be highly resistant to proteases, including trypsin, chymotrypsin, and papain, which are all found in the intestinal lumen.

Properties

SEB is a relatively stable compound that is easily soluble in water. It is moderately resistant to temperature fluctuations and can withstand boiling at 100º C for several minutes. In the freeze-dried state, SEB can be stored for more than a year. For aerosol exposures, the effective dose, or ED50 (dose capable of incapacitating 50% of the exposed human population), is 0.0004 mcg/kg of body weight, and the lethal dose, or LD50, is 0.02 mcg/kg.[12]

Pathophysiology

Mechanism of toxicity

Many of the effects of staphylococcal enterotoxin B (SEB) are mediated stimulation of T lymphocytes by the host's immune system.[13] The toxin binds directly to the major histocompatability complex (MHC) class II proteins on target cells, subsequently stimulating the proliferation of large numbers of T lymphocytes. SEB is a "bacterial superantigen" because it can form a "bridge" between the MHC II on the antigen-presenting cells and the T-cell receptors on both CD4 and CD8 T cells, thereby bypassing the normal antigen processing and presenting mechanism. This bridging effect causes the release of massive amounts of cytokines, specifically interleukin 2 (IL-2), tumor necrosis factor alpha (TNF-α), and interferons.

The cytokines cause a recruitment of additional inflammatory cells. In addition, there is a relative deficient activation of negative counter-regulatory feedback loops. Taken together, the body's own inflammatory response most likely mediates many of the toxic effects of SEB.

Ingestion of SEB produces profound gastrointestinal (GI) symptoms, including anorexia, nausea, vomiting, and diarrhea, which are believed to be mediated through the release of cytokines from T cells in the lamina propria of the intestines. Animal studies have shown that the severe pulmonary edema associated with aerosol exposure is likely secondary to T-cell proliferation within the respiratory mucosa and not the toxin itself.[2, 8, 14]

SEB has been studied in multiple animal models over the past 40 years. Some of the most recent studies in rabbits and pigs, like others in the past, involve direct inoculation with intravenous administration of SEB. In these studies, GI symptoms began as early as 4 hours post injection followed by terminal shock at 96 hours.[15]

Epidemiology

Frequency

United States

The actual incidence of SEB-related food poisoning is unknown; many cases are so mild that patients do not seek treatment. Additionally, diagnoses in the emergency department are usually presumptive, and a number of other diseases may mimic SEB-induced gastroenteritis.

Mortality/Morbidity

The gastrointestinal form of staphylococcal enterotoxin B (SEB) toxicity, while potentially debilitating for short durations, is rarely fatal with adequate hydration.

No relevant aggregate data are available regarding the mortality and morbidity of inhalational SEB exposure.

Updated CDC search revealed a report from the Minnesota Department of Health in 1986 where six cases of toxic shock syndrome were reported after infection with influenza B.  Two of the six died; four patients were identified after two initial cases were reported, of those four only one developed erythroderma (rash), and three of the four eventually desquamated. 

Age

Very young and elderly persons are likely the most susceptible to a complicated course.

 

Presentation

History

Historical clues are important in diagnosing enterotoxin-induced gastroenteritis.

  • After either gastrointestinal or inhalational exposure, a nonspecific flulike illness may develop, with symptoms to include myalgias, headache, chills, and fever.

  • GI symptoms start within several hours (typically 4-7) of ingestion of contaminated foods, beginning with significant nausea, vomiting, and intestinal cramping, followed by urgency and profuse watery nonbloody diarrhea. Symptoms normally resolve within 12-24 hours. Multiple family members or patrons of the same eating establishment may be affected.

Ingestion of staphylococcal enterotoxin B (SEB) that is produced and excreted by Staphylococcus aureus in improperly refrigerated, stored, and handled foodstuffs results in food poisoning[16] :

  • The incubation period is 3-12 hours (rarely up to 18 h) after ingestion.

  • Classic symptoms are an abrupt onset of intense nausea, vomiting, cramping abdominal pain, and diarrhea, which incapacitate the patient.

  • Most cases are self-limited and resolve in 8-24 hours.

Inhalation of SEB does not occur in the natural setting and should be considered a result of an intentional event.[2, 17]

  • After respiratory exposure to aerosolized SEB, the clinician would most likely be presented with numerous patients of all ages within a short period of time (most likely within 1-6 h of an exposure) who were exposed at a common location and developed respiratory difficulty. Because of the difficulties in obtaining large quantities of the toxin and difficulty in efficient dispersion as an open-air aerosol, this location most likely would be an enclosed space, such as a gymnasium, arena, or office building.

  • Symptom onset after inhaling SEB may vary from 3-12 hours. Sudden onset of headache, fever, myalgia, nonproductive cough, chills, shortness of breath, and retrosternal pain can be caused by SEB at low doses via inhalation.

  • Respiratory symptoms may include dyspnea, nonproductive cough, and retrosternal chest pain. Disease may progress with increasing respiratory distress, hypoxia, and ultimately respiratory failure depending on the degree of systemic inflammation and resulting pulmonary edema.

  • Fevers can range from 103º-106ºF and may last up to 5 days.

  • The cough may last up to 4 weeks.

  • Vital signs should be followed closely in order to monitor for signs of multiorgan failure.

  • Inhalational exposure to higher levels of SEB may lead to septic shock and death.

Animal experiments in mice have shown that SEB can lead to symptoms after intranasal and conjunctival exposure. Ocular exposure is associated with conjunctivitis and periorbital edema. These two exposure routes can also lead to systemic activation of the immune system. The clinical significance in humans is unknown.[17, 18]

Physical

Physical examination in staphylococcal enterotoxin B (SEB) intoxication may be unremarkable, but, most likely, the patient presents with complaints of acute onset and either appears in significant diffuse crampy abdominal pain or acutely short of breath. Generally speaking SEB intoxication manifests as fever, vomiting, myalgias, diarrhea, headache, and in severe cases toxic shock.[8, 16]

Gastrointestinal exposure

If the route of entry of the toxin is GI, patients may appear dehydrated, depending on the severity of nausea and vomiting, and often complain of acute abdominal cramping and watery, nonbloody diarrhea.

Physical examination may reveal hypotension, tachycardia, hyperperistalsis, and diffuse nonlocalizing abdominal pain. Any stool or diarrhea is hemoglobin negative, barring other pathology.

Inhalational exposure

In inhalation of aerosolized SEB, patients are acutely and significantly short of breath and complain of severe substernal chest pain. Examination, however, usually reveals clear lung fields with no evidence of consolidation or effusion. Other than a reflexive tachycardia, which is likely to be seen, cardiac examination is normal.[19]

With significant inhalational exposure, the patient may display pulmonary edema or signs and symptoms consistent with acute respiratory distress syndrome (ARDS).

Most patients also have a fever up to 103o -106o F if significant pulmonary involvement has occurred.

Causes

The vast majority of community-acquired cases result from improper handling of food or by coughing or sneezing during food prepartion and handling.  S aureus grows rapidly and secretes enterotoxins, especially in cream, mayonnaise, unrefrigerated meats, dairy, and bakery products.

After toxin is produced in improperly refrigerated, stored, and handled foodstuffs, ingestion of staphylococcal enterotoxin B (SEB) causes food poisoning. Inhalational exposure would most likely be related to a terrorist or biologic warfare event. Case reports have documented intranasal exposure secondary to nasal packing after surgical procedure,s as S aureus does colonize the nasal passages.

 

DDx

 

Workup

Laboratory Studies

See the list below:

  • Although staphylococcal enterotoxin B (SEB) can be confirmed through enzyme-linked immunosorbent assay, by rapid fluorescence-based immunoassays of tissue or body fluids, diagnosis is largely clinical and by epidemiologic factors rather than by assays of tissue or body fluids.[20]

  • Neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate may be observed in SEB intoxication.

  • Toxin may be identified in nasal swabs from persons exposed to respiratory aerosol within the preceding 12-24 hours, offering an avenue of early diagnosis in the battlefield.

  • Rabbit studies have shown that accumulation of SEB in the serum is transient but is detectable in the urine for up to several hours after exposure. Urine samples should be collected for testing.[21]

  • Most patients develop a significant antibody response to SEB and acute and convalescent sera should be drawn for retrospective analysis and possibly diagnosis.

Imaging Studies

See the list below:

  • Radiographs of the chest appear normal unless the patient has had significant aerosolized exposure, in which case pulmonary edema or an ARDS presentation is evident.

  • Routine abdominal films for SEB gastroenteritis are not necessary but may exhibit significant intestinal gas with no free air.

 

Treatment

Approach Considerations

Treatment of staphylococcal enterotoxin B (SEB) illness is supportive:

  • In the event of dehydration, vigorous administration of intravenous fluids is indicated.

  • For patients exposed via inhalation, supportive treatment with humidified oxygen may be all that is necessary, although significant exposure may dictate intubation and assisted ventilation with high oxygen concentrations.

  • The efficacy of steroids in SEB-induced pulmonary edema or acute respiratory distress syndrome (ARDS) has not been demonstrated.

Emergency Department Care

Treatment of staphylococcal enterotoxin B (SEB) illness is limited to supportive care, with special attention to elimination of hypotension and hypoxia and pain control as needed.[2, 22]  Options are as follows:

  • Cough suppressants and acetaminophen for fever will make the patient more comfortable.
  • Antiemetics should be provided for nausea in food poisoning as necessary.
  • Mechanical ventilation may be required in severe cases.
  • Vasopressors and diuretics may be required in severe cases.
  • Antibiotics have not demonstrated efficacy in SEB intoxication, and steroids have not been shown to be effective in SEB-induced pulmonary edema.
  • The mainstay of treatment should be directed towards sepsis and septic shock.
  • Dexamethasone, or even doxycycline, may have a role as adjunctive therapy; both have been shown, in in vitro and mice studies, to downregulate the cytokine response during infection with SEB. [23, 24]

Consultations

Consultations are dictated by the patient's physiologic condition, as follows:

  • If a terrorist attack using SEB is suspected, expeditiously inform local law enforcement personnel, including the local Federal Bureau of Investigation.

  • In the event that a cluster of patients present with similar symptoms, either of pulmonary or GI origin, notify local public health officials to begin epidemiologic investigation.

 

Follow-up

Further Inpatient Care

See the list below:

  • Disposition is dictated by the patient's condition after appropriate observation in the ED. In general, patients who are asymptomatic at rest with no shortness of breath, tolerable chest discomfort, and no progression of symptoms may be discharged home with appropriate follow-up instructions, including a caution to avoid any exertion for at least 24 hours.

  • Patients with continued vomiting who are unable to maintain their own hydration or those with significant dehydration require admission to at least an observation unit.

Deterrence/Prevention

See the list below:

  • Food-borne staphylococcal enterotoxin B (SEB) can be prevented by proper storage of dairy products and proper storage and preparation of meat products.

  • Any contaminated food should be destroyed.

  • SEB is not dermally active and can be removed from surfaces/skin with standard soap and water (ie, good handwashing).

  • Secondary aerosol exposure of SEB from infected patients is unlikely to be a hazard.

Prognosis

See the list below:

  • Prognosis with appropriate treatment is excellent in both food-borne and inhalation staphylococcal enterotoxin B (SEB).

  • Some respiratory symptoms, including nonproductive cough, may persist for up to 4 weeks.

  • Severe inhalational cases may result in death from pulmonary edema and respiratory failure.

Patient Education

Dairy products must be stored properly, and meat products must be stored and prepared properly.

For patient education information, see the First Aid and Injuries Center, as well as Biological Warfare and Personal Protective Equipment.

Special considerations

No human vaccine against staphylococcal enterotoxin B (SEB) is currently available. Use protective masks if the use of SEB in biological warfare is threatened.

SEB toxoid is a poor mucosal immunogen and efforts at traditional formalin-inactivated toxoid-based vaccines have been abandoned in favor of recombinant, site-directed attenuated mutants. Several of these new vaccine candidates are in development.[25]

Experimental use of passive immunotherapy can reduce mortality in animals but only if administered within 4-8 hours of inhalational exposure. Correlation of treatment in humans has not been proven.

Since SEB causes symptoms when inhaled at low doses, it can render up to 80% or more of exposed personnel clinically ill and unable to perform their duties for up to 1-2 weeks.

The US military once referred to SEB by the code name PG, and the toxin was part of the US stockpile prior to its destruction in 1972.

With more advanced technology available, research is showing promise in the development of newer, faster bioassays to detect the presence of SEB, even on the battlefield.[26, 27]