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CBRNE - Staphylococcal Enterotoxin B

Bruce A Gleason, MD, Resident Physician, Department of Emergency Medicine, C R Darnall Army Medical Center, Ft Hood, Texas
Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center

Updated: Apr 29, 2009

Introduction

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. SEB normally exerts its effect on the intestines and, therefore, is termed an enterotoxin. Not all toxins result in a lethal outcome, but they may result in significant morbidity.¹

Staphylococcal enterotoxin B (SEB) is the toxin most commonly associated with classic food poisoning. It has also been demonstrated to cause a nonmenstrual toxic shock syndrome (TSS).² 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.³

Source

Staphylococcal enterotoxin B (SEB) is 1 of 7 originally identified enterotoxins produced by certain strains of the coagulase-positive S aureus bacteria, a gram-positive cocci that form clumps. Research has elucidated the structures of numerous enterotoxin-like superantigens, with two new enterotoxins, now known as SES and SET, just discovered in 2008.⁴ S aureus is known to colonize the nasal passages and axillae in humans.

Structure

Staphylococcal enterotoxin B (SEB) consists of 239 amino acid residues and has a molecular weight of 28 kd. It is 1 of the 6 least antigenically distinct enterotoxin proteins that have been identified (A, B, C, D, E, G). SEB has 2 distinct tightly "packed" domains that have a very complex tertiary structure. It is this compact structure that enables SEB to be highly resistant to proteases, including trypsin, chymotrypsin, and papain, which are all found in the intestinal lumen.

Properties

Staphylococcal enterotoxin B (SEB) is a relatively stable compound that is easily soluble in water. It is moderately resistant to temperature fluctuations and can withstand boiling at 100 º 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, and the lethal dose, or LD₅₀, is 0.02 mcg/kg.⁵

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. 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 b (TNF-b), and interferons. 

The cytokines not only cause a recruitment of additional inflammatory cells but 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.^1,3,6

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 data are available regarding the mortality and morbidity of inhalational SEB exposure.

Age

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

Clinical

History

Historical clues are important in diagnosing enterotoxin-induced gastroenteritis.

• After either gastrointestinal or inhalational exposure, a nonspecific flu-like illness may develop, with symptoms to include myalgias, headache, chills, and fever.
• GI symptoms start within several hours 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.

• 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 staphylococcal enterotoxin B (SEB) does not occur in the natural setting and should be considered a result of an intentional event.^1,8

• 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.

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 abdominal pain or acutely short of breath. Symptoms are of abrupt onset.^3,7

• 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 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.  On 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. 
  • 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 103^o -106^o F if significant pulmonary involvement has occurred.

Causes

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 been documented of intranasal exposure secondary to nasal packing after surgical procedures as S aureus does colonize the nasal passages.

Differential Diagnoses

Workup

Laboratory Studies

• Although staphylococcal enterotoxin B (SEB) can be confirmed through enzyme-linked immunosorbent assay or 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.
• 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.¹⁰
• 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

• 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.

Other Tests

• Other tests are indicated based on the patient's physiologic condition or progress of the disease syndrome.

Treatment

Prehospital Care

Treatment of staphylococcal enterotoxin B 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 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.^1,11

• 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.

Consultations

Consultations are dictated by the patient's physiologic condition.

• If a terrorist attack using staphylococcal enterotoxin B (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

• 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

• 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

• 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 risk 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 excellent patient education resources, visit eMedicine's Bioterrorism and Warfare Center. Also, see eMedicine's patient education articles Biological Warfare and Personal Protective Equipment.

Miscellaneous

Medicolegal Pitfalls

• Failure to recognize staphylococcal enterotoxin B (SEB) intoxication may lead to a nonmenstrual toxic shock syndrome. In all probability, very young and elderly patients are more susceptible.
• Failure to report sources of SEB (eg, restaurant) may result in epidemic spread of infection.

Special Concerns

• Prophylaxis: 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.¹²
• 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.
• Staphylococcal enterotoxin B (SEB) in biological warfare 
  • 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.^13,14

References

1. Woods JB, Darling RG, Dembek Z, et al. USAMRIID Medical Management of Biological Casualties Handbook. 6^th ed. April 2005.

2. CDC. Toxic-shock syndrome, United States, 1970-1982. MMWR Morb Mortal Wkly Rep. Apr 30 1982;31(16):201-4. [Medline].

3. Ulrich RG, Sidell S, Taylor TJ. Staphylococcal enterotoxin B and related pyogenic toxins. In: Textbook of Military Medicine. Part I. Warfare, Weaponry and the Casualty. Vol 3. 1997:621-631.

4. Ono HK, Omoe K, Imanishi K, Iwakabe Y, Hu DL, Kato H. Identification and characterization of two novel staphylococcal enterotoxins, types S and T. Infect Immun. Nov 2008;76(11):4999-5005. [Medline].

5. Papageorgiou AC, Tranter HS, Acharya KR. Crystal structure of microbial superantigen staphylococcal enterotoxin B at 1.5 A resolution: implications for superantigen recognition by MHC class II molecules and T-cell receptors. J Mol Biol. Mar 20 1998;277(1):61-79. [Medline].

6. Mattix ME, Hunt RE, Wilhelmsen CL, Johnson AJ, Baze WB. Aerosolized staphylococcal enterotoxin B-induced pulmonary lesions in rhesus monkeys (Macaca mulatta). Toxicol Pathol. May-Jun 1995;23(3):262-8. [Medline].

7. Tierney LK, McPhee SJ, Papadakis MA. Current Medical Diagnosis and Treatment. 1998.

8. Rajagopalan G, Sen MM, Singh M, Murali NS, Nath KA, Iijima K, et al. Intranasal exposure to staphylococcal enterotoxin B elicits an acute systemic inflammatory response. Shock. Jun 2006;25(6):647-56. [Medline].

9. Rajagopalan G, Smart MK, Patel R, David CS. Acute systemic immune activation following conjunctival exposure to staphylococcal enterotoxin B. Infect Immun. Oct 2006;74(10):6016-9. [Medline].

10. Khan AS, Cao CJ, Thompson RG, Valdes JJ. A simple and rapid fluorescence-based immunoassay for the detection of staphylococcal enterotoxin B. Mol Cell Probes. Apr-Jun 2003;17(2-3):125-6. [Medline].

11. Virtual Naval Hospital, US Army Medical Research Institute of Infectious Diseases. Medical Management of Biological Casualties Handbook. 1998.

12. Mantis NJ. Vaccines against the category B toxins: Staphylococcal enterotoxin B, epsilon toxin and ricin. Adv Drug Deliv Rev. Jun 17 2005;57(9):1424-39. [Medline].

13. Yang M, Kostov Y, Bruck HA, Rasooly A. Carbon nanotubes with enhanced chemiluminescence immunoassay for CCD-based detection of Staphylococcal enterotoxin B in food. Anal Chem. Nov 15 2008;80(22):8532-7. [Medline].

14. Soto CM, Martin BD, Sapsford KE, Blum AS, Ratna BR. Toward single molecule detection of staphylococcal enterotoxin B: mobile sandwich immunoassay on gliding microtubules. Anal Chem. Jul 15 2008;80(14):5433-40. [Medline].

Keywords

staphylococcal enterotoxin B, SEB, exotoxin, symptoms, treatment, Staphylococcus aureus, S aureus, enterotoxin, food poisoning, gastroenteritis, nonmenstrual toxic shock syndrome, TSS, biological warfare agent, biowarfare weapon, SEB toxicity, staphylococcal enterotoxin B toxicity, SEB exposure, staphylococcal enterotoxin B exposure, enterotoxin-induced gastroenteritis, SEB ingestion, SEB inhalation, staphylococcal enterotoxin B ingestion, staphylococcal enterotoxin B inhalation, terrorism

Contributor Information and Disclosures

Author

Bruce A Gleason, MD, Resident Physician, Department of Emergency Medicine, C R Darnall Army Medical Center, Ft Hood, Texas
Bruce A Gleason, MD is a member of the following medical societies: American College of Emergency Physicians and Emergency Medicine Residents Association
Disclosure: Nothing to disclose.

Coauthor(s)

Kermit D Huebner, MD, FACEP, Research Director, Carl R Darnall Army Medical Center
Kermit D Huebner, MD, FACEP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, Association of Military Surgeons of the US, Society for Academic Emergency Medicine, and Society of USAF Flight Surgeons
Disclosure: Nothing to disclose.

Medical Editor

Jerry L Mothershead, MD, Medical Readiness Consultant, Medical Readiness and Response Group, Battelle Memorial Institute; Advisor, Technical Advisory Committee, Emergency Management Strategic Healthcare Group, Veteran's Health Administration; Adjunct Associate Professor, Department of Military and Emergency Medicine, Uniformed Services University of the Health Sciences
Jerry L Mothershead, MD is a member of the following medical societies: American College of Emergency Physicians and National Association of EMS Physicians
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Rick Kulkarni, MD, Medical Director, Assistant Professor of Surgery, Section of Emergency Medicine, Yale-New Haven Hospital
Rick Kulkarni, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Emergency Medicine, American College of Emergency Physicians, American Medical Association, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: WebMD Salary Employment

CME Editor

John D Halamka, MD, MS, Associate Professor of Medicine, Harvard Medical School, Beth Israel Deaconess Medical Center; Chief Information Officer, CareGroup Healthcare System and Harvard Medical School; Attending Physician, Division of Emergency Medicine, Beth Israel Deaconess Medical Center
John D Halamka, MD, MS is a member of the following medical societies: American College of Emergency Physicians, American Medical Informatics Association, Phi Beta Kappa, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.

Chief Editor

Robert G Darling, MD, FACEP, Clinical Assistant Professor of Military and Emergency Medicine, Uniformed Services University of the Health Sciences, F Edward Hebert School of Medicine; Associate Director, Center for Disaster and Humanitarian Assistance Medicine
Robert G Darling, MD, FACEP is a member of the following medical societies: American College of Emergency Physicians, American Medical Association, and Association of Military Surgeons of the US
Disclosure: Nothing to disclose.

The authors and editors of eMedicine gratefully acknowledge the contributions of previous author, Danielle M Pesce, DO, to the development and writing of this article.

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