Trichothecene Mycotoxins (T2) Signs and Symptoms
Exposure causes skin pain, pruritus, redness, vesicles, necrosis and sloughing of epidermis. Effects on the airway include nose and throat pain, nasal discharge, itching and sneezing, cough, dyspnea, wheezing, chest pain and hemoptysis. Toxin also produces effects after ingestion or eye contact. Severe poisoning results in prostration, weakness, ataxia, collapse, shock, and death. Diagnosis: Should be suspected if an aerosol attack occurs in the form of "yellow rain" with droplets of yellow fluid contaminating clothes and the environment. Confirmation requires testing of blood, tissue and environmental samples. Treatment: There is no specific antidote. Superactivated charcoal should be given orally if swallowed. Prophylaxis: The only defense is to wear a protective mask and clothing during an attack. No specific immunotherapy or chemotherapy is available for use in the field. Decontamination: The outer uniform should be removed and exposed skin should be decontaminated with soap and water. Eye exposure should be treated with copious saline irrigation. Once decontamination is complete, isolation is not required.
Overview The trichothecene mycotoxins are low molecular weight (250-500 daltons) nonvolatile compounds produced by filamentous fungi (molds) of the genera Fusarium, Myrotecium, Trichoderma, Stachybotrys and others. The structures of approximately 150 trichothecene derivatives have been described in the literature. These substances are relatively insoluble in water but are highly soluble in ethanol, methanol and propylene glycol. The trichothecenes are extremely stable to heat and ultraviolet light inactivation. Heating to 500o F for 30 minutes is required for inactivation, while brief exposure to NaOH destroys toxic activity. The potential for use as a BW toxin was demonstrated to the Russian military shortly after World War II when flour contaminated with species of Fusarium was baked into bread that was ingested by civilians. Some developed a protracted lethal illness called alimentary toxic aleukia (ATA) characterized by initial symptoms of abdominal pain, diarrhea, vomiting, prostration, and within days fever, chills, myalgias and bone marrow depression with granulocytopenia and secondary sepsis. Survival beyond this point allowed the development of painful pharyngeal/laryngeal ulceration and diffuse bleeding into the skin (petechiae and ecchymoses), melena, bloody diarrhea, hematuria, hematemesis, epistaxis and vaginal bleeding. Pancytopenia, and gastrointestinal ulceration and erosion were secondary to the ability of these toxins to profoundly arrest bone marrow and mucosal protein synthesis and cell cycle progression through DNA replication.
History and Significance Mycotoxins allegedly have been used in aerosol form ("yellow rain") to produce lethal and nonlethal casualties in Laos (1975-81), Kampuchea (1979-81), and Afghanistan (1979-81). It has been estimated that there were more than 6,300 deaths in Laos, 1,000 in Kampuchea, and 3,042 in Afghanistan. The alleged victims were usually unarmed civilians or guerrilla forces. These groups were not protected with masks and chemical protective clothing and had little or no capability of destroying the attacking enemy aircraft. These attacks were alleged to have occurred in remote jungle areas which made confirmation of attacks and recovery of agent extremely difficult. Much controversy has centered about the veracity of eyewitness and victim accounts, but there is enough evidence to make agent use in these areas highly probable.
Clinical Features T2 and other mycotoxins may enter the body through the skin and aerodigestive epithelium. They are fast acting potent inhibitors of protein and nucleic acid synthesis. Their main effects are on rapidly proliferating tissues such as the bone marrow, skin, mucosal epithelia, and germ cells. In a successful BW attack with trichothecene toxin (T2), the toxin(s) will adhere to and penetrate skin, be inhaled, and swallowed. Clothing will be contaminated and serve as a reservoir for further toxin exposure. Early symptoms beginning within minutes of exposure include burning skin pain, redness, tenderness, blistering, and progression to skin necrosis with leathery blackening and sloughing of large areas of skin in lethal cases. Nasal contact is manifested by nasal itching and pain, sneezing, epistaxis and rhinorrhea; pulmonary/tracheobronchial toxicity by dyspnea, wheezing, and cough; and mouth and throat exposure by pain and blood tinged saliva and sputum. Anorexia, nausea, vomiting and watery or bloody diarrhea with abdominal crampy pain occurs with gastrointestinal toxicity. Eye pain, tearing, redness, foreign body sensation and blurred vision may follow entry of toxin into the eyes. Skin symptoms occur in minutes to hours and eye symptoms in minutes. Systemic toxicity is manifested by weakness, prostration, dizziness, ataxia, and loss of coordination. Tachycardia, hypothermia, and hypotension follow in fatal cases. Death may occur in minutes, hours or days. The commonest symptoms were vomiting, diarrhea, skin involvement with burning pain, redness and pruritus, rash or blisters, bleeding, and dyspnea.
Diagnosis Rapid onset of symptoms in minutes to hours supports a diagnosis of a chemical or toxin attack. Mustard agents must be considered but they have an odor, are visible, and can be rapidly detected by a field available chemical test. Symptoms from mustard toxicity are also delayed for several hours after which mustard can cause skin, eye and respiratory symptoms. Staphylococcal enterotoxin B delivered by an aerosol attack can cause fever, cough, dyspnea and wheezing but does not involve the skin and eyes. Nausea, vomiting, and diarrhea may follow swallowing of inhaled toxin. Ricin inhalation can cause severe respiratory distress, cough, nausea and arthralgias. Swallowed agent can cause vomiting, diarrhea, and gastrointestinal bleeding, but it spares the skin, nose and eyes. Specific diagnosis of T-2 mycotoxins in the form of a rapid diagnostic test is not presently available in the field. Removal of blood, tissue from fatal cases, and environmental samples for testing using a gas liquid chromatography-mass spectrometry technique will confirm the toxic exposure. This system can detect as little as 0.1-1.0 ppb of T-2. This degree of sensitivity is capable of measuring T-2 levels in the plasma of toxin victims.
Medical Management Use of a chemical protective mask and clothing prior to and during a mycotoxin aerosol attack will prevent illness. If a soldier is unprotected during an attack the outer uniform should be discarded within 4 hours and decontaminated by exposure to 5% hypochlorite for 6-10 hours. The skin should be thoroughly washed with soap and uncontaminated water if available. The M291 skin decontamination kit should also be used to remove skin adherent T-2. Superactive charcoal can absorb swallowed T-2 and should be administered to victims of an unprotected aerosol attack. The eyes should be irrigated with normal saline or water to remove toxin. No specific antidote or therapeutic regimen is currently field available. All therapy is symptomatic and supportive.
Physical protection of the skin and airway are the only proven effective methods of protection during an attack. Immunological (vaccines) and chemoprotective pretreatments are being studied in animal models, but are not available for field use by the warfighter.
Staphylococcal Enterotoxin B Summary Signs and Symptoms
From 3-12 hours after aerosol exposure, sudden onset of fever, chills, headache, myalgia, and nonproductive cough. Some patients may develop shortness of breath and retrosternal chest pain. Fever may last 2 to 5 days, and cough may persist for up to 4 weeks. Patients may also present with nausea, vomiting, and diarrhea if they swallow toxin. Higher exposure can lead to septic shock and death. Diagnosis: Diagnosis is clinical. Patients present with a febrile respiratory syndrome without CXR abnormalities. Large numbers of soldiers presenting with typical symptoms and signs of SEB pulmonary exposure would suggest an intentional attack with this toxin.
Treatment is limited to supportive care. Artificial ventilation might be needed for very severe cases, and attention to fluid management is important. Prophylaxis: Use of protective mask. There is currently no human vaccine available to prevent SEB intoxication. Decontamination: Hypochlorite (0.5% for 10-15 minutes) and/or soap and water. Destroy any food that may have been contaminated. Overview Staphylococcus aureus produces a number of exotoxins, one of which is Staphylococcal enterotoxin B, or SEB. Such toxins are referred to as exotoxins since they are excreted from the organism; however, they normally exert their effects on the intestines and thereby are called enterotoxins. SEB is one of the pyrogenic toxins that commonly causes food poisoning in humans after the toxin is produced in improperly handled foodstuffs and subsequently ingested. SEB has a very broad spectrum of biological activity. This toxin causes a markedly different clinical syndrome when inhaled than it characteristically produces when ingested. Significant morbidity is produced in individuals who are exposed to SEB by either portal of entry to the body.
History and Significance SEB has caused countless endemic cases of food poisoning. Often these cases have been clustered, due to common source exposure in a setting such as a church picnic or passengers eating the same toxin-contaminated food on an airliner. Although this toxin would not be likely to produce significant mortality on the battlefield, it could render up to 80 percent or more of exposed personnel clinically ill and unable to perform their mission for a fairly prolonged period of time. Therefore, even though SEB is not generally thought of as a lethal agent, it may incapacitate soldiers for up to two weeks, making it an extremely important toxin to consider.
Toxin Characteristics Staphylococcal enterotoxins are extracellular products produced by coagulase-positive staphylococci. They are produced in culture media and also in foods when there is overgrowth of the staph organisms. At least five antigenically distinct enterotoxins have been identified, SEB being one of them. These toxins are heat stable. SEB causes symptoms when inhaled at very low doses in humans: a dose of several logs lower than the lethal dose by the inhaled route would be sufficient to incapacitate 50 percent of those soldiers so exposed. This toxin could also be used (theoretically) in a special forces or terrorist mode to sabotage food or low volume water supplies.
Mechanism of Toxicity Staphylococcal enterotoxins produce a variety of toxic effects. Inhalation of SEB can induce extensive pathophysiological changes to include widespread systemic damage and even septic shock. Many of the effects of staphylococcal enterotoxins are mediated by interactions with the host's own immune system. The mechanisms of toxicity are complex, but are related to toxin binding directly to the major histocompatibility complex that subsequently stimulates the proliferation of large numbers of T cell lymphocytes. Because these exotoxins are extremely potent activators of T cells, they are commonly referred to as bacterial superantigens. These superantigens stimulate the production and secretion of various cytokines, such as tumor necrosis factor, interferon-(, interleukin-1 and interleukin-2, from immune system cells. Released cytokines are thought to mediate many of the toxic effects of SEB.
Clinical Features Relevant battlefield exposures to SEB are projected to cause primarily clinical illness and incapacitation. However, higher exposure levels can lead to septic shock and death. Intoxication with SEB begins 3 to 12 hours after inhalation of the toxin. Victims may experience the sudden onset of fever, headache, chills, myalgias, and a nonproductive cough. More severe cases may develop dyspnea and retrosternal chest pain. Nausea, vomiting, and diarrhea will also occur in many patients due to inadvertently swallowed toxin, and fluid losses can be marked. The fever may last up to five days and range from 103 to 106o F, with variable degrees of chills and prostration. The cough may persist up to four weeks, and patients may not be able to return to duty for two weeks. Physical examination in patients with SEB intoxication is often unremarkable. Conjunctival injection may be present, and postural hypotension may develop due to fluid losses. Chest examination is unremarkable except in the unusual case where pulmonary edema develops. The chest X-ray is also generally normal, but in severe cases increased interstitial markings, atelectasis, and possibly overt pulmonary edema or an ARDS picture may develop.
Diagnosis As is the case with botulinum toxins, intoxication due to SEB inhalation is a clinical and epidemiologic diagnosis. Because the symptoms of SEB intoxication may be similar to several respiratory pathogens such as influenza, adenovirus, and mycoplasma, the diagnosis may initially be unclear. All of these might present with fever, nonproductive cough, myalgia, and headache. SEB attack would cause cases to present in large numbers over a very short period of time, probably within a single 24 hour period. Naturally occurring pneumonias or influenza would involve patients presenting over a more prolonged interval of time. Naturally occurring staphylococcal food poisoning cases would not present with pulmonary symptoms. SEB intoxication tends to progress rapidly to a fairly stable clinical state, whereas pulmonary anthrax, tularemia pneumonia, or pneumonic plague would all progress if left untreated. Tularemia and plague, as well as Q fever, would be associated with infiltrates on chest radiographs. Nerve agent intoxication would cause fasciculations and copious secretions, and mustard would cause skin lesions in addition to pulmonary findings; SEB inhalation would not be characterized by these findings. The dyspnea associated with botulinum intoxication is associated with obvious signs of muscular paralysis, bulbar palsies, lack of fever, and a dry pulmonary tree due to cholinergic blockade; respiratory difficulties occur late rather than early as with SEB inhalation. Laboratory findings are not very helpful in the diagnosis of SEB intoxication. A nonspecific neutrophilic leukocytosis and an elevated erythrocyte sedimentation rate may be seen, but these abnormalities are present in many illnesses. Toxin is very difficult to detect in the serum by the time symptoms occur; however, a serum specimen should be drawn as early as possible after exposure. Data from rabbit studies clearly show that SEB in the serum is transient; however, it accumulates in the urine and can be detected for several hours post exposure. Therefore, urine samples should be obtained and tested for SEB. High SEB concentrations inhibit kidney function. Because most patients will develop a significant antibody response to the toxin, acute and convalescent serum should be drawn which may be helpful retrospectively in the diagnosis.
Medical Management Currently, therapy is limited to supportive care. Close attention to oxygenation and hydration are important, and in severe cases with pulmonary edema, ventilation with positive end expiratory pressure and diuretics might be necessary. Acetaminophen for fever, and cough suppressants may make the patient more comfortable. The value of steroids is unknown. Most patients would be expected to do quite well after the initial acute phase of their illness, but most would generally be unfit for duty for one to two weeks.
Although there is currently no human vaccine for immunization against SEB intoxication, several vaccine candidates are in development. Preliminary animal studies have been encouraging and a vaccine candidate is nearing transition to advanced development and safety and immunogenicity testing in man. Experimentally, passive immunotherapy can reduce mortality, but only when given within 4-8 hours after inhaling SEB.
Source: U.S. Army Handbook on infectious Diseases August 1996