CBRNE - T-2 Mycotoxins

In 1931, several Ukrainian veterinarians reported a unique disease in horses that was characterized by lip edema, stomatitis, oral necrosis, rhinitis, and conjunctivitis. This clinical effect progressed through well-defined stages including pancytopenia, coagulopathy, neurologic compromise, superinfections, and death. On autopsy, the afflicted animals were found to have diffuse hemorrhage and necrosis of the entire alimentary tract, giving rise to the name alimentary toxic aleukia (ATA).[8]

The potential use for T-2 mycotoxin as a biological weapon was later realized in Orenburg, Russia, during World War II when civilians consumed wheat that was unintentionally contaminated with the Fusarium fungi. The victims developed protracted lethal illness with a disease pattern similar to ATA. In 1940, Soviet scientists coined the term stachybotryotoxicosis to describe the acute syndrome (sore throat, bloody nasal discharge, dyspnea, cough, and fever) resulting from the inhalation of Stachybotrys mycotoxin. Twenty years later, the trichothecene mycotoxin was discovered, and the T-2 toxin was isolated.[9]

The allegations surrounding the use of T-2 mycotoxin as a biological warfare agent remains a controversy to this day. Based on extensive eyewitness and victim accounts, the aerosolized form of T-2 mycotoxin called "yellow rain" was delivered by low-flying aircraft that dropped the yellow oily liquid on the victims.

T-2 mycotoxin has been allegedly used during the military conflicts in Laos (1975-81), Kampuchea (1979-81), and Afghanistan (1979-81) to produce lethal and nonlethal casualties. More than 6300 deaths in Laos, 1000 in Kampuchea, and 3000 in Afghanistan have been attributed to yellow rain exposure.[10] Although several United States chemical weapons experts have matched samples from the Laos conflict to trichothecene signature, these charges have been disputed by other weapons experts who contend T-2 mycotoxins may have occurred naturally in Laos and that exposure was due to the ingestion of contaminated foods.[11] Moreover, the same experts contend that yellow discoloration described on the foliage was merely the residue from fecal matter of honey bees.[9]

Victim reports from the 1991 Desert Storm campaign have also alleged the possibility of a T-2 mycotoxin exposure from a detonated Iraqi missile over a US military camp in Saudi Arabia.[11] According to UNSCOM, Iraq researched trichothecene mycotoxins, including T-2 mycotoxin, and was capable of its possession.[8] However, these matters remain unresolved, and much of the key information and data from these incidents remain classified.

For related information, see Medscape's Disaster Preparedness and Aftermath Resource Center.

Trichothecene mycotoxins are markedly cytotoxic and potentially immunosuppressive. They are potent fast-acting inhibitors of protein and nucleic acid synthesis. The toxin primarily exerts effects that are similar to those of a radiation injury by negatively impacting protein levels and RNA and DNA synthesis in eukaryotic cells, thus inhibiting cellular functions, such as the cell cycle and resulting in apoptosis.[12]

Molecular studies involving the use of rodent and human cell lines suggest T-2 toxin also induces apoptosis, programmed cell death, through reactive oxygen species–mediated mitochondrial pathway.[13, 14] Typically, T-2 toxin is thought to bind and inactivate the peptidyl-transferase activity at the transcription site.[15] This results in the inhibition of protein synthesis, the effect of which is most pronounced in actively proliferating cells such as those found in the skin, gastrointestinal tract, and bone marrow. Additionally, T-2 toxin is thought to disrupt DNA polymerases, terminal deoxynucleotidyl transferase, monoamine oxidase, and several proteins involved in the coagulation pathway.[16]

Routes of exposure

The trichothecene mycotoxins are well absorbed by topical, oral, and inhalational routes. As a dermal irritant and blistering agent, it is thought to be 400 times more potent than sulfur mustard.[17] As an inhalational agent, its activity is considered comparable to that of mustard or lewisite.[7] Mycotoxin is unique in that the systemic toxicity can result from any route of exposure (dermal, oral, or inhalational).

 

Trichothecene mycotoxin exposures in the United States have largely been due to accidental ingestion of contaminated foodstuff. In 1993, however, an unusually high number of fatal pulmonary hemorrhages in infants originating from a small region of Ohio raised suspicion that the cause may have been due to trichothecene mycotoxin exposure in the homes secondary to mold overgrowth.[18] Moreover, several cases of sudden infant death syndrome (SIDS) were thought to be related to Stachybotrys mycotoxin exposure in the homes secondary to mold overgrowth resulting from a flood.[19] No well-documented epidemiologic information is available for exposure to T-2 mycotoxin as a result of bioweapon deployment other than the alleged uses in the previously mentioned military conflicts.

Several cases of "sick building syndrome" have been reported in Montreal, Canada. Dust samples collected and analyzed from the ventilation systems of suspected office buildings revealed trace amounts of at least 4 trichothecenes including T-2 toxin. This was dismissed as mold overgrowth in the ventilation system.[20]

 

Prognosis of mycotoxin exposure is difficult to assess, since the amount of toxin in previous human ingestions has not been documented. Death from actual toxin ingestion is much less of a concern than the sequelae of immune compromise and successive infection. This is supported by the documented history of the ingestion version of the disease (ATA). No current literature predicts the outcome of T-2 mycotoxin poisoning.

Airway compromise may be observed when the disease process includes significant airway edema or hemorrhage.

No human mortality or morbidity data are reported for T-2 mycotoxin use as a bioweapon. Information regarding mortality from ingestion of contaminated food is quite varied, with 10-60% mortality rate reported in Russia's Orenburg district.[9]  Mortality figures from the Kampuchea and Afghanistan uses of mycotoxin as a bioweapon do not report mortality rates, only total number of deaths.[10]  Not knowing the number of exposed individuals as related to the number of fatalities makes the calculation of mortality rates impossible.

Patients with cutaneous symptoms may report exposure to clouds of a yellow-colored smoke or aerosol, but blue and green aerosols have also been reported.[11] Patients may report having seen yellow droplets on clothing. Immediate skin pain and burning on exposed surfaces is described. Eye pain and burning also should be reported.[3]

Suspicion of the toxin being placed in an ingested food source may exist. Ingested toxin probably has no taste, since no documentation supports a foul odor or taste in previous epidemics of toxin ingestion. This is further supported by the historical experience that many individuals become ill when exposed to contaminated food without any suspicion of having ingested tainted food.[21]

The most common symptoms occurring with most exposures include the following[2] :

• Skin (or oral) pain (burning)
• Skin redness or rash
• Vomiting
• Diarrhea
• Dyspnea
• Bleeding

The early signs and symptoms of T-2 toxin poisoning do reflect the route of exposure. However, irrespective to the route of entry, the systemic toxicity follows a protracted course of illness that is well characterized. Early symptoms can manifest within seconds of exposure depending on the dose of exposure. Symptoms become prominent after minutes to hours upon exposure. They are described by the respective organ system.

No specific neurologic signs or symptoms are related to the toxin except for mild ataxia, which reflects systemic toxicity.

Head, eyes, ears, nose, throat (HEENT) manifestations are as follows:

• Ocular exposure causes tearing, pain, conjunctivitis, and blurred vision.
• Nasal mucosa results in sinus irritation, pain, rhinorrhea, sneezing, and potentially epistaxis.
• Oral and oropharyngeal exposure results in pain and blood-tinged saliva and sputum.

Respiratory manifestations are as follows:

• Cough, dyspnea and wheezing
• Delayed signs can include hemoptysis

Cardiovascular manifestations are as follows:

• Tachycardia
• Vascular collapse in severe toxin exposure

Gastrointestinal manifestations are as follows:

• Nausea and vomiting
• Anorexia
• Watery diarrhea with abdominal cramping

Dermal manifestations are as follows:

• Painful erythema and tenderness
• Blistering and bullous lesions, leading to desquamation
• Necrosis and sloughing of dermal layer

Systemic manifestations are as follows:

• Severe toxin exposure can result in early systemic toxicity.
• Severe dizziness, ataxia, and prostration
• Tachycardia
• Hypothermia
• Vascular collapse

Alimentary toxic aleukia

Alimentary toxic aleukia (ATA) is a clinical syndrome that results from chronic exposure to T-2 toxin.[2]  ATA has four stages, which mirror the stages of radiation sickness.

Stage 1

This stage may be seen in the emergency department. This stage results from the acute injury to the exposed cells and tissue. The symptoms reflect the route of toxin exposure.

Stage 2

This stage occurs weeks after the exposure. Insult to the bone marrow initially produces a transient lymphocytosis. This is soon followed by bone marrow suppression due to the antimitotic effects of T-2 toxin. The result is significant leukopenia, granulocytopenia, and thrombocytopenia.

Stage 3

This stage also occurs weeks after the exposure and is considered the hemorrhagic stage. The patient exhibits petechial hemorrhages, especially of the mucosal areas of the nasopharynx and oropharynx. These lesions develop to form ulcerated and necrotic lesions, which can result in significant bleeding from the esophagus and the gastrointestinal tract. Moreover, the edema that accompanies the mucosal injury may threaten the airway. Also, severe coagulopathy may occur. During this stage, the patient is at a higher risk for sepsis because the immune system is significantly compromised.

Stage 4

During the recovery phase, the necrotic lesions heal and the bone marrow recovers.

With growing health concerns related to mold exposures and its related morbidity and mortality, devices have been developed to detect environmental mycotoxin exposure. To date, no data exist to differentiate the expected background levels of these substances from potential toxic and/or intentional contamination.

T-2 toxin is rapidly metabolized to HT-2, T2-triol, and T-2 tetraol within hours after exposure.[22] While these toxin metabolites may be detected in body fluids, tissue, and stomach contents for up to 28 days following exposure, these results are unlikely to be available to help the medical provider manage the patient. Newer urine assays detect T-2 metabolite for up to one week after exposure.[8] Definitive diagnosis must be made in a reference laboratory using thin-layer or gas-liquid chromatography, mass or nuclear magnetic resonance spectrometry, radioimmunoassay, and enzyme-linked immunosorbent assay (ELISA) techniques.[23]

• Perform immediate postexposure laboratory studies to assess for other disease conditions in the differential diagnosis.

• When considering T-2 mycotoxin exposure as the cause of the illness, collect nasal, throat, or respiratory secretions and send for mass spectrometric evaluation.

• Collect serum, urine, and/or tissue samples for toxin detection from patients who are in the postexposure phase. ELISA screening tests and antibody assays that screen for mycotoxin exposure are available.

• Observing the absolute lymphocyte count over time may differentiate those individuals destined to develop bone marrow suppression.

• Coagulation panel may help identify patients who are at risk for developing severe coagulopathy.

No specific imaging tests help diagnose T-2 toxin exposure.

Warning: Mycotoxin is a potent dermally active toxin that is transmissible in the health care setting. Do not approach the patient without observing universal precaution. Use hazardous materials teams in patient rescue and decontamination.

Decontamination is of paramount importance to avoid cross-contamination. Remove all of the patient's clothing, and clean and scrub the entire skin surface with soap and water. Washing the contaminated area of the skin within 6 hours postexposure can remove 80-98% of the toxin and has been demonstrated to prevent skin lesions and death in experimental animals.[24]  Contain clothing to avoid contamination of the health care environment.

Available only to the US Department of Defense and many NATO military forces is the Reactive Skin Decontamination Lotion (RSDL). The proposed mechanism of action is neutralization of traditional chemical warfare agents by a combination of physical removal and nucleophilic breakdown, which renders the original toxic substance nontoxic.[2, 25]

For patients in extremis, attention to airway, breathing, and circulation per Advanced Trauma Life Support (ATLS) protocol needs to occur immediately as decontamination is being performed. While one team member is caring for issues involving the airway, breathing, and circulation, another member should be concerned primarily with patient decontamination.

Provide supportive measures addressing cardiovascular status as necessary. If the patient complains of eye pain or tearing, irrigate the eyes with copious amounts of water. No specific antidote exists for this toxin. General supportive measures are indicated.

Warning: Mycotoxin is a potent dermally active toxin that is transmissible in the health care setting. Do not approach the patient without observing universal precautions. Never assume that a patient has been decontaminated in the prehospital setting. Reassess the patient's decontamination status. If the degree of prehospital decontamination is uncertain, rewash the patient to ensure the safety of staff and facility.

For patients in extremis, attention to airway, breathing, and circulation per ATLS protocol needs to occur immediately as decontamination is being performed. While one team member is caring for issues involving the airway, breathing, and circulation, another member should be concerned primarily with patient decontamination.

Remove all clothing, and clean and scrub the patient's entire skin surface with soap and water. Washing the contaminated area of the skin within 6 hours postexposure can remove 80-98% of the toxin and has been demonstrated to prevent skin lesions and death in experimental animals.[24] Contain clothing to avoid contamination of the health care environment.

While no human studies have been conducted, survival benefits have been shown in animal models with the following treatment after T-2 toxin exposure. 

• Use of activated charcoal to absorb T-2 toxin from the gut regardless of the portal of entry within 1 hour of exposure. ^[26]
• Dexamethasone administration (1 mg/kg at 12, 24, and 48 h) increased the survival rate in mice from zero to greater than 50%. ^[27]
• Although not proven clinically, a theoretical use exists for administering colony-stimulating factors to patients presenting with bone marrow suppression.

No specific antidote is available for T-2 mycotoxin exposure. Provide supportive measures, addressing respiratory and cardiovascular status as necessary. If the patient complains of eye pain or tearing, irrigate the eyes with copious amounts of water.

In all suspected cases involving T-2 mycotoxin exposure, admission to the hospital is warranted. Supportive care should be instituted with particular attention to the prevention of superinfection. Depending on the time of exposure and the presenting symptoms, serial lymphocyte count may help identify patients who are immunocompromised.

Required consultants are dictated by the disease course. Pulmonary consultation may be required for severe dyspnea of hemoptysis. A hematologist may be consulted for patients presenting with severe pancytopenia. Contact the local poison control center for additional clinical guidance. Some larger cities' poison control centers may have specific guidelines to follow concerning weapons of mass destruction.

Consult the Federal Bureau of Investigations and Department of Homeland Security in any situation when nuclear, biological, or chemical weapon exposure is suspected.

Physical barrier protection of the skin, mucous membranes, and airway provided by use of HAZMAT suits or chemical protective mask and clothing, such as MOPP gear, are the only effective methods of protection. The Skin Exposure Reduction Paste Against Chemical Warfare Agents (SERPACWA) has been shown to block dermal irritation in animal studies and can be applied at closure points of protective garments as well as to any exposed skin. It is FDA-approved for use in conjunction with MOPP gear to reduce or delay the absorption of chemical warfare agents through the skin when SERPACWA is applied prior to exposure.[2]

The use of activated charcoal is advocated to patients who have orally ingested the toxin. Some sources advocate the use of activated charcoal even after inhalational exposure, with the rationale that the toxin that is adherent to the oral mucosa may be bound.[28] While not clinically tested in humans, theoretical use exists for administering colony-stimulating factors to patients presenting with bone marrow suppression.

Class Summary

These agents are used to neutralize toxins.[26]

Activated charcoal (Liqui-Char, Super-Char, Insta-Char, Actidose)

Believed to adsorb ingested toxin, thereby preventing absorption and removing toxin from the GI tract, preventing further cellular damage.

Class Summary

These agents are used to correct severe neutropenia.

Filgrastim (Neupogen)

Granulocyte colony-stimulating factor that activates and stimulates production, maturation, migration, and cytotoxicity of neutrophils. Although not demonstrated or indicated for use in T-2 mycotoxin exposure, may be theoretical use for granulocyte-stimulating factors for patients presenting with severe neutropenia; in this setting, conduct use with hematology consultation.