Sex: M
Vaccine: SMALL
Symptoms: Enterovirus test negative, Fatigue, Fluid replacement, Fungal test negative, General physical health deterioration
Clinical narrative: Collapsed abruptly/passed out; Narrow complex tachycardia; Disseminated intravascular coagulation; Encephalopathy; Hepatic encephalopathy; Renal failure; Hyperthermia; Thrombocytosis; Leukocytosis; Did not sleep well; Was very thirsty all night; Bilateral leg cramps; Emesis; Pain; Fatigue; Refractory cardiac arrest; Increasing liver enzymes; SPV-associated probable myocarditis; These reports have been updated with information received through data reconciliation conducted between manufacturers.  This is a clinical trial and scientific literature case (Mfg# 2012-00924), also downloaded via VAERS (#443712) in review of data.   The following is the narrative from the case:  "This case was received on 23 January 2012 via a third-party query tool search on the VAERS database, under reference number 443712.  An 18-year-old male patient with allergy to primaquine, and who was G6PD deficient had received the following vaccinations on 15 November 2011:  smallpox (vaccinia) vaccine, live (ACAM2000, lot number VV040003A), typhoid (Typhim Vi, lot number B1026), and anthrax (Biothrax, lot number FAV294) and eight days later, on 23 November 2011 the patient was on a 5 mile run and passed out.  His heart rate was greater than 180 beats/minute and he had a temperature of 102.9 degrees Fahrenheit.  He was administered adenosine and underwent cardioversion with intravenous fluids (IVF) and was admitted to the ICU and placed on broad spectrum antibiotics.  An unspecified culture was drawn without reported results. The patient experienced progressive rhabdomyolysis, disseminated intravascular coagulation (DIC), renal failure, pain, and encephalopathy.  He was treated with "cryo", fresh frozen plasma (FFP), fluids, pressors and ultimately transferred to another facility.  Laboratory data revealed leukocytosis, thrombocytosis, decreased fibrinogen and prolonged prothrombin-time/partial thromboplastin time (PT/PPT), elevated liver enzymes, increased creatine, increased creatine kinase, transient elevated troponin I (TNIs).  The patient had no other active medications except for Doxycycline taken prophylactically for malaria approximately 2 days prior.  The patient died on an unspecified date.  Follow-up information was received 13 March 2012.  According to the reporter, they had no report in their files indicating the patient expired, and they were unable to provide any additional information at the time of the report. Note: Any requests for follow-up information on this case should be sent directly to the sponsor of this study. This study case was received from the investigator in the above mentioned trial on 23 May 2013. Eight days post vaccination, on 23 November 2011, the subject was diagnosed with non-specific myocarditis.  On 27 November 2011, the Troponin I results (01.31) were abnormal. On 25 November 2011, ECG and Echocardiogram were abnormal. Lumbar puncture and MRI of the brain, spinal cord and heart were not performed. The event outcome was fatal (date of fatal outcome not reported).  Follow-up information was received from the investigator on 29 May 2013 with additional information retrieved from the scientific literature on 30 May 2013. Abnormal troponin I on 27 November 2011 was 1.31 ng/ml. The following is verbatim from the article: Case: A previously healthy 18-year-old was admitted to the hospital for presumed heat stroke after collapsing during a 5-mile run. He was initially alert and oriented, febrile and tachycardic. Laboratory data failed to reveal any abnormalities on a toxicology screen but was notable for an elevated serum creatine phosphokinase (CPK) and lactate, 204 U/L and 9.2 mmol/L, respectively. A review of his medical record revealed vaccination for smallpox 8 days prior to presentation. Supportive therapy failed to prevent the patient from developing disseminated intravascular coagulopathy with rapidly upward trending liver enzymes. CPK level and urinalysis demonstrated myoglobunirua. He progressed to multiple organ dysfunction syndrome with hepatic encephalopathy and acute kidney injury requiring dialysis. On hospital day five he became hypotensive and developed a fatal arrhythmia. Autopsy revealed a dilated cardiomyopathy (DCM) with histologic evidence of myocarditis, a necrotic liver, an infarcted right adrenal gland and an edematous brain with patchy areas of acute neuronal necrosis directly attributed to immunologic consequences of the smallpox vaccine. Discussion: To our knowledge, this is the first case of death from the smallpox vaccine in a young, healthy, active person. Myocarditis is well-reported; however, in this pt. myocarditis silently progressed to DCM as a result of a systemic immunologic response to the vaccine. The same immunologic response coupled with exertion which occurred post-vaccine day 8, the peak of expected response to vaccine, likely led to his multi-organ system failure and death. Continuous vigilance for adverse reactions to smallpox vaccine is warranted."  Follow-up information was received from the investigator on 06 December 2013:  The consensus decision from the Committee regarding the event(s) reported is that they do not meet the case definition for myocarditis, pericarditis or subclinical myopericarditis.  The review of comprehensive safety of this case reviewed material of daily hospital records from 23 November 2011 to 28 November 2011 including physicians' and nurses' notes, laboratory summaries, radiology summaries and a post-mortem report, totaling 473 pages. The presentation was an 18-year-old male who collapsed during a 5-mile run, seven days after receiving smallpox and anthrax vaccinations. He was found initially to be tachycardic and incoherent by EMT. The hospital course was after he was stabilized with crystalloid resuscitation his mental status normalized and he was found to be febrile and continued to be tachycardic. He reported that he was poorly conditioned before undertaking the five-mile run. He was a large man, weighing 90 Kg. Broad spectrum antibiotic therapy was initiated. Soon he complained of muscle pain and developed marked CPK elevation, reaching levels near 200,000 iu/L which persisted throughout his course. Multiorgan failure then ensued including hepatic and renal failure and DIC. Dialysis was instituted, depleted clotting factors were periodically replaced, and he was considered for liver transplantation. An echocardiogram showed a normal EF and upper limit of normal LV dimensions. ECGs were reported to show only sinus tachycardia with no suggestion of myocarditis or pericarditis. On the sixth hospital day he developed hepatic encephalopathy, was intubated and later arrested during dialysis. A resuscitation attempt was unsuccessful. Post mortem autopsy revealed no macroscopic or microscopic evidence for myocarditis. Organ findings were typical of a non-specific multiorgan insult.  There was no autopsy evidence for infection. A CDC report found there was no immunohistochemical or molecular evidence for enterovirus, parvovirus B19 or influenza viruses A and B in the heart, and no evidence for viral infection of the liver.  The conclusion was that this was an unfortunate but straightforward case of rhabdomyolysis caused by extreme exertion in an untrained individual with a large muscle mass. There was no evidence of myocarditis or pericarditis or any etiological role of vaccination.  Follow-up information was received on 23 July 2014 in which this case was referenced in a literature article. Additional cases captured from this article include 2009-00544 and 2014SA099797.  No further information was available.  The following is the narrative retrieved from VAERS data (18JAN2012).  Per records, patient was in 5 mile run and passed out--HR>180s and T~102.9 - adenosine and cardioversion with IVF-admitted to ICU-placed on broad spectrum Abx and Cx drawn. Progressive, rhabdomyolysis, DIC, renal failure, pain, and encephalopthy. Tx with cryo, ffp, fluids, pressors and ultimately transferred to another facility.  11JUN2018: This report has been updated with information received through data reconciliation. The updates to the primary case include: clinical trial information, literature references (2), reporter, patient, laboratory/diagnostic detail; the narrative from the case was added including company comments. Sanofi case 2012-00924 has been merged into the Emergent case 12AV00003RG.  Follow-up information derived from a full-text article, was received on 19MAY2023.   It described a 18-year-old, male patient who "collapsed abruptly/passed out" (PT: Loss of consciousness), had "narrow complex tachycardia" (PT: Tachycardia), "hyperthermia" (PT: Hyperthermia) "fatigue" (PT: Fatigue), "did not sleep well" (PT: Sleep disorder) "was very thirsty all night" (PT: Thirst), had "bilateral leg cramps" (PT: Muscle spasms), "emesis" (PT: Vomiting),  "increasing liver enzymes" (PT: Hepatic enzyme increased) , "refractory cardiac arrest" (PT: Cardiac arrest) and "SPV-associated probable myocarditis" (PT: Myocarditis) following the immunisation with ACAM2000 (smallpox vaccine, live).  Case report:  A 18-year-old male was in good health having completed basic training during peak summer heat with extensive physical activity without difficulties (running 2 miles or more in greater than 100-degree F). He tolerated his initial immunizations (meningococcal PS, diphtheria-tetanus, inactivated polio vaccine, hepatitis B) with no adverse effects. He had a fit-for-duty examination with documented normal blood pressure, body mass index (BMI) 24, no tobacco, alcohol, or regular medication use. Glucose-6-phosphate dehydrogenase (G6PD) deficiency was documented. The patient was without any diagnoses that impacted the ability to deploy or receive the smallpox vaccine (SPV). Coronary artery disease or cardiomyopathy was not present in the patient. The patient administered smallpox vaccine along with Typhoid Vi (Typhoid vaccine), anthrax vaccine (ANTH) as concomitant vaccines. The patient's cardiac risk factor was noted as 0.  On the 8th day post smallpox vaccine (SPV), acute symptom onset was started during peak cytokine activation window for immune response to 1st dose of SPV. It was reported that the patient did not sleep well, was very thirsty all night, had fatigue and he did not feel prepared for a longer run (5-miles) but he denied feeling sick and decided to try the run. On same day, the outdoor temperature was 45-degree Fahrenheit (F). During the initial run, he complained of bilateral leg cramps and that was the last thing he remembered during his interview after initial resuscitation.  On same day at late AM, he collapsed abruptly and came in and out of consciousness according to observers. Emergency services was arrived. The initial rhythm strip with narrow complex tachycardia (170-200 bpm). He was treated with intravenous adenosine 6 mg and then 12 mg due to no initial response. Emesis episode was followed by sedation with etomidate for onsite cardioversion 120 joules without response. The patient awoke briefly complaining of jaw and leg pains with dizziness and shortness of breath (respiratory rate 24/min). His initial Glasgow Coma Scale score was 12 (mild-moderate brain injury) with initial oxygen (O2) saturation of 95-97 percent). He received 400 mL of normal saline and was transferred to the emergency room. On same day at PM, the patient was combative and had a temperature of 102.9-degree F. He received an additional 2 Liters of normal saline bolus, evaporating cooling measures and acetaminophen 950 mg. He had sinus tachycardia and an initial glucose of 52 mg/dL treated with an amp of D50 and associated improvement in mental status. The head computed tomography (CT) and chest X-ray was normal. The patient was stabilized and admitted for observation and care.  During the clinical course of hospitalisation of over 5 days, no evidence of specific infection (negative urine and blood cultures for bacterial, viral, fungal etiologies) was noted, but the patient had a deteriorating clinical course with increasing liver enzymes, renal insufficiency, and refractory cardiac arrest. The patient underwent certain laboratory investigations which included negative viral polymerase chain reaction (PCR) studies (including vaccinia of the heart tissue), negative toxicology studies and the peak troponin (ng/mL) was 1.310. After 13 days following SPV vaccination, the patient died. The histology at autopsy confirmed prolonged ischemia and final diagnosis attributed events to SPV associated myocarditis as cause of death.   The final consensus of the case revealed that end-stage terminal heart no longer showed classic histologic evidence of myocarditis which was patchy in distribution and may have been missed even early in the disease. Neuropathology: there was no evidence of encephalitis. Immunohistochemical testing was positive for orthopoxvirus at immunization site but negative for other organ specimens (heart, lung, liver) and enlarged lymph node was noted. The polymer chain reaction (PCR) screening was negative for enterovirus, human parvovirus B19, adenovirus, influenza A and B (heart, liver, and lung tissues), liver negative for hepatitis B surface antigen and core antigen. Immunohistochemistry of the heart showed moderate immunoglobulin G (IgG) deposition in the heart; quantitative autoantibody titers to cardiac myosin, beta-1,2 adrenergic receptors, M2 receptor were mildly elevated. Ryanodine receptor isoform 1 (RYR1) genetic screen for hyperthermia risk was negative.  Author's comment: An extensive multidisciplinary clinical review with additional testing subsequently resulted in a causality assessment that recurrent supraventricular arrythmia secondary to SPV-associated probable myocarditis was likely a significant contributor to the initiating presentation and eventual outcome. Death was most likely due to myocarditis induced by immunologic consequences of the smallpox vaccination. The temporal relationship of the vaccination to the onset of illness, clinical history, laboratory results, and histology support this conclusion. It was likely that the 5-mile run precipitated the initial syncopal episode by increasing demand on the compromised heart. It was unlikely that hyperthermia played a role in this death, given that the temperature on the day of the run was less than 45 degrees, and that the decedent was young and healthy, and had completed basic training during the heat of the summer. It was difficult to exclude a contribution from G6PD deficiency, but it was unlikely to have been significant, given that the decedent had been previously asymptomatic even under extreme physical stress. There was also no apparent role for G6PD deficiency in the development of myocarditis. It was possible that cross reactivity of anti-cardiac antibodies to skeletal muscle may have contributed to myoglobinuria, although there was no histologic correlation in skeletal muscle.  Based on the above available information in the source document, two individual case safety reports (14000046SP and 12AV00003RG) were created and linked in the database.  Company comment: It was reported that a 18-year-old male who received ACAM2000, complained of not sleeping well, faituge, and thirst 8 days following vaccination. He then decided to go for a run when the outdoor temperature was 45-degree Fahrenheit during which he collapsed abruptly and came in and out of consciousness according to observers. Patient was revived by paramedics and complained of bilateral leg cramps and his initial rhythm strip showed narrow complex tachycardia. He then had an emesis episode, jaw and leg pains, dizziness and shortness of breath. Temperature reported at 102.9 degrees F.  Labs noted increased liver enzymes, disseminated intravascular coagulation, thrombocytosis, leukocytosis, encephalopathy, but no infection.  After 13 days following ACAM2000, the patient died. The histology at autopsy confirmed prolonged ischemia and final diagnosis attributed events to smallpox vaccine associated myocarditis and it's immunologic consequences as cause of death. Based upon the absence of other known etiologies, and no reported implication to other vaccines or underlying health conditions, the temporal relationship of ACAM2000 cannot be ruled out and the causality of sleep disorder, thirst, loss of consciousness, muscle spasms, tachycardia, vomiting, pain, hyperthermia, increasing liver enzymes, disseminated intravascular coagulation, thrombocytosis, renal failure, encephalopathy, leukocytosis, hepatic encephalopathy, refractory cardiac arrest, and myocarditis is assessed as possible.  Per the medical examiner's assessment, it is likely that the 5-mile run precipitated the initial syncopal episode by increasing demand on the compromised heart. In addition, it should also be noted that the patient was G6PD deficient which may have contributed to the development of the events. The case is considered serious as per medical assessment.; Sender's Comments: It was reported that a 18-year-old male who received ACAM2000, complained of not sleeping well, faituge, and thirst 8 days following vaccination. He then decided to go for a run when the outdoor temperature was 45-degree Fahrenheit during which he collapsed abruptly and came in and out of consciousness according to observers. Patient was revived by paramedics and complained of bilateral leg cramps and his initial rhythm strip showed narrow complex tachycardia. He then had an emesis episode, jaw and leg pains, dizziness and shortness of breath. Temperature reported at 102.9 degrees F.  Labs noted increased liver enzymes, disseminated intravascular coagulation, thrombocytosis, leukocytosis, encephalopathy, but no infection.  After 13 days following ACAM2000, the patient died. The histology at autopsy confirmed prolonged ischemia and final diagnosis attributed events to smallpox vaccine associated myocarditis and it's immunologic consequences as cause of death. Based upon the absence of other known etiologies, and no reported implication to other vaccines or underlying health conditions, the temporal relationship of ACAM2000 cannot be ruled out and the causality of sleep disorder, thirst, loss of consciousness, muscle spasms, tachycardia, vomiting, pain, hyperthermia, increasing liver enzymes, disseminated intravascular coagulation, thrombocytosis, renal failure, encephalopathy, leukocytosis, hepatic encephalopathy, refractory cardiac arrest, and myocarditis is assessed as possible.  Per the medical examiner's assessment, it is likely that the 5-mile run precipitated the initial syncopal episode by increasing demand on the compromised heart. In addition, it should also be noted that the patient was G6PD deficient which may have contributed to the development of the events. The case is considered serious as per medical assessment.; Reported Cause(s) of Death: SPV associated myocarditis