(a) Pandemic influenza countermeasures injury table.

(b) Qualifications and aids to interpretation (table definitions and requirements). The following definitions and requirements shall apply to the Table set forth in paragraph (a) of this section and only apply for purposes of this subpart.

(1) Anaphylaxis. Anaphylaxis is an acute, severe, and potentially lethal systemic reaction that occurs as a single discrete event with simultaneous involvement of two or more organ systems. Most cases resolve without sequelae. Signs and symptoms begin minutes to a few hours after exposure. Death, if it occurs, usually results from airway obstruction caused by laryngeal edema or bronchospasm and may be associated with cardiovascular collapse. Other significant clinical signs and symptoms may include the following: Cyanosis, hypotension, bradycardia, tachycardia, arrhythmia, edema of the pharynx and/or trachea and/or larynx with stridor and dyspnea. There are no specific pathological findings to confirm a diagnosis of anaphylaxis.

(2) Deltoid bursitis. Deltoid bursitis is an inflammation of the bursa that lies beneath the deltoid muscle and between the acromion process and the rotator cuff. Subdeltoid bursitis manifests with pain in the lateral aspect of the shoulder similar to rotator cuff tendonitis. The presence of tenderness on direct palpation beneath the acromion process distinguishes this bursitis from rotator cuff tendonitis. Similar to tendonitis, isolated bursitis will have full passive range of motion. Other causes of bursitis such as trauma (other than from vaccination), metabolic disorders, and systemic diseases such as rheumatoid arthritis, dialysis, and infection will not be considered Table injuries. This list is not exhaustive. The deltoid bursitis must occur in the same shoulder that received the pandemic influenza vaccine.

(3) Vasovagal syncope. Vasovagal syncope (also sometimes called neurocardiogenic syncope) means loss of consciousness (fainting) and loss of postural tone caused by a transient decrease in blood flow to the brain occurring after the administration of an injected countermeasure. Vasovagal syncope is usually a benign condition but may result in falling and injury with significant sequelae. Vasovagal syncope may be preceded by symptoms such as nausea, lightheadedness, diaphoresis, and/or pallor. Vasovagal syncope may be associated with transient seizure-like activity, but recovery of orientation and consciousness generally occurs simultaneously. Loss of consciousness resulting from the following conditions will not be considered vasovagal syncope: Organic heart disease; cardiac arrhythmias; transient ischemic attacks; hyperventilation; metabolic conditions; neurological conditions; psychiatric conditions; seizures; trauma; and situational as can occur with urination, defecation, or cough. This list is not complete. Episodes of recurrent syncope occurring after the applicable time period are not considered to be sequelae of an episode of syncope meeting the Table requirements.

(4) Guillain-Barré Syndrome (GBS). (i) GBS is an acute monophasic peripheral neuropathy that currently is known to encompass a spectrum of four clinicopathological subtypes described below. For each subtype of GBS, the interval between the first appearance of symptoms and the nadir of weakness is between 12 hours and 28 days. This is followed in all subtypes by a clinical plateau with stabilization at the nadir of symptoms, or subsequent improvement without significant relapse. Death may occur without a clinical plateau. Treatment related fluctuations in all subtypes of GBS can occur within 9 weeks of GBS symptom onset and recurrence of symptoms after this time frame would not be consistent with GBS.

(ii) The most common subtype in North America and Europe, comprising more than 90 percent of cases, is acute inflammatory demyelinating polyneuropathy (AIDP) which has the pathologic and electrodiagnostic features of focal demyelination of motor and sensory peripheral nerves and nerve roots. Another subtype called acute motor axonal neuropathy (AMAN) is generally seen in other parts of the world and is predominated by axonal damage that primarily affects motor nerves. AMAN lacks features of demyelination. Another less common subtype of GBS includes acute motor and sensory neuropathy (AMSAN), which is an axonal form of GBS that is similar to AMAN, but also affects the sensory nerves and roots. AIDP, AMAN, and AMSAN are typically characterized by symmetric motor flaccid weakness, sensory abnormalities, and/or autonomic dysfunction caused by autoimmune damage to peripheral nerves and nerve roots. The diagnosis of AIDP, AMAN, and AMSAN requires bilateral flaccid limb weakness and decreased or absent deep tendon reflexes in weak limbs; a monophasic illness pattern; an interval between onset and nadir of weakness between 12 hours and 28 days; subsequent clinical plateau (the clinical plateau leads to either stabilization at the nadir of symptoms, or subsequent improvement without significant relapse); and, the absence of an identified more likely alternative diagnosis. Death may occur without a clinical plateau.

(iii) Fisher syndrome (FS), also known as Miller-Fisher Syndrome, is a subtype of GBS characterized by ataxia, areflexia, and ophthalmoplegia, and overlap between FS and AIDP may be seen with limb weakness. The diagnosis of FS requires bilateral ophthalmoparesis; bilateral reduced or absent tendon reflexes; ataxia; the absence of limb weakness (the presence of limb weakness suggests a diagnosis of AIDP); a monophasic illness pattern; an interval between onset and nadir of weakness between 12 hours and 28 days; subsequent clinical plateau (the clinical plateau leads to either stabilization at the nadir of symptoms, or subsequent improvement without significant relapse); no alteration in consciousness; no corticospinal track signs; and, the absence of an identified more likely alternative diagnosis. Death may occur without a clinical plateau.

(iv) Evidence that is supportive, but not required, of a diagnosis of all subtypes of GBS includes electrophysiologic findings consistent with GBS or an elevation of cerebral spinal fluid (CSF) protein with a total CSF white blood cell count below 50 cells per microliter. The results of both CSF and electrophysiologic studies are frequently normal in the first week of illness in otherwise typical cases of GBS.

(v) For GBS to qualify as a Table injury there must not be a more likely alternative diagnosis for the weakness. Exclusionary criteria for the diagnosis of all subtypes of GBS include the ultimate diagnosis of any of the following conditions: Chronic immune demyelinating polyradiculopathy (“CIDP”), carcinomatous meningitis, brain stem encephalitis (other than Bickerstaff brainstem encephalitis), myelitis, spinal cord infarct, spinal cord compression, anterior horn cell diseases such as polio or West Nile virus infection, subacute inflammatory demyelinating polyradiculoneuropathy, multiple sclerosis, cauda equina compression, metabolic conditions such as hypermagnesemia or hypophosphatemia, tick paralysis, heavy metal toxicity (such as arsenic, gold, or thallium), drug-induced neuropathy (such as vincristine, platinum compounds, or nitrofurantoin), porphyria, critical illness neuropathy, vasculitis, diphtheria, myasthenia gravis, organophosphate poisoning, botulism, critical illness myopathy, polymyositis, dermatomyositis, hypokalemia, or hyperkalemia. The above list is not exhaustive.

(5) Tracheal stenosis. (i) Postintubation tracheal stenosis means an iatrogenic (caused by medical treatment) and symptomatic stricture of the airway (narrowing of the windpipe) resulting from:

(A) Trauma or necrosis from an endotracheal tube; or

(B) Stomal injury from a tracheostomy; or

(C) A combination of the two.

(ii) Tracheal stenosis or narrowing due to tumors (malignant or benign), infections of the trachea (such as tuberculosis, fungal diseases), radiotherapy, tracheal surgery, trauma, congenital, and inflammatory or autoimmune diseases will not be considered post-intubation tracheal stenosis. Post-intubation tracheal stenosis requires either tracheostomy with placement of a tracheostomy tube or endotracheal intubation. Diagnosis requires symptoms of upper airway obstruction such as stridor (inspiratory wheeze) or exertional dyspnea (increased shortness of breath with exertion), and positive radiologic studies showing abnormal narrowing of the trachea or bronchoscopic evaluation that demonstrates abnormal narrowing.

(6) Ventilator-Associated Pneumonia (VAP) and Ventilator-Associated Tracheobronchitis (VAT). (i) VAP is defined as an iatrogenic pneumonia caused by the medical treatment of mechanical ventilation. Similarly, VAT is an iatrogenic infection of the trachea and/or bronchi caused by mechanical ventilation. The initial manifestation of VAP and VAT must occur more than 48 hours after intubation (placement of the breathing tube) and up to 48 hours after extubation (removal of the breathing tube). VAP will be considered to be present when the patient demonstrates a new or progressive radiographic infiltrate that is in the lungs and consistent with pneumonia, fever, leukocytosis (increased white blood cell count) or leucopenia (decreased white blood cell count), purulent (containing pus) tracheal secretions from a tracheal aspirate, and a positive lower respiratory tract culture. The positive lower respiratory tract culture is a diagnostic requirement only if there has not been a change in antibiotics in the 72 hours prior to collection of the culture. In addition, a tracheal aspirate that does not demonstrate bacteria or inflammatory cells in a patient without a change in antibiotics in the previous 72 hours is unlikely to be VAP and shall not be considered a condition set forth in the Table.

(ii) VAT will be considered to be present when the patient demonstrates fever, leukocytosis or leukopenia, purulent tracheal secretions, and a positive tracheal aspirate culture in the absence of a change of antibiotics within the 72 hours prior to culture. Tracheal colonization with microorganisms is common in intubated patients, but in the absence of clinical findings is not a sign of VAT.

(7) Ventilator-Induced Lung Injury (VILI). VILI results from mechanical trauma such as volutrauma leading to rupture of alveoli (air sacs in the lungs where oxygen and carbon dioxide are exchanged with the blood) with subsequent abnormal leakage of air. VILI manifests as iatrogenic pneumothorax (abnormal air from alveolar rupture in the pleural space), pneumomediastinum (abnormal air from alveolar rupture in the mediastinum (middle part of the chest between the lungs)), pulmonary interstitial emphysema (abnormal air in the lung interstitial space between the alveoli), subpleural air cysts (an extreme form of pulmonary emphysema where the abnormal air in the interstitial space has pooled into larger pockets), subcutaneous emphysema (abnormal air from alveolar rupture that has dissected into the skin), pneumopericardium (abnormal air from alveolar rupture that has traveled to the pericardium (covering of the heart)), pneumoperitoneum (abnormal air from alveolar rupture that has moved into the abdominal space), or systemic air embolism (abnormal air from alveolar rupture that has moved into the blood). To qualify as Table injuries, these manifestations must occur in patients who are being mechanically ventilated at the time of initial manifestation of the VILI.

(8) Bleeding events. Bleeding events are defined as excessive or abnormal bleeding in patients who are under the pharmacologic effects of anticoagulant therapy provided for extracorporeal membrane oxygenation (ECMO) treatment.

(c) Smallpox countermeasures injury table.

(d) Qualifications and aids to interpretation (table definitions and requirements). The following definitions and requirements shall apply to the Table set forth in paragraph (c) of this section and only apply for purposes of this subpart.

(1) Anaphylaxis. Anaphylaxis is an acute, severe, and potentially lethal systemic reaction that occurs as a single discrete event with simultaneous involvement of two or more organ systems. Most cases resolve without sequelae. Signs and symptoms begin within minutes to a few hours after exposure. Death, if it occurs, usually results from airway obstruction caused by laryngeal edema or bronchospasm and may be associated with cardiovascular collapse. Other significant clinical signs and symptoms may include the following: Cyanosis, hypotension, bradycardia, tachycardia, arrhythmia, edema of the pharynx and/or trachea and/or larynx with stridor and dyspnea. There are no specific pathological findings to confirm a diagnosis of anaphylaxis.

(2) Vasovagal syncope. Vasovagal syncope (also sometimes called neurocardiogenic syncope) means loss of consciousness (fainting) and loss of postural tone caused by a transient decrease in blood flow to the brain occurring after the administration of an injected countermeasure. Vasovagal syncope is usually a benign condition, but may result in falling and injury with significant sequelae. Vasovagal syncope may be preceded by symptoms, such as nausea, lightheadedness, diaphoresis (sweating), and/or pallor. Vasovagal syncope may be associated with transient seizure-like activity, but recovery of orientation and consciousness generally occurs simultaneously. Loss of consciousness resulting from the following conditions will not be considered vasovagal syncope: Organic heart disease, cardiac arrhythmias, transient ischemic attacks, hyperventilation, metabolic conditions, neurological conditions, psychiatric conditions, seizures, trauma, and situational as can occur with urination, defecation, or cough. This list is not complete as other conditions that are not associated with the vaccine also may cause loss of consciousness. Episodes of recurrent syncope occurring after the applicable timeframe are not considered to be sequelae of an episode of syncope meeting the Table 2 requirements.

(3) Significant local skin reaction. Significant local skin reaction is an unexpected and extreme response at the vaccination or inoculation site that results in a significant scar that is serious enough to require surgical intervention. The onset of this injury is the initial skin lesion at the vaccination site that generally occurs with replication-competent smallpox vaccinations. Minor scarring or minor local reactions do not constitute a Table 2 injury. A robust take, defined as an area of redness at the vaccination site that exceeds 7.5 cm in diameter with associated swelling, warmth and pain, is generally considered an expected response to the vaccination or inoculation. A robust take, in itself, does not constitute a Table 2 injury, even when the redness and swelling involves the entire upper arm with associated enlargement and tenderness of the glands (lymph nodes) in the underarm (axilla).

(4) Stevens-Johnson syndrome/Toxic epidermal necrolysis (SJS/TEN). SJS/TEN is a spectrum of acute hypersensitivity reactions that affects skin, mucous membranes, and sometimes, internal organs (systemic toxicity) associated with the use or administration of replication- competent smallpox vaccines. For purposes of Table 2, both skin and mucous membrane rash or lesions must be present. Rash or lesion distribution must be widespread. Rash must not have a symmetric acral distribution (affecting arms, hands, legs or feet). Two or more mucosal sites must be involved. Mucosal lesions generally manifest as painful lesions in sites, such as the mouth or eyes. Skin rash or lesions in SJS/TEN usually consist of red or purple raised areas (erythematous macules), blisters, and ulcerations.

(5) Inadvertent autoinoculation (IA). IA is the spread of vaccinia virus from an existing vaccination site to a second location usually by scratching the vaccination site and subsequently spreading the virus, which produces a new vaccinial lesion on the same person who received the vaccination. IA is the most common adverse event associated with the replication-competent smallpox vaccine.

(6) Generalized vaccinia (GV). GV is a vaccinial infection that occurs from the spread of vaccinia from an existing vaccination or inoculation site, with the use or administration of a replication-competent smallpox vaccine, to otherwise normal skin, resulting in multiple new areas of vaccinial rash or lesions. The vaccinia is believed to be spread through the blood. The rash or lesions, characterized by multiple blisters (vesicles or pustules), generally evolve in a similar sequence or manner as the original vaccination site.

(7) Eczema vaccinatum (EV). EV is the transmission or the spread of vaccinia virus from a vaccination site, after the use or administration of a replication-competent smallpox vaccine, to skin that has been affected by, or is currently affected with, eczema or atopic dermatitis. EV is characterized by lesions that include multiple blisters (vesicles or pustules), which generally evolve in a similar sequence or manner as the original vaccination site. The lesions may come together to form larger lesions. Lesions may also spread to patches of skin that have never been involved with eczema or atopic dermatitis. The new lesions, if cultured, will be positive for vaccinia virus. A person with EV may become severely ill with signs and symptoms that involve the whole body (systemic illness), such as fever, malaise, or enlarged glands (lymph nodes).

(8) Progressive vaccinia (PV). PV is the failure to initiate the healing process in an initial vaccination or inoculation site, after the use or administration of a replication-competent smallpox vaccine, by 21 days after exposure to vaccinia, with progressive ulceration or necrosis at the vaccination site leading to a large destructive ulcer. PV is seen in people who are immunocompromised (have an impaired immune system) and is characterized by a complete or near complete lack of inflammation or absence of inflammatory cells in the dermis of the skin at the vaccination site. The diagnosis of PV may be made before 21 days after exposure, especially in a known immunocompromised individual who develops a lesion at the vaccination site. PV may spread through the blood to any location in the body. No one who experiences a significant healing process of the vaccination site within 21 days after receipt of the replication-competent smallpox vaccine or exposure to vaccinia has PV.

(9) Post-vaccinial encephalopathy, encephalitis, and encephalomyelitis (PVEM). PVEM is a spectrum of overlapping conditions that includes post-vaccinial encephalopathy, encephalitis, and encephalomyelitis, and, for the purposes of Table 2, is treated as one injury. For the purposes of Table 2, PVEM is an autoimmune central nervous system injury that occurs after the use or administration of a replication-competent smallpox vaccine. In rare cases, the vaccinia virus is isolated from the central nervous system. Manifestations usually occur abruptly and may include fever, vomiting, loss of appetite (anorexia), headache, general malaise, impaired consciousness, confusion, disorientation, delirium, drowsiness, seizures, language difficulties (aphasia), coma, muscular incoordination (ataxia), urinary incontinence, urinary retention, and clinical signs consistent with inflammation of the spinal cord (myelitis), such as paralysis or meningismus (meningeal irritation). Long-term central nervous system impairments, such as paralysis, seizure disorders, or developmental delays are known to occur as sequelae of the acute PVEM. No clinical criteria, radiographic findings, or laboratory tests are specific for the diagnosis of PVEM. Symptoms that occur before 5 days or more than 14 days after receiving the smallpox vaccine should not be attributed to it. In addition, encephalopathy caused by an infection, a toxin, a metabolic disturbance, a structural lesion, a genetic disorder, or trauma would not meet the Table 2 definition.

(10) Vaccinial myocarditis, pericarditis, or myopericarditis (MP). For purposes of Table 2, MP is vaccinial myocarditis, pericarditis, or myopericarditis. Vaccinial myocarditis is defined as an inflammation of the heart muscle (myocardium) because of receiving the replication-competent smallpox vaccine. Vaccinial pericarditis is defined as an inflammation of the covering of the heart (pericardium) because of receiving the smallpox vaccine. Vaccinial myopericarditis is defined as an inflammation of both the heart muscle and its covering because of receiving the smallpox vaccine. The inflammation associated with MP may range in severity from very mild (subclinical) to life threatening. In many mild cases, myocarditis is diagnosed solely by transient electrocardiographic (EKG) abnormalities (e.g., ST segment and T wave changes), increased cardiac enzymes, or mild echocardiographic abnormalities. Arrhythmias, abnormal heart sounds, heart failure, and death may occur in more severe cases. Pericarditis generally manifests with chest pain, abnormal heart sounds (pericardial friction rub), EKG abnormalities (e.g., ST segment and T wave changes), and/or increased fluid accumulation around the heart. A Table 2 injury of MP requires sufficient evidence in the medical records of the occurrence of acute MP.

(11) Transfusion-related acute lung injury (TRALI). TRALI is defined as the onset of respiratory distress within 6 hours in non-critically ill patients, and 72 hours in critically ill patients, after receipt of blood products containing plasma, in this case, VIGIV. The relative level of illness will be determined on a case-by-case basis after reviewing the medical records and the medical history. The respiratory distress is the result of receiving a plasma containing transfusion (VIGIV) and subsequently developing pulmonary edema, respiratory distress, and hypoxia. TRALI occurs as the result of an antibody response in the host to the donor antibodies within the plasma product. Pulmonary edema is non-cardiac in nature and does not occur more than 72 hours after receiving VIGIV. Pulmonary edema occurring more than 72 hours after receiving a blood product containing plasma (VIGIV) or associated with cardiac dysfunction is not TRALI and is excluded as a countermeasure-related injury. TRALI has been identified as a major cause of mortality in those individual receiving plasma-containing transfusions. A Table 2 injury for TRALI has occurred in a recipient if there is sufficient evidence in the medical record of an occurrence of TRALI and the pulmonary edema is not caused by cardiac dysfunction or other causes and occurs within 72 of receiving a blood product containing plasma, in this case VIGIV.

(12) Acute renal failure (ARF). ARF is the sudden loss of the kidneys' ability to perform their main function of eliminating excess fluids and electrolytes (salts), as well as waste material from the blood. ARF, which is also called acute kidney injury, develops rapidly over a few hours or a few days. ARF can be fatal and requires intensive treatment; however, ARF may be reversible. ARF may cause permanent loss of kidney function, or end-stage renal disease necessitating dialysis or transplant. A Table 2 injury for ARF has occurred if there is sufficient evidence in the medical record of an occurrence of ARF within the identified timeframe and the individual received the associated countermeasure (VIGIV).

(13) Drug-induced aseptic meningitis (DIAM). (i) DIAM is an inflammation of the meninges (linings of the brain) that is not caused by a bacteria or virus, but is caused by a drug or medication. The symptoms of meningitis include severe headache, nuchal (neck) rigidity, drowsiness, fever, photophobia (light sensitivity), painful eye movements, nausea, and vomiting. Discontinuation of the medication leads to a resolution of the symptoms. DIAM is thought to occur because of an immunological hypersensitivity reaction to a specific medication. In the case of immunoglobulins, DIAM may be precipitated by the immunologically active components within the plasma or because of the stabilizers used within the product. The symptoms of DIAM may reoccur with another exposure to the offending agent.

(ii) A Table 2 injury for DIAM has occurred in a recipient if there is sufficient evidence in the medical record of an occurrence of DIAM within the identified timeframe and the individual received the associated countermeasure (VIGIV). DIAM occurring in the absence of the use of VIGIV, or DIAM occurring with the use of VIGIV outside the established timeframe of onset, which is any time after the first dose and up to 48 hours after the last dose of this medication, is not a Table 2 injury.

(14) Hemolysis. Hemolysis is the physical breakdown of red blood cells (RBCs) either through natural attrition or as caused by external factors. The RBC's function is to transport oxygen throughout the body in the hemoglobin contained within the RBC. Additionally, the RBCs contain the majority of the body's potassium stores. With hemolysis, the body is unable to transport oxygen effectively, and the person develops hypoxia. Additionally, the rapid breakdown of the cell releases large amounts of potassium into the blood stream, which can cause abnormal heart rhythms and cardiac arrest. In severe cases of hemolysis, a blood transfusion may be required to correct the resulting anemia. A Table 2 injury for hemolysis has occurred if there is sufficient evidence in the medical record of an occurrence of hemolysis, and the patient received the associated countermeasure (VIGIV). Hemolysis occurring in the absence of the use of VIGIV and outside of the timeframe of 12 hours to 14 days after receiving VIGIV is not a Table 2 injury. Hemolysis occurring from a more likely alternative diagnosis, such as infections, toxins, poisons, hemodialysis, or medications, is not a Table 2 injury. This list of conditions that can cause hemolysis, not associated with VIGIV, is not exhaustive, and all additional diagnoses within the medical documentation will be evaluated.

[80 FR 47416, Aug. 7, 2015, as amended at 86 FR 45657, Aug. 16, 2021]