Author + information
- Published online March 27, 2007.
- Larry M. Baddour, MD, Co-Chair,
- Zhi-Jie Zheng, MD, PhD, Co-Chair,
- Darwin R. Labarthe, MD, MPH, PhD, FAHA and
- Siobhán O’Connor, MD, MPH
Definition and Classifications
Emerging infections are those with a rising incidence over recent decades and those that threaten to increase, encompassing both newly emerging and re-emerging infections. The emergence of a new infectious agent in the population, the new recognition of a previously undetected circulating agent, or the realization that a noncommunicable disease is actually caused by infection contribute to this group of microbial threats, unrelated to any possible intentional release of biologic agents or bioterrorism (1). As with the scope of the larger body of all infections and infectious diseases, the capacity of emerging infections to affect the cardiovascular system varies from none to limited or increased risk. However, this task force report will focus on the possible cardiovascular implications of emerging infectious diseases and infection with select agents designated to have potential for intentional release.
A wide range of infectious agents that can emerge in spontaneous epidemics or be disseminated in bioterrorist attacks can affect the cardiovascular system. Many of these infectious agents have caused disease sporadically (e.g., botulism, tularemia) or endemically (e.g., viral hemorrhagic fevers) in certain parts of the world for centuries; others are relative newcomers (e.g., severe acute respiratory syndrome or SARS, Nipah virus). Some of these agents (e.g., smallpox) do not occur naturally at present and even one confirmed case would signal a likely bioterrorist event.
When focusing on the select potential agents of bioterrorism, as well as emerging infectious diseases, the clinical syndromes catalogued by the U.S. Department of Health and Human Services are as varied as the pathogens that produce them (2,3). With some, the direct clinical impact is limited to 1 organ system, as in the case of Clostridium botulinumtoxin-induced neuroparalytic illness (4). Other agents can affect multiple organ systems, as in the case of Coxiella burnetiiinfection, which affects both pulmonary and hepatic systems (5). Additional factors accentuate the complexity of bioterrorism-related illnesses. The temporal onset of different clinical manifestations following exposure can vary. For example, Q fever endocarditis is an illness of chronic infection; whereas pneumonia is seen acutely following exposure (5). However, naturally occurring infections with most of the designated bioterrorism agents are rarely seen in the U.S. today. Because of this, many clinicians are unfamiliar with the associated clinical syndromes and may not initially recognize when an illness stems from exposure to one of these agents, much less from intentional release in a bioterrorism attack (6).
The Centers for Disease Control and Prevention (CDC) has classified certain diseases and agents into 3 relatively high-priority categories (A, B, and C) (2,3). These diseases and agents are summarized in Tables 1 and 2.⇓⇓Diseases and agents in Category A have the highest priority because they can be disseminated or transmitted easily from person to person, result in high mortality rates, have the potential for major public health impact, may cause public panic and social disruption, and require special action for public health preparedness. Diseases and agents in Category B are moderately easy to disseminate, result in moderate morbidity rates and low mortality rates, and require specific enhancements of the diagnostic capacity and enhanced disease surveillance. Diseases and agents in Category C include emerging pathogens that could be engineered for mass dissemination in the future because of availability, ease of production and dissemination, and the potential for high morbidity and mortality rates and major public health impact.
This report focuses on the Category A, B, and C agents, but an unlimited number of other potential, nonbioterrorism, microbial threats exist from natural evolution, transformation, and transmission of existing pathogens, including emerging and re-emerging infectious diseases, as well as from genetically engineered variants or “mosaics” that can multiply the potential transmissibility, morbidity, and mortality of agents released in a terrorist attack.
Many of the Category A, B, and C agents injure the myocardium, pericardium, or endothelium by direct infection or infiltration or through a chemical toxin (e.g., ricin). For some, the evidence of direct effects stems from multiple observations. For others, information rests on a single or a small set of anecdotal reports. Although such direct injury could harm even healthy individuals with a previously normal cardiovascular system, the reality is that most of the currently known, high-risk agents are not directed at the cardiovascular system per se. Greater concern comes from secondary effects on the heart and vasculature when these agents cause prolonged or severe fever, sepsis, shock, dehydration, central and peripheral nervous system dysfunction, anemia, hypoxia, renal, and/or hepatic impairment.
Cardiovascular specialists should have a general working knowledge of the common bioterrorist agents (6). Table 2highlights the clinical presentation, evaluation, and laboratory testing for a number of diseases and agents that are of particular concern to our national security (3,7). It is important for clinicians to remember that although most of the Category A, B, and C agents are disseminated and transmitted by aerosolized droplets or secretions that enter the victim via the respiratory route (e.g., weaponized anthrax spores, ricin), notable exceptions exist (e.g., cutaneous anthrax exposure).
Known Cardiovascular Syndromes Associated With Category A, B, and C Agents and Diseases
Four cardiovascular syndromes are caused by bioterrorism agents: 1) endocarditis, 2) myocarditis, 3) pericarditis, and 4) vasculitis. The heart is the primary site of endocarditis, myocarditis, and pericarditis pathology, while vasculitis affects the vascular tissues. The mechanisms of pathology are varied, ranging from direct tissue invasion by the microbe—transient or persistent—to complications of a local or systemic immune response to infection.
Distinguishing the microbial etiology of each syndrome can be challenging; whether intentionally released for bioterrorism or naturally occurring, different infectious agents can cause indistinguishably similar clinical signs and symptoms. Thus, it may not be obvious to clinicians, at least early in a bioterrorism attack, that a cardiovascular syndrome is due to biological warfare, especially if the biological agent does not grow or grows slowly in the culture media routinely used by clinical laboratories to detect naturally occurring pathogens. Characteristic signs and symptoms of each of the 4 cardiovascular syndromes are briefly outlined in the subsequent sections.
The clinical features of infective endocarditis depend, in part, on the virulence of the infecting organism(s), the exposure dose, and the host response to that infection (8). With more aggressive pathogens, clinical evidence may develop within hours to days of establishment of infection. With less virulent microorganisms, the onset of infection is more subtle and initially nonspecific, often delaying diagnosis by weeks or even months.
A majority of patients manifest fever. Other signs of systemic toxicity or sepsis may be present with endocarditis due to aggressive pathogens but are usually absent in patients with subacute to chronic infection. Other nonspecific findings include chills, malaise, fatigue, night sweats, weakness, weight loss, myalgias, and arthralgias.
The development of secondary complications of endocarditis often prompts a consideration of the correct diagnosis. This includes the presence of a cardiac murmur due to valvular insufficiency (or rarely, stenosis) caused by destruction of components of the valve apparatus. Other indications of infective endocarditis are signs of left- or right-sided ventricular failure and systemic or pulmonary vascular embolic events, including acute evidence of tissue damage or organ dysfunction, such as stroke, pleuritic chest pain, extremity or digit ischemia, and visual loss.
Blood cultures are critical to establish the diagnosis and the etiology of infective endocarditis cases and other syndromes of intracardiac or intravascular infection. When a blood culture is negative due to recent administration of antibiotics or the fastidious growth characteristics of the infecting pathogen (such characteristics are manifested by some of the bioterrorism agents), the diagnosis of endocarditis may be less obvious, particularly if only nonspecific clinical findings are present. In such cases, echocardiography, particularly transesophageal echocardiography in adults, may be used to establish a diagnosis of endocarditis (8,9). Similarly, serology (detection of antibodies to the infectious agent), immunohistochemistry, and testing for the presence of pathogen deoxyribonucleic acid, may be key to the diagnosis of blood and tissue culture-negative endocarditis (10). These latter methods of diagnosis are particularly useful to identify certain naturally occurring pathogens that could be used for bioterrorism attacks, including Coxiella burnetii, Franciscella tularensis, and Chlamydia psittaci.
Myocarditis is associated with many more infectious and noninfectious causes than endocarditis. In addition, seasonal outbreaks of myocarditis may occur as a result of several viral etiologies. As a result, clinicians are likely to link an increased number of myocarditis cases to a viral epidemic, which could delay the recognition of a bioterrorism attack.
Unlike infective endocarditis, myocarditis can be asymptomatic and, depending on the etiology, may resolve itself without specific antimicrobial treatment (11,12). Thus, most cases of myocarditis are undiagnosed. This makes it difficult to quantify a background rate in the population and to detect any increased frequency of myocarditis induced by changing infectious exposures. When symptoms do occur, chest pain is predominant and palpitations, shortness of breath, and cough may be present. Additional signs of myocarditis include recent or current fever, tachycardia, pericardial friction rub, signs of congestive heart failure, and the presence of a third heart sound.
Cardiomegaly and vascular congestion on chest radiograph and ST-segment elevation and T-wave inversion on serial electrocardiograms may be present (11). Echocardiogram and cardiac magnetic resonance imaging (MRI) with gadolinium are useful for assessing ventricular wall motion and left ventricular ejection fraction (11). Inflammatory changes in the myocardium may be seen on MRI showing areas of reduced contrast perfusion and enhanced delayed ventricular wall uptake.
These symptoms, signs, and diagnostic indicators, however, are common to myocarditis of multiple etiologies. Laboratory studies that detect microbes and viruses, systemically or in myocardial tissue, and/or document the serologic response to a particular infection, are needed to delineate the infectious etiology—whether naturally occurring or due to an intentional bioterrorist release. The clinician must be prepared (perhaps educated or trained) to recognize the array of potential etiologies of myocarditis, including in this context, the rarer potential select agent causes and the rare possibility of a bioterrorism event. Clinicians should also be familiar with the route to appropriate testing of adequately collected and processed specimens at a proficient laboratory and to alerting public health officials of unusual findings so they might assess for a cluster or larger group of cases and, if found, investigate the cause.
Many conditions affect both the myocardium and the pericardium. Primary involvement of one or the other cardiac structure, however, is usually clinically definable (13,14).
Chest pain is the most common symptom of pericarditis. The pain is usually, but not always, associated with a rub heard on cardiac auscultation and is typically worse when the patient lies supine, swallows, or takes deep breaths. The individual may experience fever, as well as dyspnea that could be a manifestation of cardiac tamponade due to pericardial effusion caused by pericarditis. Other evidence of tamponade may include a pulsus paradoxus greater than 10 mm Hg and a prominent X descent with loss of the Y descent in the jugular venous pressure.
An electrocardiogram usually shows ST-segment elevation in all lead tracings as early changes in pericarditis. Large pericardial effusions may cause reduced QRS voltage and electrical alternans. Echocardiography is an important tool to determine whether an effusion is present and to estimate its size and whether early hemodynamic compromise exists due to the effusion in the pericardial space (14). Identification of an infectious etiology is important since interventions are available for certain bacteria. Blood cultures, serology, polymerase chain reaction (PCR), or reverse transcriptase-PCR of blood, its components, and even pericardial fluid assist in this diagnosis.
Infection of the peripheral vascular system has been reported with several of the potential infectious select agents of bioterrorism. In vasculitis, the involvement ranges from infection and inflammation with or without mycotic aneurysm of large and medium vessel walls to that of small vessels and even superficial cutaneous leukocytoclastic vasculitis; for each implicated infectious etiology, the available body of evidence varies from large to anecdotal. As with endocarditis and myocarditis, this complication of bacterial or viral infection is more often attributed to common agents than to the possible select agents of bioterrorism.
In some vasculitis cases, infection of the arterial wall may not be apparent. In some, local, systemic, or both clinical manifestations occur (15,16). Local findings include pain due to aneurysmal dilation of the arterial wall. In addition, vessel rupture with bleeding can cause pain. Pain may also be due to arterial emboli that precipitate local or distal ischemia. The findings of distal ischemia include skin changes, diminishment or absence of palpable pulse, and eventual gangrene. A mass may be palpable with aneurysm or aneurysm formation. Bleeding, when in the brain or central nervous system, may present as severe headache, neurologic deficit, and/or mental status decline. Local soft tissue findings of inflammation may be apparent when more superficial arteries, usually in an extremity, are infected. Gastrointestinal bleeding, which can range from indolent to severe and sudden, may complicate abdominal aortic aneurysms that erode into the gastrointestinal tract.
The systemic findings of vasculitis include sepsis. In these patients, blood cultures are usually positive and leukocytosis is frequently present. Relapsing bacteremia following an initial course and response to antibiotics may be a valuable clue to the correct diagnosis. Depending on the cause, serology and PCR can be valuable adjuncts to the diagnosis of vasculitis and identification of an infectious etiology, as could culture, immunopathology, and molecular diagnostic tools (e.g., PCR) of any surgical resection or biopsy tissue.
The choice of imaging modality to evaluate whether an aneurysm is present varies depending on location of the infection. For intracranial evaluation, cerebral arteriography is optimal, although MRI angiography is also used. Computed tomography scanning is useful for aortic examination and for more distal arteries. Echocardiography is useful for evaluation of the most proximal segment of the aorta.
Select Diseases and Agents That May Affect the Cardiovascular System
Select Category A and B bioterrorism agents or diseases and the cardiovascular syndromes they may produce are summarized in Table 1and described in more detail in the following text. These descriptions are based on the review of existing reports in the literature through a systematic literature search on PubMed. For all except Q fever, cardiovascular syndromes are uncommonly reported.
Category A Diseases and Agents
Direct involvement of cardiovascular structures by Francisella tularensis, the agent of tularemia, is clinically rare. Only 1 case of infective endocarditis has been described (17), so that characterization of the illness is not possible. Pericarditis has been reported in a small number of patients, both in the pre-antibiotic era (18) and recently (19). In these patients, concomitant pneumonia was frequent, and the presentation was acute.
Category B Diseases and Agents
Infection due to Brucellaspecies is uncommon in the U.S. Cardiovascular complications have been reported to occur in 2% or less of patients who develop brucellosis. Infective endocarditis is the most common cardiovascular syndrome in these individuals. Most reported cases of Brucella-associated endocarditis have occurred in males, age 40 years and younger (20,21). These individuals present with a chronic infection, and valvular cusp calcification (22).
Endocarditis can complicate both pre-existing normal and abnormal cardiac valves. The aortic valve is most often involved, but lack of use of transesophageal echocardiography could underestimate the frequency of mitral valve infection, in addition to structural complications. Myocardial abscess and systemic embolization may occur, although less frequently than with other types of bacterial endocarditis (23). The usual cause of death due to Brucellaendocarditis is congestive heart failure (23).
Other rare cardiovascular syndromes associated with brucellosis include myocarditis, pericarditis, and infective endarteritis. However, the numbers of cases with each syndrome is so small that characterization of these conditions is difficult (24–28). It is important to note, however, that aortic involvement with mycotic aneurysm formation is often associated with infective spondylodiscitis due to Brucellaspecies (29,30).
Cases of psittacosis-associated endocarditis, myocarditis, and pericarditis have been described (31–33). Mortality is frequent among patients with Chlamydia psittaci-associated infective endocarditis, who typically present with highly destructive valvular infection (33). Some patients experience pulmonary complaints, which is consistent with the route of exposure to the pathogen. Respiratory symptoms have also been identified in cases of myocarditis and pericarditis due to C. psittaci. Because congestive heart failure can complicate all 3 syndromes (endocarditis and myocarditis most commonly), it may be difficult to determine whether C. psittaciis directly or indirectly responsible for the pulmonary symptoms.
A history of avian contact is commonly reported among humans who develop cardiac infection due to C. psittaci. Culture of the organism from blood and infected tissues is difficult. Because of the rarity of cardiac infection produced by C. psittaci, clinicians rarely order serology or immunohistochemical studies for this agent, and the sensitivity and specificity of testing in clinical laboratories may vary. Thus, infection may remain undiagnosed.
Q fever is a worldwide zoonosis caused by Coxiella burnetii, a strictly intracellular, gram-negative bacterium, which lives in the monocyte/macrophage, its host phagocytic cell. It is a particularly infectious organism, with the minimal infective dose being 1 to 5 organisms, and it is usually transmitted following contact with infected animals (34,35).
Clinically, the disease is polymorphic and nonspecific and may present in an acute or chronic form. The most common signs and symptoms of acute Q fever are prolonged fever or flu-like syndrome of unexplained origin, granulomatous hepatitis, and atypical pneumonia, although up to 50% of patients may be asymptomatic (5,36,37).
Infective endocarditis is the major manifestation of chronic Q fever (5,37), but routine blood cultures of affected patients are often negative for C. burnetii(38). Q fever endocarditis is estimated to account for at least 5% of the more than 800 cases of endocarditis diagnosed in France from 1949 through 2000 (36).
The major risk factors for developing chronic endocarditis following Q fever are pre-existing valvular disease, especially a prosthetic valve, and other comorbidities, such as cancer (39). Currently, most cases of Q fever endocarditis are diagnosed serologically by detecting antibodies to C. burnetii(40). High levels of anti-phase I antibodies are found in individuals with chronic Q fever, while anti-phase II antibodies predominate in acute Q fever. Diagnosis of Q fever endocarditis can also be made by isolating C. burnetiiin cell culture, by PCR, or by immunohistochemistry (40).
Myocarditis has been reported as a manifestation of C. burnetiiinfection, with approximately 30 cases of acute and chronic Q fever cited in the literature over the last 20 years (41–43). Myocarditis occurred in 0.6% to 0.8% of patients with acute Q fever in 2 case series of 1276 and 1117 patients (41,42). Dyspnea, chest pain, and palpitation were the most common symptoms. Many patients also experienced dilated cardiomyopathy, which usually led to heart failure (41). Only 1 case of pericarditis with C. burnetiiinfection has been reported (44).
The long-term effects of Q fever on the cardiovascular system are not clear. A study of a large outbreak of Q fever in 1983 in Switzerland suggested that people with Q fever have an increased risk of vascular disease after 12 years of follow-up (45). However, another follow-up study of 147 patients from the 1989 Q fever outbreak in Birmingham, United Kingdom, did not find any increased risk (46).
Confirming a diagnosis of Q fever requires serologic testing to detect the presence of antibodies to C. burnetiiantigens. In most laboratories, the indirect immunofluorescence assay is the most dependable and widely used method. C. burnetiimay also be identified in infected tissues using immunohistochemical staining and deoxyribonucleic acid detection methods.
Infections due to salmonellae are common, and their incidence appears to be increasing in the U.S. and other countries (47,48). Although S. Typhiand S. Paratyphiinfect humans only, the nontyphoidal salmonellae are widely spread in nature and are commonly found in some animal species and occasionally in humans. In humans, the nontyphoidal salmonellae are important foodborne pathogens that cause gastroenteritis, bacteremia, and subsequent focal infection. In the U.S., an estimated 1.4 million Salmonellainfections occur annually, resulting in approximately 45000 hospitalizations and 600 deaths (48–50). Salmonellosis accounts for about 30% of deaths resulting from foodborne illnesses in the U.S. (48).
The major risk factors for salmonellosis and bacteremia are extremes of age and certain immunocompromised conditions, such as alteration of endogenous bowel flora of the intestine, diabetes, malignancy, autoimmune disorders, reticuloendothelial blockade, HIV infection, therapeutic immunodeficiency, and sickle cell anemia (51–53). Anatomical disruptions, including atherosclerotic endovascular lesions and prosthetic devices, may serve as foci for persistent Salmonellainfection.
Salmonellainfection may present in 5 different clinical forms: 1) asymptomatic chronic carrier status, 2) gastroenteritis, 3) enteric fever, 4) bacteremia, and 5) extraintestinal localized complications (54). The most serious (although rare) complication is the development of endovascular infection (e.g., endocarditis and infected aortic aneurysm). The prognosis for patients with these conditions is poor. Salmonellaendocarditis usually occurs in patients with pre-existing heart problems and often causes severe valvular destruction, with a case fatality rate of 70% (54). About one-fourth of Salmonellaendocarditic cases are nonvalvular (mural); and one-fourth of Salmonellaendocarditic patients have associated lumbar osteomyelitis; however, their survival rates have not been reported (54). Salmonellapericarditis often presents with cardiac or pulmonary symptoms, but typical signs of pericardial disease (pulsus paradoxus, friction rub) or characteristic electrocardiograph changes (low voltage, elevated ST-segments) are uncommon. Salmonellamay also infect the peripheral or visceral arteries, but the abdominal aorta is the most frequent site of vascular infection (55). Most of these patients are men over the age of 50 years with pre-existing atherosclerosis of the aorta who do not have a previous history of gastroenteritis and no survival with medical therapy alone has been reported. Salmonellaemay also cause rare cases of myocarditis, but the pathogenesis is unclear (56,57).
The diagnosis of an endovascular infection is often not established until an advanced stage. But early diagnosis, before infection spreads to other areas of the circulatory system, is crucial for survival. To identify Salmonellaeas the cause of the illness, providers should send stool samples to the laboratory for testing when gastrointestinal symptoms occur. Once Salmonellahas been identified, further testing can determine its type and which antibiotics should be used to treat it.
In addition to antibiotic therapy, surgical removal of infected areas may be required. Guidelines for surgical removal have been proposed and these, along with increased use of ampicillin for endovascular infection, may be responsible for the increased survival rates in recent years.
Direct clinical involvement of cardiovascular structures by Burkholderia pseudomallei, the agent of melioidosis, is rare. Only 2 cases of pericardial melioidosis have been described (58,59) so characterization of this illness is not possible. Vasculitis (mycotic aneurysm) due to B. pseudomalleihas been described but is also a rare event.
In 1 literature review that described 12 cases of mycotic aneurysm due to B. pseudomallei, only 2 of the patients had aortic arch involvement (60). The ages of these 12 patients ranged from 42 to 70 years, suggesting a possible predilection to atherosclerosis. Among 9 cases with a reported underlying illness, 1 had diabetes mellitus, 1 had hypertension, and 1 had prior B. pseudomalleiinfection. Trauma and soil exposure were noted in only 3 patients, and 3 patients died due to infectious complications. The areas of case origin include southeast Asia, Taiwan, Mainland China, and Australia, consistent with the indigenous distribution of the bacterium. A single case of cutaneous polyarteritis nodasa associated with B. pseudomalleihas been also described in a young Thai woman (61).
Recent events have demonstrated that bioterrorists have the ability to disseminate biologic agents in the U.S. and may be capable of causing widespread social panic. Health care providers including cardiologists can play a key role in the initial recognition of a potential bioterrorism attack (62,63). By being familiar with infectious agents of highest priority, providers can expedite diagnosis and initial management, and lead to a successful public health response to such attacks. Many resources are available to health care providers to learn more about relevant agents and diseases, as well as their effects on cardiovascular system.
The Task Force thus recommends that health care providers:
1. Be familiar with major agents and diseases that may be used for bioterrorism attacks, as categorized and described by the CDC (3,7). Detailed information on these agents and diseases can be obtained through CDC’s Web site at http://www.bt.cdc.gov/agent/agentlist.asp. A summary description of the select Category A and B diseases and agents is presented in Table 2.
2. Be aware of signs and symptoms and the clinical diagnosis and management of the 4 major cardiovascular syndromes—endocarditis, myocarditis, pericarditis, and vasculitis—that certain potential bioterrorism agents might induce.
3. Consider the possibility of bioterrorism when one of the Category A agents is found to produce disease in a single patient in the absence of obvious risk factors. The likelihood of bioterrorism involvement increases significantly if more than 1 patient presents with illness from 1 of these agents.
4. Ensure that clinical laboratories save isolates from cases that may represent illness from biologic agents of bioterrorism and contact state health departments for guidance.
5. Obtain thorough family and environmental histories from patients to ascertain whether other close contacts have had similar illnesses.
6. Clinicians should be familiar with the public health reporting requirements in their locale. Contact infection control personnel and appropriate public health authorities if a patient is diagnosed with any of these agents or diseases.
We have shown that multiple infectious agents with the potential for use in a bioterrorist attack could have a profound impact on the cardiovascular system of the affected individuals, especially in those with underlying cardiovascular disease. Cardiologists and other health care providers need to familiarize themselves with these agents and diseases, as well as with symptoms they are likely to cause. In this way, they can be prepared to quickly identify the potential involvement of a bioterrorist agent or disease in a patient’s condition to both provide appropriate treatment and assist the appropriate authorities in responding quickly to a potential attack.
APPENDIX 1 ACCF/AHA/CDC Consensus Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats: Task Force I—Relationships with Industry
|Dr. Larry M. Baddour declared that his institution (Mayo Clinic) has financial relationships with infectious disease companies. The other authors of this report declared that they have no relationships with industry pertinent to this topic.|
- American College of Cardiology Foundation and the American Heart Association, Inc.
Task Force I References
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- Definition and Classifications
- Known Cardiovascular Syndromes Associated With Category A, B, and C Agents and Diseases
- Select Diseases and Agents That May Affect the Cardiovascular System
- Summary Statement
- APPENDIX 1 ACCF/AHA/CDC Consensus Conference Report on Emerging Infectious Diseases and Biological Terrorism Threats: Task Force I—Relationships with Industry
- Task Force I References