Swine influenza, also called pig influenza, swine flu, hog flu and pig flu, is an infection caused by any one of several types of swine influenza viruses. Swine influenza virus (SIV) or swineorigin influenza virus (SOIV) is any strain of the influenza family of viruses that isendemic in pigs. As of 2009, the known SIV strains include influenza C and the subtypes of influenza A known as H1N1, H1N2, H2N1, H3N1,H3N2, and H2N3. Swine influenza virus is common throughout pig populations worldwide. Transmission of the virus from pigs to humans is not common and does not always lead to human flu, often resulting only in the production of antibodies in the blood.
If transmission does cause human flu, it is calledzoonotic swine flu. People with regular exposure to pigs are at increased risk of swine flu infection. During the mid20th century, identification of influenza subtypes became possible, allowing accurate diagnosis of transmission to humans. Since then, only 50 such transmissions have been confirmed. These strains of swine flu rarely pass from human to human. Symptoms of zoonotic swine flu in humans are similar to those of influenza and of influenzalike illness in general, namely chills, fever, sore throat, muscle pains, severeheadache, coughing, weakness and general discomfort. In August 2010, the World Health Organization declared the swine flu pandemic officially over.
The influenza virion (as the infectious particle is called) is roughly spherical. It is an enveloped virus – that is, the outer layer is a lipid membrane which is taken from the host cell in which the virus multiplies. Inserted into the lipid membrane are ‘spikes’, which are proteins – actually glycoproteins, because they consist of protein linked to sugars – known as HA (hemagglutinin) and NA (neuraminidase). These are the proteins that determine the subtype of influenza virus (A/H1N1, for example). The HA and NA are important in the immune response against the virus; antibodies (proteins made to combat infection) against these spikes may protect against infection. The NA protein is the target of the antiviral drugs Relenza and Tamiflu. Also embedded in the lipid membrane is the M2 protein, which is the target of the antiviral adamantanes – amantadine and rimantadine.
Of the three genera of influenza viruses that cause human flu, two also cause influenza in pigs, with influenza A being common in pigs and influenza C being rare.3 Influenza B has not been reported in pigs. Within influenza A and influenza C, the strains found in pigs and humans are largely distinct, although because of reassortment there have been transfers of genes among strains crossing swine, avian, and human species boundaries. Influenza C
Influenza viruses infect both humans and pigs, but do not infect birds.4 Transmission between pigs and humans have occurred in the past.5 For example, influenza C caused small outbreaks of a mild form of influenza amongst children in Japan6 and California.6 Because of its limited host range and the lack of genetic diversity in influenza C, this form of influenza does not cause pandemics in humans.7 Influenza A
Swine influenza is known to be caused by influenza A subtypes H1N1,8 H1N2,8 H2N3,9 H3N1,10 and H3N2.8 In pigs, four influenza A virus subtypes (H1N1, H1N2,H3N2 and H7N9) are the most common strains worldwide.11 In the United States, the H1N1 subtype was exclusively prevalent among swine populations before 1998; however, since late August 1998, H3N2 subtypes have been isolated from pigs. As of 2004, H3N2 virus isolates in US swine and turkey stocks were triple reassortants, containing genes from human(HA, NA, and PB1), swine (NS, NP, and M), and avian (PB2 and PA) lineages.12 In August 2012, the Center for Disease Control and Prevention confirmed 145 human cases (113 in Indiana, 30 in Ohio, one in Hawaii and one in Illinois) of H3N2v since July 2012.13 The death of a 61yearold Madison County, Ohio woman is the first in the nation associated with a new swine flu strain. She contracted the illness after having contact with hogs at the Ross County Fair.14 Surveillance
Although there is no formal national surveillance system in the United States to determine what viruses are circulating in pigs,15 an informal surveillance network in the United States is part of a world surveillance network.
Swine influenza was first proposed to be a disease related to human flu during the 1918 flu pandemic, when pigs became ill at the same time as humans.17 The first identification of an influenza virus as a cause of disease in pigs occurred about ten years later, in 1930.18 For the following 60 years, swine influenza strains were almost exclusively H1N1. Then, between 1997 and 2002, new strains of three different subtypes and five different genotypes emerged as causes of influenza among pigs in North America. In 1997–1998,H3N2 strains emerged. These strains, which include genes derived by reassortment from human, swine and avian viruses, have become a major cause of swine influenza in North America. Reassortment between H1N1 and H3N2 produced H1N2. In 1999 in Canada, a strain of H4N6 crossed the species barrier from birds to pigs, but was contained on a single farm.18 The H1N1 form of swine flu is one of the descendants of the strain that caused the 1918 flu pandemic.1920 As well as persisting in pigs, the descendants of the 1918 virus have also circulated in humans through the 20th century, contributing to the normal seasonal epidemics of influenza.
However, direct transmission from pigs to humans is rare, with only 12 recorded cases in the U.S. since 2005.21 Nevertheless, the retention of influenza strains in pigs after these strains have disappeared from the human population might make pigs a reservoir where influenza viruses could persist, later emerging to reinfect humans once human immunity to these strains has waned.22 Swine flu has been reported numerous times as a zoonosis in humans, usually with limited distribution, rarely with a widespread distribution. Outbreaks in swine are common and cause significant economic losses in industry, primarily by causing stunting and extended time to market. For example, this disease costs the British meat industry about £65 million every year.23 1918 pandemic in humans
The 1918 flu pandemic in humans was associated with H1N1 and influenza appearing in pigs;20 this may reflect a zoonosis either from swine to humans, or from humans to swine. Although it is not certain in which direction the virus was transferred, some evidence suggests, in this case, pigs caught the disease from humans.17 For instance, swine influenza was only noted as a new disease of pigs in 1918, after the first large outbreaks of influenza amongst people.17 Although a recent phylogenetic analysis of more recent strains of influenza in humans, birds, and swine suggests the 1918 outbreak in humans followed a reassortment event within a mammal,24 the exact origin of the 1918 strain remains elusive.25 It is estimated that anywhere from 50 to 100 million people were killed worldwide.2026 1976 U.S. outbreak
Main article: 1976 swine flu outbreak
On February 5, 1976, a United States army recruit at Fort Dix said he felt tired and weak. He died the next day, and four of his fellow soldiers were later hospitalized. Two weeks after his death, health officials announced the cause of death was a new strain of swine flu. The strain, a variant of H1N1, is known as A/New Jersey/1976 (H1N1). It was detected only from January 19 to February 9 and did not spread beyond Fort Dix.27
U.S. President Ford receives a swine flu vaccination
This new strain appeared to be closely related to the strain involved in the 1918 flu pandemic. Moreover, the ensuing increased surveillance uncovered another strain in circulation in the U.S.: A/Victoria/75 (H3N2) spread simultaneously, also caused illness, and persisted until March.27 Alarmed public health officials decided action must be taken to head off another major pandemic, and urged President Gerald Ford that every person in the U.S. be vaccinated for the disease.28 The vaccination program was plagued by delays and public relations problems.29 On October 1, 1976, immunizations began, and three senior citizens died soon after receiving their injections. This resulted in a media outcry that linked these deaths to the immunizations, despite the lack of any proof the vaccine was the cause. According to science writer Patrick Di Justo, however, by the time the truth was known—that the deaths were not proven to be related to the vaccine—it was too late. “The government had long feared mass panic about swine flu—now they feared mass panic about the swine flu vaccinations.”
This became a strong setback to the program.30 There were reports of GuillainBarré syndrome, a paralyzing neuromuscular disorder, affecting some people who had received swine flu immunizations. Although if a link exists is still not clear, this syndrome may be a side effect of influenza vaccines. As a result, Di Justo writes, “the public refused to trust a governmentoperated health program that killed old people and crippled young people.” In total, 48,161,019 Americans, or just over 22% of the population, had been immunized by the time the National Influenza Immunization Program was effectively halted on December 16, 1976.31 32 Overall, there were 1098 cases of GuillainBarré Syndrome (GBS) recorded nationwide by CDC surveillance, 532 of which occurred after vaccination and 543 before vaccination.
About one to two cases per 100,000 people of GBS occur every year, whether or not people have been vaccinated.34 The vaccination program seems to have increased this normal risk of developing GBS by about to one extra case per 100,000 vaccinations.34 Recompensation charges were filed for over 4000 cases of severe vaccination damage, including 25 deaths, totalling US$ 3.5 billion, by 1979.35 The CDC stated most studies on modern influenza vaccines have seen no link with GBS,343637 Although one review gives an incidence of about one case per million vaccinations,38 a large study in China, reported in the NEJM, covering close to 100 million doses of H1N1 flu vaccine, found only 11 cases of GuillainBarre syndrome, which is lower than the normal rate of the disease in China; “The riskbenefit ratio, which is what vaccines and everything in medicine is about, is overwhelmingly in favor of vaccination.”39 1988 zoonosis
In September 1988, a swine flu virus killed one woman and infected others. A 32year old woman, Barbara Ann Wieners, was eight months pregnant when she and her husband, Ed, became ill after visiting the hog barn at a county fair in Walworth County, Wisconsin. Barbara died eight days later, after developing pneumonia.40 The only pathogen identified was an H1N1 strain of swine influenza virus.41 Doctors were able to induce labor and deliver a healthy daughter before she died. Her husband recovered from his symptoms. Influenzalike illness (ILI) was reportedly widespread among the pigs exhibited at the fair. Of the 25 swine exhibitors aged 9 to 19 at the fair, 19 tested positive for antibodies to SIV, but no serious illnesses were seen. The virus was able to spread between people, since one to three health care personnel who had cared for the pregnant woman developed mild, influenzalike illnesses, and antibody tests suggested they had been infected with swine flu, but there was no community outbreak.4243 1998 US outbreak in swine
In 1998, swine flu was found in pigs in four U.S. states. Within a year, it had spread through pig populations across the United States. Scientists found this virus had originated in pigs as a recombinant form of flu strains from birds and humans. This outbreak confirmed that pigs can serve as a crucible where novel influenza viruses emerge as a result of the reassortment of genes from different strains.444546 Genetic components of these 1998 triplehybrid stains would later form six out of the eight viral gene segments in the 2009 flu outbreak.4748495051 2007 Philippine outbreak in swine
This section requires expansion. (April 2009)
On August 20, 2007, the Department of Agriculture officers investigated the outbreak (epizootic) of swine flu in Nueva Ecija and central Luzon, Philippines. The mortality rate is less than 10% for swine flu, unless there are complications like hog cholera. On July 27, 2007, the Philippine National Meat Inspection Service (NMIS) raised a hog cholera “red alert” warning over Metro Manila and five regions of Luzon after the disease spread to backyard pig farms in Bulacan and Pampanga, even if these tested negative for the swine flu virus.5253 2009 Northern Ireland outbreak in swine Since November 2009, 14 deaths as a result of swine flu in Northern Ireland have been reported. The majority of the victims were reported to have preexisting health conditions which had lowered their immunity.
This closely corresponds to the 19 patients who had died in the year prior due to swine flu, where 18 of the 19 were determined to have lowered immune systems. Because of this, many mothers who have just given birth are strongly encouraged to get a flu shot because their immune systems are vulnerable. Also, studies have shown that people between the ages of 15 and 44 have the highest rate of infection. Although most people now recover, having any conditions that lower one’s immune system increases the risk of having the flu become potentially lethal. In Northern Ireland now, approximately 56% of all people under 65 who are entitled to the vaccine have gotten the shot, and the outbreak is said to be under control.
H1N1 virus pandemic history
A study conducted in 2009, and published in the journal Nature, has managed to establish the evolutionary origin of the flu strain of swine origin (SOIV).55 The phylogenetic origin of the flu virus that caused the 2009 pandemics can be traced before 1918. Around 1918, the ancestral virus, of avian origin, crossed the species boundaries and infected humans as human H1N1. The same phenomenon took place soon after in America, where the human virus was infecting pigs; it led to the emergence of the H1N1 swine strain, which later became the classic swine flu. The new human H1N1 flu strain of avian origin kept transmitting among human populations until around 1957, when there was a coinfection between this strain and the avian H1N1 in humans. A reassortment event led to the development of a new strain (H2N2). From this point onwards, no outbreaks of H1N1 were reported in humans until around 1976. New events of reassortment were not reported until 1968, when the avian strain H1N1 infected humans again; this time the virus met the strain H2N2, and the reassortment originated the strain H3N2. This strain has remained as a stable flu strain until now.
The mid1970s were important for the evolution of flu strains. First, the reemergence of the human H1N1 strain became a seasonal strain. Then, a small outbreak of swine H1N1 occurred in humans, and finally, the human H2N2 strain apparently became extinct. Around 1979, the avian H1N1 strain infected pigs and gave rise to Euroasiatic swine flu and H1N1 Euroasiatic swine virus, which is still being transmitted in swine populations. The critical moment for the 2009 outbreak was between 1990 and 1993. A triple reassortment event in a pig host of North American H1N1 swine virus, the human H3N2 virus and avian H1N1 virus generated the swine H1N2 strain. Finally, the last step in SOIV history was in 2009, when the virus H1N2 coinfected a human host at the same time as the Euroasiatic H1N1 swine strain.
This led to the emergence of a new human H1N1 strain, which caused the 2009 pandemic. On June 11, 2009, the World Health Organization raised the worldwide pandemic alert level to Phase 6 for swine flu, which is the highest alert level.56 This alert level means that the swine flu had spread worldwide and there were cases of people with the virus in most countries. The pandemic level identifies the spread of the disease or virus and not necessarily the severity of the disease. Swine flu spread very rapidly worldwide due to its high humantohuman transmission rate and due to the frequency of air travel.
Transmission between pigs
Influenza is quite common in pigs, with about half of breeding pigs having been exposed to the virus in the US.57 Antibodies to the virus are also common in pigs in other countries.57 The main route of transmission is through direct contact between infected and uninfected animals.11 These close contacts are particularly common during animal transport.Intensive farming may also increase the risk of transmission, as the pigs are raised in very close proximity to each other.5859 The direct transfer of the virus probably occurs either by pigs touching noses, or through dried mucus. Airborne transmission through the aerosols produced by pigs coughing or sneezing are also an important means of infection.11The virus usually spreads quickly through a herd, infecting all the pigs within just a few days.2 Transmission may also occur through wild animals, such as wild boar, which can spread the disease between farms.60 Transmission to humans
People who work with poultry and swine, especially those with intense exposures, are at increased risk of zoonotic infection with influenza virus endemic in these animals, and constitute a population of human hosts in which zoonosis and reassortment can cooccur.61 Vaccination of these workers against influenza and surveillance for new influenza strains among this population may therefore be an important public health measure.62 Transmission of influenza from swine to humans who work with swine was documented in a small surveillance study performed in 2004 at the University of Iowa.
This study, among others, forms the basis of a recommendation that people whose jobs involve handling poultry and swine be the focus of increased public health surveillance.61 Other professions at particular risk of infection are veterinarians and meat processing workers, although the risk of infection for both of these groups is lower than that of farm workers.64 Interaction with avian H5N1 in pigs Pigs are unusual as they can be infected with influenza strains that usually infect three different species: pigs, birds and humans.65 This makes pigs a host where influenza viruses might exchange genes, producing new and dangerous strains.65 Avian influenza virus H3N2 is endemic in pigs in China, and has been detected in pigs in Vietnam, increasing fears of the emergence of new variant strains.66 H3N2 evolved from H2N2 by antigenic shift.67 In August 2004, researchers in China found H5N1 in pigs.
Main symptoms of swine flu in swine
These H5N1 infections may be quite common; in a survey of 10 apparently healthy pigs housed near poultry farms in West Java, where avian flu had broken out, five of the pig samples contained the H5N1 virus. The Indonesian government has since found similar results in the same region. Additional tests of 150 pigs outside the area were negative.6970
Signs and symptoms
In pigs, influenza infection produces fever, lethargy, sneezing, coughing, difficulty breathing and decreased appetite.11 In some cases the infection can cause abortion. Although mortality is usually low (around 1–4%),2 the virus can produce weight loss and poor growth, causing economic loss to farmers.11 Infected pigs can lose up to 12 pounds of body weight over a three to fourweek period.11 In humans
Main symptoms of swine flu in humans
Direct transmission of a swine flu virus from pigs to humans is occasionally possible (called zoonotic swine flu). In all, 50 cases are known to have occurred since the first report in medical literature in 1958, which have resulted in a total of six deaths.72 Of these six people, one was pregnant, one had leukemia, one had Hodgkin’s lymphoma and two were known to be previously healthy.72 Despite these apparently low numbers of infections, the true rate of infection may be higher, since most cases only cause a very mild disease, and will probably never be reported or diagnosed.
In this video, Dr. Joe Bresee, with CDC’s Influenza Division, describes the symptoms of swine flu and warning signs to look for that indicate the need for urgent medical attention. See also: See this video with subtitles on YouTube
According to the Centers for Disease Control and Prevention (CDC), in humans the symptoms of the 2009 “swine flu” H1N1 virus are similar to those of influenza and of influenzalike illness in general. Symptoms include fever, cough, sore throat, body aches, headache,chills and fatigue. The 2009 outbreak has shown an increased percentage of patients reporting diarrhea and vomiting.74 The 2009 H1N1 virus is not zoonotic swine flu, as it is not transmitted from pigs to humans, but from person to person. Because these symptoms are not specific to swine flu, a differential diagnosis of probable swine flu requires not only symptoms, but also a high likelihood of swine flu due to the person’s recent history.
For example, during the 2009 swine flu outbreak in the United States, the CDC advised physicians to “consider swine influenza infection in the differential diagnosis of patients with acute febrile respiratory illness who have either been in contact with persons with confirmed swine flu, or who were in one of the five U.S. states that have reported swine flu cases or in Mexico during the seven days preceding their illness onset.” A diagnosis of confirmed swine flu requires laboratory testing of a respiratory sample (a simple nose and throat swab).75 The most common cause of death is respiratory failure. Other causes of death are pneumonia (leading to sepsis),76 high fever (leading to neurological problems), dehydration (from excessive vomiting and diarrhea), electrolyte imbalance and kidney failure.77 Fatalities are more likely in young children and the elderly. Diagnosis
Thermal scanning of passengers arriving at Singapore Changi airport The CDC recommends real time PCR as the method of choice for diagnosing H1N1.78 This method allows a specific diagnosis of novel influenza (H1N1) as opposed to seasonal influenza. Nearpatient pointofcare tests are in development.
Prevention of swine influenza has three components: prevention in swine, prevention of transmission to humans, and prevention of its spread among humans. In swine Methods of preventing the spread of influenza among swine include facility management, herd management, and vaccination (ATCvetcode: QI09AA03). Because much of the illness and death associated with swine flu involves secondary infection by other pathogens, control strategies that rely on vaccination may be insufficient. Control of swine influenza by vaccination has become more difficult in recent decades, as the evolution of the virus has resulted in inconsistent responses to traditional vaccines. Standard commercial swine flu vaccines are effective in controlling the infection when the virus strains match enough to have significant crossprotection, and custom (autogenous) vaccines made from the specific viruses isolated are created and used in the more difficult cases.
Present vaccination strategies for SIV control and prevention in swine farms typically include the use of one of several bivalent SIV vaccines commercially available in the United States. Of the 97 recent H3N2 isolates examined, only 41 isolates had strong serologic crossreactions with antiserum to three commercial SIV vaccines. Since the protective ability of influenza vaccines depends primarily on the closeness of the match between the vaccine virus and the epidemic virus, the presence of nonreactive H3N2 SIV variants suggests current commercial vaccines might not effectively protect pigs from infection with a majority of H3N2 viruses.
The United States Department of Agriculture researchers say while pig vaccination keeps pigs from getting sick, it does not block infection or shedding of the virus.83 Facility management includes using disinfectants and ambient temperature to control viruses in the environment. They are unlikely to survive outside living cells for more than two weeks, except in cold (but above freezing) conditions, and are readily inactivated by disinfectants.2 Herd management includes not adding pigs carrying influenza to herds that have not been exposed to the virus. The virus survives in healthy carrier pigs for up to three months, and can be recovered from them between outbreaks. Carrier pigs are usually responsible for the introduction of SIV into previously uninfected herds and countries, so new animals should be quarantined.57 After an outbreak, as immunity in exposed pigs wanes, new outbreaks of the same strain can occur.2 In humans
Prevention of pigtohuman transmission
Swine can be infected by both avian and human flu strains of influenza, and therefore are hosts where the antigenic shifts can occur that create new influenza strains. The transmission from swine to humans is believed to occur mainly in swine farms, where farmers are in close contact with live pigs. Although strains of swine influenza are usually not able to infect humans, this may occasionally happen, so farmers and veterinarians are encouraged to use face masks when dealing with infected animals. The use of vaccines on swine to prevent their infection is a major method of limiting swinetohuman transmission. Risk factors that may contribute to swinetohuman transmission include smoking and, especially, not wearing gloves when working with sick animals, thereby increasing the likelihood of subsequent handtoeye, handtonose or handtomouth transmission.84 Prevention of humantohuman transmission
Influenza spreads between humans when infected people cough or sneeze, then other people breathe in the virus or touch something with the virus on it and then touch their own face.85 “Avoid touching your eyes, nose or mouth. Germs spread this way.”86 Swine flu cannot be spread by pork products, since the virus is not transmitted through food.85 The swine flu in humans is most contagious during the first five days of the illness, although some people, most commonly children, can remain contagious for up to ten days. Diagnosis can be made by sending a specimen, collected during the first five days, for analysis.
Thermal imaging camera and screen, photographed in an airport terminal in Greece thermal imaging can detect elevated body temperature, one of the signs of the virus H1N1 (swine influenza). Recommendations to prevent spread of the virus among humans include using standard infection control, which includes frequent washing of hands with soap and water or with alcoholbased hand sanitizers, especially after being out in public.88 Chance of transmission is also reduced by disinfecting household surfaces, which can be done effectively with a diluted chlorine bleach solution.89 Experts agree handwashing can help prevent viral infections, including ordinary and the swine flu infections. Also, avoiding touching one’s eyes, nose or mouth with one’s hands helps to prevent the flu.86 Influenza can spread in coughs or sneezes, but an increasing body of evidence shows small droplets containing the virus can linger on tabletops, telephones and other surfaces and be transferred via the fingers to the eyes, nose or mouth.
Alcoholbased gel or foam hand sanitizers work well to destroy viruses and bacteria. Anyone with flulike symptoms, such as a sudden fever, cough or muscle aches, should stay away from work or public transportation, and should contact a doctor for advice.90 Social distancing, another tactic, is staying away from other people who might be infected, and can include avoiding large gatherings, spreading out a little at work, or perhaps staying home and lying low if an infection is spreading in a community. Public health and other responsible authorities have action plans which may request or require social distancing actions, depending on the severity of the outbreak. Vaccination
Main article: 2009 flu pandemic vaccine
Vaccines are available for different kinds of swine flu. The U.S. Food and Drug Administration (FDA) approved the new swine flu vaccine for use in the United States on September 15, 2009.91 Studies by the National Institutes of Health show a single dose creates enough antibodies to protect against the virus within about 10 days.92 In the aftermath of the 2009 pandemic, several studies were conducted to see who received influenza vaccines. These studies show that whites are much more likely to be vaccinated for seasonal influenza and for the H1N1 strain than African Americans 93 This could be due to several factors. Historically, there has been mistrust of vaccines and of the medical community from African Americans. Many African Americans do not believe vaccines or doctors to be effective. This mistrust stems from the exploitation of the African American communities during studies like the Tuskegee study. Additionally, vaccines are typically administered in clinics, hospitals, or doctor’s offices. Many people of lower socioeconomic status are less likely to receive vaccinations because they do not have health insurance.
As swine influenza is rarely fatal to pigs, little treatment beyond rest and supportive care is required.57 Instead, veterinary efforts are focused on preventing the spread of the virus throughout the farm, or to other farms.11 Vaccination and animal management techniques are most important in these efforts. Antibiotics are also used to treat this disease, which although they have no effect against the influenza virus, do help prevent bacterial pneumonia and other secondary infections in influenzaweakened herds.57 In humans
If a person becomes sick with swine flu, antiviral drugs can make the illness milder and make the patient feel better faster. They may also prevent serious flu complications. For treatment, antiviral drugs work best if started soon after getting sick (within two days of symptoms). Beside antivirals, supportive care at home or in a hospital focuses on controlling fevers, relieving pain and maintaining fluid balance, as well as identifying and treating any secondary infections or other medical problems.
The U.S. Centers for Disease Control and Prevention recommends the use of oseltamivir (Tamiflu) or zanamivir (Relenza) for the treatment and/or prevention of infection with swine influenza viruses; however, the majority of people infected with the virus make a full recovery without requiring medical attention or antiviral drugs.94 The virus isolated in the 2009 outbreak have been found resistant toamantadine and rimantadine. In the U.S., on April 27, 2009, the FDA issued Emergency Use Authorizations to make available Relenza and Tamiflu antiviral drugs to treat the swine influenza virus in cases for which they are currently unapproved. The agency issued these EUAs to allow treatment of patients younger than the current approval allows and to allow the widespread distribution of the drugs, including by volunteers.