Because medications to treat acute illness due to influenza are just recently appearing, there is a tendency to accept the existence of influenza and to forget the fact that 49,000 Americans die annually from the flu and its complications. In addition, the resulting hospitalizations and medical care cost the healthcare system up to $12 billion each year. Sadly, there are underused vaccines that can prevent many of the hospitalizations and deaths, thus lessening the suffering and financial burden of this disease. This course will explore the history of influenza, symptoms, communicability, care of the patient, the makeup of the virus, avian and swine types of flu, vaccine issues, and pandemic planning. Reproducible patient education materials will be included. The vital roles of the healthcare professional and community involvement will be stressed.
This course is designed to help healthcare professionals and allied personnel understand influenza and their role in its prevention.
NetCE is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. NetCE is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's Commission on Accreditation. NetCE is approved by the California Nursing Home Administrator Program as a provider of continuing education. Provider number 1622. NetCE is approved to offer continuing education through the Florida Board of Nursing Home Administrators, Provider #50-2405. NetCE, #1092, is approved as a provider for social work continuing education by the Association of Social Work Boards (ASWB) www.aswb.org through the Approved Continuing Education (ACE) Program. NetCE maintains responsibility for the program. ASWB Approval Period: 03/13/2016 to 03/13/2019. Social workers should contact their regulatory board to determine course approval for continuing education credits. NetCE is accredited by the International Association for Continuing Education and Training (IACET). NetCE complies with the ANSI/IACET Standard, which is recognized internationally as a standard of excellence in instructional practices. As a result of this accreditation, NetCE is authorized to issue the IACET CEU. NetCE is approved as a provider of online continuing education for certified nursing assistants through the California Department of Public Health Licensing and Certification Division. Nurse Aide Certification (NAC) Provider #7005.
NetCE designates this enduring material for a maximum of 10 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. NetCE designates this continuing education activity for 10 ANCC contact hour(s). NetCE designates this continuing education activity for 5 pharmacotherapeutic/pharmacology contact hour(s). NetCE designates this continuing education activity for 12 hours for Alabama nurses. Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 10 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit. Completion of this course constitutes permission to share the completion data with ACCME. Social workers participating in this intermediate to advanced course will receive 10 Clinical continuing education clock hours, in accordance with the Association of Social Work Boards. This home study course is approved by the Florida Board of Nursing Home Administrators for 5 credit hour(s). This course is approved by the California Nursing Home Administrator Program for 10 hour(s) of continuing education credit - NHAP#1622010-5406/P. California NHAs may only obtain a maximum of 10 hours per course. NetCE is authorized by IACET to offer 1 CEU(s) for this program. AACN Synergy CERP Category A.
In addition to states that accept ANCC, NetCE is approved as a provider of continuing education in nursing by: Alabama, Provider #ABNP0353, (valid through December 12, 2017); California, BRN Provider #CEP9784; California, LVN Provider #V10662; California, PT Provider #V10842; Florida, Provider #50-2405; Iowa, Provider #295; Kentucky, Provider #7-0054 through 12/31/2017.
In addition to states that accept ASWB, NetCE is approved as a provider of continuing education by the following state boards: Alabama State Board of Social Work Examiners, Provider #0515; Florida Board of Clinical Social Work, Marriage and Family Therapy and Mental Health Counseling, CE Broker Provider #50-2405; Illinois Division of Professional Regulation for Social Workers, License #159.001094; Illinois Division of Professional Regulation for Licensed Professional and Clinical Counselors, License #197.000185; Illinois Division of Professional Regulation for Marriage and Family Therapists, License #168.000190; Texas State Board of Social Worker Examiners, Approval #3011; Texas State Board of Examiners of Professional Counselors, Approval #1121; Texas State Board of Examiners of Marriage and Family Therapists, Approval #425.
This activity is designed to comply with the requirements of California Assembly Bill 1195, Cultural and Linguistic Competency.
The purpose of this course is to help healthcare professionals minimize the burden of influenza on their patients and their communities. Information is included to help healthcare professionals accept the importance of influenza vaccine in lessening the impact of the disease on their patients, preventing complications and hospitalizations, and saving healthcare dollars.
Upon completion of this course, you should be able to:
- Articulate the history and burden of influenza on the community.
- Explain the types of influenza viruses, including the H and N designations.
- Describe the symptoms, transmission, and diagnosis of influenza.
- Distinguish between influenza and influenza-like illnesses.
- Identify complications of influenza.
- Articulate the effectiveness and importance of the influenza vaccines.
- Implement a system to increase vaccine administration to vulnerable patients.
- Describe the best method of hand hygiene and other ways of protecting against influenza.
- List the current antiviral medications available and their use.
- Teach family members how to care for people with the flu, including interventions for non-English-proficient patients and caregivers.
- Identify the significance of avian and swine influenza, particularly issues related to pandemic disease.
Elizabeth T. Murane, PHN, BSN, MA, received her Bachelor’s degree in nursing from the Frances Payne Bolton School of Nursing, Case Western Reserve University in Cleveland, Ohio and a Master of Arts in Nursing Education from Teachers College, Columbia University, New York, New York.
Her nursing experience includes hospital nursing on pediatric, medical, and surgical units. She lived for 15 years in a village in Eastern Papua New Guinea providing medical and linguistic/literacy services for the villagers. She was a public health nurse for a year with the Brooklyn, New York Health Department and 20 years with the Shasta County Public Health Department in Redding, California. As a public health nursing director, she developed response plans for environmental and health issue disasters for both Shasta County and adjacent Tehama County Public Health Departments. Currently, Ms. Murane volunteers in the Infection Control Department of Mercy Medical Center Redding, a Dignity Health member.
Contributing faculty, Elizabeth T. Murane, PHN, BSN, MA, has disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
Ronald Runciman, MD
Jane C. Norman, RN, MSN, CNE, PhD
Alice Yick Flanagan, PhD, MSW
The division planners have disclosed no relevant financial relationship with any product manufacturer or service provider mentioned.
The purpose of NetCE is to provide challenging curricula to assist healthcare professionals to raise their levels of expertise while fulfilling their continuing education requirements, thereby improving the quality of healthcare.
Our contributing faculty members have taken care to ensure that the information and recommendations are accurate and compatible with the standards generally accepted at the time of publication. The publisher disclaims any liability, loss or damage incurred as a consequence, directly or indirectly, of the use and application of any of the contents. Participants are cautioned about the potential risk of using limited knowledge when integrating new techniques into practice.
It is the policy of NetCE not to accept commercial support. Furthermore, commercial interests are prohibited from distributing or providing access to this activity to learners.
- INFLUENZA VIRUS
- INFLUENZA DISEASE
- INFLUENZA-LIKE ILLNESSES
- COMPLICATIONS OF INFLUENZA
- INFLUENZA VACCINE
- PROMOTING THE USE OF INFLUENZA VACCINE
- OTHER METHODS TO PREVENT INFLUENZA
- ANTIVIRAL MEDICATIONS
- CARE OF THE INFLUENZA PATIENT
- AVIAN INFLUENZA
- SWINE INFLUENZA
- INFLUENZA PANDEMIC
- GLOSSARY OF TERMS
- APPENDIX 1
- APPENDIX 2
- APPENDIX 3
- Works Cited
- Evidence-Based Practice Recommendations Citations
Supported browsers for Windows include Microsoft Internet Explorer 9.0 and up, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Supported browsers for Macintosh include Safari, Mozilla Firefox 3.0 and up, Opera 9.0 and up, and Google Chrome. Other operating systems and browsers that include complete implementations of ECMAScript edition 3 and CSS 2.0 may work, but are not supported.
#94422: Influenza: A Comprehensive Review
Influenza is a disease that is often accepted as "a part of life." While considered bothersome, it is not perceived to be a "serious" disease. However, new diseases, such as sudden acute respiratory syndrome (SARS), make headlines because of hospitalizations and fatalities. Much effort and money is expended to contain or find a way to prevent new diseases like SARS, but little notice is given to the fact that in the United States, influenza and pneumonia hospitalize more than 200,000 people and cause an average of 49,000 deaths each year [1,2]. The cost of a flu epidemic is estimated to be $12 billion . The pain and suffering caused by influenza is not considered when discussing costs [3,4]. Between 1957 and 1986, 19 different annual influenza epidemics in the United States caused up to 40,000 deaths per year. Direct annual costs for medical care alone were between $1 billion and $3 billion . A study based on 2010 Census data found that the annual economic costs of influenza varied from $13,900 to $957.5 million across U.S. counties, with a median of $2.47 million . It has been estimated that the economic costs of the next influenza pandemic in the United States will be $713 million to $166.5 billion in direct healthcare costs (e.g., outpatient visits, hospitalization) alone . Large amounts of time, energy, and money have been spent to find a vaccine against SARS while the flu vaccine, though not perfect, is markedly underused.
In 2014, pneumonia/influenza was listed as one of the top 10 causes of death in all age groups, except for children younger than 1 year of age . As the cause of death, pneumonia/influenza ranked sixth in children 1 to 9 years of age, eighth in those 10 to 24 years of age, tenth in those 25 to 64 years of age, and sixth in those 85 years of age and older. When all age groupings were combined, pneumonia/influenza ranked eighth as a leading cause of death, ahead of nephritis and intentional self-harm (9th and 10th, respectively) . Influenza is the only communicable disease still listed as a leading cause of death in the United States.
In this course, the term "influenza" is defined strictly as an acute viral respiratory illness caused by influenza A or B, occurring in seasonal outbreaks and periodic epidemics and characterized by the abrupt onset of systemic symptoms (e.g., malaise, fever, myalgia, headache) and cough. (Note: This is not to be confused with the gastroenteritis syndrome of nausea, vomiting, and diarrhea often erroneously referred to as "flu.") Influenza occurs mainly in winter months (October to March) in temperate climates north of the equator. In the United States, "flu season" usually begins in November, peaks in late December or January, and is generally over by March. However, earlier outbreaks in October can also occur and peak activity may continue as late as March. Surveillance conducted by the Centers for Disease Control and Prevention (CDC) of laboratories and outpatient facilities in 2015–2016 showed that influenza activity peaked in mid-March, one of the later season peaks on record. For example, in 2012–2013, influenza activity peaked much earlier (late December) [9,10]. In 2010, the CDC distributed a health advisory via the Health Alert Network that H3N2 influenza was detected in a number of U.S. states. The last significant outbreak (319 cases) was reported in 2012 . Each summer some localized outbreaks and sporadic cases occur. Often there is no history of recent travel or epidemiologic links between such outbreaks. It was expected that the viruses causing these cases would be antigenically similar to A/Hong Kong/4801/2014-like H3N2, a component in the 2016–2017 vaccine . In contrast, the 2009 H1N1 (swine flu) virus was first detected in the United States in April 2009 .
Because it takes two weeks to develop the immunity provided by the flu vaccine, most campaigns to immunize the population occur from the middle of October through November. However, immunization through December and early January is encouraged for those who were not vaccinated earlier. Persons of any age with chronic conditions that increase their risk of complications from influenza should be immunized as early as September.
All age groups are susceptible to influenza, but children have the highest infection rate. Rates of serious illness and death from seasonal influenza are higher among those who are 65 years of age and older with medical conditions that place them at increased risk for complications from influenza. Approximately 90% of the 49,000 annual fatalities resulting from influenza occur in those who are 65 years of age or older . However, much media attention is directed to fatalities among children. Pediatric deaths increased markedly during the 2009–2010 H1N1 (swine flu) pandemic, with 276 deaths reported . Particularly during pandemics, the burden of disease borne by younger individuals; in the 2009 H1N1 pandemic, which caused illness in 60 million Americans, 90% of hospitalizations and deaths were in persons younger than 65 years of age .
The economic burden of influenza on the community, the potential excess mortality among vulnerable members of the population, and the benefit to be derived from simple preventive measures and regular immunization are often under-recognized by the public and medical professionals alike. One study reported that increasing the annual percentage of adults receiving the influenza vaccine from 37% to 90% would save 12,000 lives each year . Studies of influenza mortality between 1976 and 1999 show that influenza A (H3N2), a swine flu, had a 57% mortality rate for the flu seasons between 1976 and 1990 and a 90% rate between 1990 and 1999 .
The term "influenza" originated in Italy sometime in the 15th century from an epidemic that was attributed to the "influence of the stars." In 1580, there was a worldwide epidemic that, from written description, was most likely caused by the influenza virus. Several other pandemics have occurred throughout the centuries. The most famous of these pandemics, the "Spanish flu," lasted for 10 months in 1918–1919 and resulted in an estimated 21 million deaths worldwide, with approximately 500,000 of these deaths in the United States . Other more recent pandemics include the "Asian flu" (1957), "Hong Kong flu" (1968), "Swine flu" (1976), and "Swine flu" (2009).
Influenza A and B are the two virus types that cause disease in humans. Influenza A virus was first isolated in 1933 by Smith, Andrews, and Laidlaw in ferrets. In 1936, influenza B virus was isolated by Francis. Swine influenza viruses (closely related to human influenza viruses) were isolated in 1930 . In that same decade, researchers discovered that influenza virus could be grown in embryonated chicken eggs. These discoveries led to the development of inactivated (killed) vaccines .
For many years, the proposed influenza epicenter has been thought to be Southeast Asia. Farming practices there bring pigs, fowl, and people into close contact, allowing swine, avian, and human flu viruses to mix. The cycle is thought to be birds to pigs to humans. Now it is clear that this cycle can occur at any place in the world where there is the domestication of animals .
Influenza belongs to the orthomyxovirus family and consists of a single-stranded, helically shaped ribonucleic acid (RNA) virus. There are three types of influenza viruses designated A, B, and C. The differentiation is made by the type of proteins within the nucleus, specifically antigenic properties in their internal nucleocapsid and matrix proteins. The individual types have different effects on the humans who become infected.
Influenza type A is the virus that causes moderate-to-severe illness in all age groups and is highly infectious, with an attack rate of 10% to 20%. It also causes influenza in pigs, birds, and other animals. There are several subtypes of influenza A.
Influenza type B generally causes milder disease. It primarily affects children but has also caused outbreaks in military camps and occasionally in long-term care facilities. It does not cause illness in animals and birds and, as a result, tends to be more stable with less antigenic change. Subtypes have not been defined for influenza B.
Influenza type C is rarely ever reported, probably because any disease it causes is usually subclinical or mild. It does not affect animals and birds.
Because type A influenza virus causes more severe illness and also occurs in animal and birds, this course will focus on influenza A.
Influenza A subtypes are defined by the occurrence of the glycoproteins hemagglutinin (H) and neuraminidase (N), which are surface antigens on the virus. The hemagglutinins H1, H2, and H3 are involved in attaching the virus to cells. The neuraminidases N1 and N2 facilitate virus penetration into cells. There are 15 different subtypes of hemagglutinins and 9 different subtypes of neuraminidases leading to several possible combinations, which are indicated in the name of the virus (e.g., H1N2, H2N3). Many combinations of the various hemagglutinin and neuraminidase antigen subtypes are possible. However, H1N1, H1N2, H2N2, and H3N2 have historically occurred in humans.
Pigs are susceptible to three of the same subtypes of influenza. Historically, they have not been infected by the H2N2 subtype. Wild waterfowl, in contrast, appear to acquire all influenza A subtypes. An additional difference is that the virus causes respiratory illness in humans, pigs, and other mammals but infects the gastrointestinal tract in wild birds without causing disease. However, the virus is shed in the bird droppings, leading to the contamination of water supplies, barnyards, farms, fields, and animal food supplies.
The genes of influenza viruses are carried on eight separate segments of RNA rather than on one long single molecule. This means that if two or more subtypes of influenza virus infect the same cell in a host, these viruses can exchange RNA segments during replication and create viruses with new gene combinations. This reassortment is termed "antigenic shift." It often occurs in pigs and is the source of influenza epidemics because the human population has little immunity to the new subtype that results.
In comparison, "antigenic drift" refers to changes in the surface glycoproteins. This does not result in a new subtype but does influence the choice of the particular influenza viral subtypes for the annual influenza vaccine. Depending on the degree of antigenic drift, immunity developed to one virus may be adequate to protect against the related virus. In other situations, the drift has resulted in enough change that there is little protection.
In the past, the influenza subtypes present in birds did not directly infect humans. A different host was usually required to complete the shift from an avian subtype to a subtype capable of infecting humans. This host has been the pig, which can be infected with avian, human, and swine influenza viruses. A possible scenario is that the food or water supply of the pig is contaminated by bird feces containing a subtype or subtypes of influenza A. The pig also acquires different influenza subtypes from other pigs and/or humans. Reassortment of the viral RNA occurs in the pig host, thus infecting other pigs. Farm workers catch the new subtype from the pigs and develop highly contagious influenza because they do not have immunity against this new subtype. Thus, a new influenza strain is launched . It is possible that antigenic shift could occur in a person who acquires a strain from a bird and also has a human strain. Realignment of H and N in the person's cells would result in a new strain. This new strain could become a pandemic if there is very little or no immunity in the human population and there is efficient, effective transmission from person to person .
Major pandemics of 1889–1891, 1918–1920, 1957–1958, and 1968–1969 have resulted from antigenic shifts. Characteristics of a pandemic are high attack rates in all age groups and a high mortality rate. Historically, pandemics have moved along trade routes, with rapidity of spread matching available transportation methods . Rapid movement of people around the world by aircraft and fewer border restrictions by partners such as the European Union allow new influenza subtypes to spread more quickly. However, cooperation among the World Health Organization (WHO), the CDC in the United States, and the European Centre for Disease Prevention and Control, which was established in 2005, has contributed to slowing the spread of the virus. Also, minimizing the transmission of influenza virus from any of the hosts to any of the other hosts (e.g., birds, pigs, humans) will decrease the antigenic shift and lessen the development of new subtypes to which the population has not developed immunity .
Research has shown that work-related travel rates affect the spread of influenza more than geographical distance or air travel . Based on 30 years of weekly data, influenza imported into a state with many inflows and outflows of workers, such as California, spreads much faster than if it enters a less-connected state, such as Wyoming. Epidemics also tend to start and spread from more populated states. This information is especially important in the event of the appearance of a new virus to which most of the population is susceptible. It usually takes five to seven weeks for annual influenza disease to spread across the continent. However, if a new strain originates in a highly connected state, it could spread to all states within two to four weeks. The study also revealed that adults, not children, are responsible for the transmission of influenza across regions because they travel farther and more frequently. One proposed intervention is to limit interregional travel to slow the spread .
The name of each influenza virus is developed following this formula :
Virus type (A or B): A/
Geographic origin (place where virus was first isolated): Wuhan/
Strain number: 395/
Year of isolation: 95/
Virus subtype (based on combination of hemagglutinin [H] and neuraminidase [N] antigens): (H3N2)
This was the principal virus isolated in the United States during most of the 1997–1998 influenza season.
Thus A/New Caledonia/20/99/(H1N1) would be read influenza A, which was first isolated in New Caledonia, strain number 20, isolated in 1999, with hemagglutinin subtype 1 antigen and neuraminidase subtype 1antigen.
As discussed, a brief definition for influenza is "respiratory illness with fever." This is a quick way for healthcare providers who are participating in the annual surveillance of influenza activity to categorize each of their patients. Approximately 1000 sentinel medical practitioners in the United States participate in the U.S. Influenza Sentinel Provider Surveillance System by providing statistics about the number of "respiratory illness with fever" cases that have been seen each week. These figures are collected weekly by designated local health departments and reported to the CDC by the corresponding state health department. The CDC compiles and publishes these figures, which give a current view and contribute to a historical picture of influenza activity for that week. Monitoring and analyzing these figures also alerts medical professionals to changes in patterns. Any change in the historical pattern is especially important in early detection of a biologic change, whether introduced naturally or by terrorist activity. Several biologic agents that could be used by a terrorist first manifest their presence with flu-like symptoms.
Uncomplicated influenza is characterized by an abrupt onset of:
Constitutional symptoms: Fever, chills, myalgia, headache, severe and persistent malaise, eye pain, light sensitivity, and substernal burning in the chest
Respiratory symptoms: Nonproductive cough, sore throat, and rhinitis
Initially, there are more constitutional than respiratory symptoms. If there are no complications, the chest is usually clear to auscultation.
Children may also experience any of the accompanying effects of fever, such as listlessness, irritability, anorexia, and convulsions. In addition, otitis media, nausea, vomiting, and diarrhea are frequently reported in children with influenza . Pneumonia and encephalopathy are serious complications in children with influenza . Elderly patients may exhibit confusion in addition to other symptoms.
The patient with influenza usually appears febrile and fatigued with hot, moist skin, a flushed face, and red watery eyes. More than half of patients infected with the influenza virus will have nasal discharge with obstruction and pharyngeal redness. Younger patients may have nontender cervical lymphadenopathy .
Influenza onset is so abrupt that many patients can pinpoint the hour in which they became ill. This is an important feature that helps distinguish influenza from other diseases with flu-like symptoms. The fever is generally 101 to 102 degrees F (38.3 to 39 degrees C). Children may run higher fevers. Patients may complain of body aches. Myalgia often localizes in the back muscles. These systemic symptoms usually last from two to three days and may persist as long as five days. Most systemic symptoms respond to antipyretics and analgesics. It is important to remember that any medications containing aspirin should never be used in children or teenagers because of the risk of Reye syndrome . This will be discussed in more detail later in this course.
Uncomplicated influenza is generally a self-limiting disease. Recovery is usually rapid, but most patients experience a decrease in strength or energy for a week or more after recovery (Figure 1).
Influenza is highly contagious, with an attack rate of 10% to 20% from the day before symptoms begin through approximately five days after onset in adults. It is spread from person to person through coughing and sneezing by the infected individual. Influenza can be spread by the airborne route, which means that a person coughing in the room can transmit the virus to others in the room without close personal contact. This is in contrast to droplet transmission in which heavier particles (droplets) are transmitted to those with close contact (less than 3–6 feet, depending on the organism). Droplet transmission also probably occurs in influenza. Airborne transmission is especially significant in congregate situations like institutions, daycare facilities, airplanes, and cruise ships .
As noted, the influenza virus may be transmitted between humans and pigs. More than 25 examples of transmission from pigs to humans have been documented in the medical literature . It is assumed that many more undocumented cases occur in individuals who work with swine. Usually, this swine-human connection is missed because the flu seasons in both pigs and people overlap. However, this connection should not be minimized. Its influence in antigenic drift or shift and the introduction of new subtypes is important to traditional transmission patterns.
Contaminated hands are a frequent source of transmission and infection. Contagious individuals cough or sneeze into their hands and deposit virus on whatever they touch. Or, they cough or sneeze the virus into the air, which settles on objects in the area. Others handle these objects and then touch their eyes, nose, or mouth and are infected. Following an incubation period of one to four days (average: two days), the individual develops symptoms. Another major factor in the spread of influenza is that it is transmitted to others before infected individuals even realize that they are sick .
Children are another source of infection, as they can be contagious for 10 or more days. In addition, young children can shed virus for up to six days before illness onset . This is one reason to discourage the practice of kissing infants and children on the mouth.
Obviously, an accurate diagnosis of influenza on the basis of symptoms alone is difficult. The quickest way to decide if the patient has influenza, or some other disease, is to use a rapid diagnostic test for influenza. However, medical practitioners should be aware that false-negative and false-positive results do occur. Within three to four days after onset of influenza, the virus can be found from throat and/or nasopharyngeal swabs. Highest viral shedding occurs during the first four days of illness. Nasopharyngeal specimens generally are more accurate. There are several rapid diagnostic tests available, and these tests can usually detect the influenza virus within 15 minutes [22,23]. The specimen to collect and the information provided by the results vary according to the test being used. These various rapid diagnostic tests for influenza A are 65% to 95% accurate . The accuracy rate depends on the particular rapid diagnostic test used and collection of the specimen at the optimum time . Other factors that may improve the accuracy of these tests include knowledge that influenza is circulating in the community and obtaining the specimen from a patient within the first four days of illness . The package insert should always be consulted as to the percentage of inaccurate results for the specific test. The rapid diagnostic test, therefore, can leave the medical practitioner with the need to base decisions about diagnosis and treatment on his or her clinical judgment . Recent immunization with intramuscular (IM) influenza vaccine will not affect a rapid diagnostic test. Intranasal vaccine will affect any serology test; however, the intranasal vaccine is no longer recommended [8,24]. Not all patients with influenza symptoms require a rapid diagnostic test. They should be done only if the results will help with the diagnosis and/or influence treatment decisions . In an institutional setting, such as a nursing home, use of a rapid test combined with a viral culture will help provide more effective treatment and allow for rapid prevention and control measures .
Culture of the virus takes a minimum of 48 hours. Another one to two days are needed to identify the virus type. Viral culture can take as long as 10 days to complete. Obviously, these tests provide information as to the virus responsible for the illness but are not practical for individual case management. Knowing the virus or viruses responsible, however, allows more accurate planning for vaccine preparations. This information also helps evaluate the effectiveness of the formulation used in the current vaccine .
Direct or indirect immunofluorescent antibody staining
Reverse transcriptase polymerase chain reaction
Immunohistochemical analysis of tissues collected during autopsy
Paired serology (comparison of antibody levels during acute and convalescent—two to three weeks later—phases). Antibodies in the convalescent specimen should be at least four times greater than in the acute specimen to confirm influenza.
For more information on available tests, please refer to the CDC's website at http://www.cdc.gov/flu/professionals/diagnosis/index.htm. Monitoring the status of influenza circulating in the community through the information provided by the CDC can also assist the practitioner in the diagnosis .
Making the correct diagnosis when a patient presents with flu-like symptoms is becoming more critical. The purpose of the discussion below is to highlight the importance of making a careful observation of the patient and obtaining an accurate history of the illness.
Because both influenza and the common cold are caused by viruses that affect the respiratory tract, distinguishing between them is important. Adults rarely develop fever with a cold (coryza) but usually have a fever of 101 to 102 degrees F (38.3 to 39 degrees C) with the flu. Headaches, muscle aches, and extreme exhaustion are mild or nonexistent with a cold but are usual and severe with the flu. The prodromal signs of sneezing, runny nose, and sore throat signal that a cold is developing and may be present for one or more days before onset. These symptoms may occur with influenza but usually occur concurrently with the sudden onset rather than signaling an approaching illness. The flu develops suddenly, without warning. Like influenza, a cold may have a dry (nonproductive) cough. Some use a "rule of thumb" to distinguish between a cold, in which symptoms are from the neck up, and influenza, which is systemic (Table 1).
INFLUENZA COMPARED TO COMMON COLD
|Clinical Presentation||Influenza||Common Cold|
|Prodrome||None||One or more days|
|Fever||101 to 102 degrees F||Rare in adults|
|Headache||May be severe||Rare|
|Myalgia||Usual, often severe||Mild|
|Tiredness/weakness||May last longer than two weeks||Mild|
|Cough||Usual, nonproductive||Mild hacking|
There are many other illnesses that initially look like influenza. For discussion and consideration in making a diagnosis, these diseases are sometimes grouped into influenza-like illnesses (ILI). Adults will average one to three ILI a year. Children can average three to six ILI in a year. The common cold is one of these, and the differences between influenza and colds have been discussed above. Other bacteria that cause ILI are Chlamydia pneumoniae, Mycoplasma pneumoniae, Streptococcus pneumoniae, and Legionella pneumophila. In addition, respiratory syncytial virus (RSV) has similar symptoms. None of these ILIs are as significant as biologic agents that may be used by a terrorist, such as anthrax, ricin, plague, and smallpox, all of which may present with influenza-like symptoms. However, they are a significant source of disease and should be considered when deciding if a patient has influenza or something else. Because bacterial diseases are treatable with antibiotics, but influenza is not, an accurate diagnosis is important. Much of the overuse of antibiotics occurs when patients request them for any illness or when careful diagnosis is not made between viral and bacterial diseases.
It may be helpful to consider the time of year in which the diagnosis is being made. Generally, pneumococcal disease peaks in the winter, as does influenza and RSV. Mycoplasma and legionellosis are more common during the summer and fall. Rhinoviruses and parainfluenza virus peak during the fall and spring. Adenoviruses circulate throughout the year . Information on the presence of influenza and predominant strains in the community can usually be found from the surveillance system maintained by the local health department .
Other information to consider is that, in healthy individuals, influenza is a self-limiting disease that strikes suddenly with most of its fury, maintains that level of illness for three to five days, and then shows improvement, even though the aftereffects of weakness and tiredness may persist for a week or more. In most other ILI diseases the patient's condition continues to worsen.
These last two considerations are not meant to figure in the diagnosis but to guide thinking about the patient's illness. For instance, if a greater than usual number of cases of ILI are being seen and it is the wrong time of year for influenza, another disease or a terrorist attack should be considered.
Some studies have been conducted on the use of clinical definitions for influenza-like illness. The results were :
Fever, cough, and acute onset accurately predict influenza 30% of the time in nonhospitalized older patients.
Fever, cough, and illness of less than seven days in hospitalized older patients with chronic cardiopulmonary disease accurately predict influenza 73% of the time.
Fever, but not cough, in vaccinated older persons with chronic lung disease was 54% specific for influenza.
Complications of influenza leading to hospitalizations and death are greater in persons 50 years of age and older, in young children, in pregnant women in the second and third trimester, and in persons of any age with underlying medical conditions. Laboratory data for the 2015–2016 influenza season indicated that 85 children younger than 18 years of age had influenza-related deaths . Since becoming a nationally notifiable condition in 2004–2005, the number of annual pediatric deaths has ranged from 37 to 171, excluding the 2009–2010 H1N1 epidemic, which will be discussed later in this course.
The major complication of influenza is pneumonia, and three types have been well-described in association with influenza epidemics: primary influenza (viral) pneumonia, secondary bacterial pneumonia, and mixed influenza/bacterial pneumonia. The incidence and mortality are highest in the elderly and in persons with underlying chronic illness, especially those with heart, lung, and renal diseases. However, in pandemic periods, half the deaths from pneumonia are seen in persons younger than 65 years of age .
Primary influenza pneumonia is the least common but most devastating form. It arises when the virus directly invades lung parenchyma and tends to present early as a rapidly deteriorating illness with high fever, profound dyspnea, and progressive respiratory failure. Patients with conditions that cause elevated left atrial pressures, such as heart failure and third-trimester pregnancy, are particularly at risk. Chest radiographs show bilateral diffuse reticulonodular opacities and basal (lower lobe) consolidation. Mortality is high.
Secondary bacterial pneumonia is the most common type and constitutes the major cause of excess morbidity and mortality in the elderly. The typical clinical presentation is a patient who appears to be convalescing from influenza only to experience an exacerbation of symptoms with renewed fever, worsening cough, purulent sputum, pleuritic chest pain, and radiographic evidence of a localized pulmonary infiltrate. The pathogens most often responsible are Streptococcus pneumoniae (50%), Staphylococcus aureus (20%), and Haemophilus influenzae. A number of factors affecting lung defense mechanisms are at play in the pathogenesis of bacterial superinfection, including :
The prime target cell for influenza virus in humans is the ciliated epithelial cell of the tracheobronchial tree.
Damage to this epithelium leads to impaired mucociliary clearance of any potential pathogens that happen to be colonizing the upper respiratory tract.
Alveolar macrophage phagocytosis is transiently impaired.
As might be expected, mixed influenza/bacterial pneumonia is a third type encountered during influenza outbreaks. This type of patient is vulnerable to severe, direct infection of the lung and happens, at the same time, to be colonized by a virulent respiratory bacterial pathogen (e.g., pneumococcus or staphylococcus).
Signs that a patient has developed pneumonia are :
Symptoms continue after the expected five to seven days
Symptoms worsen after the patient has started to improve
Fever returns and is higher than with the initial illness
Abnormal x-ray (pulmonary infiltrates)
Rales on auscultation
An unfortunate complication of influenza in patients younger than 18 years of age is Reye syndrome. Much education for parents has focused on the danger of giving aspirin to anyone younger than 18 years of age with a fever. This education has led to a decrease in Reye syndrome. Unfortunately, acetylsalicylic acid or salicylic acid is a component in some over-the-counter preparations and may be unintentionally given to a child with a fever. Influenza virus, especially influenza A virus, and varicella (chicken pox) interact with acetylsalicylic acid to produce Reye syndrome. Symptoms are nausea and vomiting, decreased consciousness and/or convulsions caused by cerebral edema, hypoglycemia, and liver failure. Parents must be reminded to read the labels of all medications and that aspirin is listed as acetylsalicylic acid .
Myositis (inflammation of muscle tissue) and rhabdomyolysis (involving striated muscle tissue) can be complications of influenza. These complications occur most often in children and are manifested by extreme muscle tenderness, especially in the legs. Myoglobulinuria may lead to renal failure in these patients. Serum creatinine phosphokinase (CPK) is markedly increased .
Influenza can be complicated by Staphylococcus aureus, leading to pneumonia as discussed above. Superinfection with S. aureus, leading to bacteremia, endocarditis, or epidural abscess, can also occur following influenza. Influenza B and S. aureus have led to toxic shock.
Other less common complications from influenza are myocarditis (inflammation of the cardiac tissues), and pericarditis (inflammation of the pericardial lining). A study conducted in Australia from 2008 to 2010 showed that recent influenza vaccination was significantly protective against acute myocardial infarction .
Besides the more common complication of bacterial or viral pneumonia, influenza can lead to the worsening of chronic bronchitis and other chronic pulmonary diseases.
Encephalitis, postencephalitic Parkinson disease, transverse myelitis, Guillain-Barré syndrome (GBS), and possibly amyotrophic lateral sclerosis have followed cases of influenza. There has been research suggesting that cases of Parkinson disease resulted from the "Spanish flu" pandemic of 1918–1919 [55,56,57,58,59,60].
Any person with a serious medical condition can be placed in jeopardy by influenza, not only from the complications listed above, but also from exacerbation of the underlying condition .
Influenza vaccine is the primary preventive measure against the virus. It is efficacious in preventing influenza. Among those at higher risk, it lessens the severity of the illness, decreases complications, reduces hospitalizations, and lowers the fatality rate. It is disappointing that a vaccine with such benefits and few side effects is not used more widely. In 2010, the CDC approved the Advisory Committee on Immunization Practices (ACIP) recommendation that all individuals 6 months of age and older should receive the influenza vaccine. This recommendation was based on the fact that historically targeting at-risk groups for influenza vaccination has not proven to be as effective as immunizing everyone. With a highly communicable disease like influenza, children are the most likely to contract and spread the infection. Nearly all children must be immune to achieve community (herd) immunity . The ACIP reaffirmed its recommendation of routine annual influenza vaccination for all persons 6 months of age or older who do not have contraindications (i.e., universal vaccination) .
In July 2010, the CDC published its recommendation that administration of the flu vaccine should begin as soon as the vaccine is received . The CDC and the ACIP repeat this recommendation for the 2016–2017 flu season . This decision was based on clinical trials that suggest protection from the influenza viruses covered by the vaccine lasts six to eight months and may last up to one year in college students. Because those 50 years of age and older have a diminished response to the vaccine, the immunity probably does not last as long .
A variety of vaccines are available for the 2016–2017 flu season, including trivalent and quadrivalent preparations (inactivated and recombinant) .
A vaccine containing an increased amount of the hemagglutinin antigen of the influenza virus was licensed by the U.S. Food and Drug Administration (FDA) in 2009 . It is a single-dose, inactivated, trivalent, injectable vaccine sold under the brand name, Fluzone High-Dose, manufactured by Sanofi-Pasteur. This high-dose vaccine was developed for individuals 65 years of age and older who are at a greater risk of hospitalization and death from seasonal flu and are known to develop lower antibody titers to the influenza virus. The vaccine is available for the 2016–2017 flu season .
Prelicensure clinical trials showed no preference for the new vaccine over other inactivated trivalent influenza vaccines. All were equally safe and equally effective at producing immunity . However, the high-dose formulation resulted in significantly higher hemagglutination inhibition titers against each strain than the standard formulation . A 2014 trial showed that recipients had 25% greater protection against influenza illness. A comparison between the standard and high-dose flu vaccines showed that in each 0.5 cc dose the standard vaccine contained 45 mcg (15 mcg of each of the three strains) while the high-dose vaccine had 180 mcg (60 mcg of each strain) .
As with the standard vaccine, the high-dose should not be given to anyone with a known hypersensitivity to egg proteins or other components of the vaccine. Vaccination with the high-dose formulation produced more frequent injection site reactions and systemic adverse events than the standard formulation, but typically they were mild and transient [4,8].
In the event of a vaccine shortage, the following high-risk groups should receive the vaccination first.
Persons 50 years of age and older have the highest fatality and hospitalization rate from influenza and its complications. Of the 49,000 annual deaths, 90% of them occur in those 65 years of age and older. In addition, 57% of the hospitalizations are in this age bracket . Those who are between 50 and 64 years of age are high risk because of the high prevalence of chronic diseases in this population. These patients often do not receive the vaccine because the publicity about the need to receive the vaccine has tended to focus on those 65 years of age and older. Only 48.1% of persons 50 to 64 years of age receive the vaccination; the vaccination rate among persons 65 years of age and older is 69.1% . In addition, Medicare pays for the vaccine after the person reaches 65 years of age. Therefore, individuals who fall into the 50 to 64 age group may be disinclined to receive the vaccine.
Persons with chronic health problems who are 6 months of age or older are at high risk for complications from influenza or exacerbation of their condition. Such chronic conditions include:
Cardiac disease, such as congestive heart failure
Pulmonary disease, such as chronic obstructive pulmonary disease, cystic fibrosis, or asthma
Diabetes and other metabolic diseases
Anemia and blood disorders, such as sickle cell disease
Persons with compromised immune systems from any cause—human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS), autoimmune conditions, cancer, long-term steroid treatment, and medications—should receive the inactivated vaccine . Because the vaccine is inactivated (killed), it can and should be given to immunosuppressed people. However, because of the depressed immune system of this group of people, the expected antibody response may not be obtained. HIV-infected patients with minimal AIDS-related symptoms and high CD4 T-lymphocyte cell counts have been shown to develop substantial antibody titers against influenza. For those with more advanced HIV disease and low CD4 T-cell counts, the vaccine might not induce protective antibody titers, and a second dose has not been shown to increase the titer. Some studies have shown that there is a temporary (two- to four-week) increase in replication of HIV after receiving the influenza vaccine . However, other studies have not demonstrated this increase nor has progression of HIV disease been shown to occur following the administration of the influenza vaccine. Each immunocompromised individual should be evaluated before the vaccine is administered because an increase in plasma HIV levels and/or a decrease in CD4 count has been transient in most, but not all, cases of those receiving the influenza vaccine .
Persons with conditions or diseases that may compromise respiratory function or increase the risk of aspiration should also be vaccinated against influenza to prevent any possible complications or damage.
All healthcare providers should receive the influenza vaccine annually. Additionally, healthcare facilities are encouraged to make available the vaccine to their workers. In its 2012 recommendations, the ACIP encouraged healthcare facilities to obtain a signed declination form from healthcare workers who refuse influenza vaccination . Those who refuse vaccination may be required to wear a mask during influenza season. This issue is not specifically discussed in the 2016–2017 recommendations .
Persons who reside in skilled nursing facilities (nursing homes) or other chronic care facilities are at high risk for influenza-related problems because of their weakened physical state and close living arrangements.
Persons 6 months to 18 years of age on long-term aspirin therapy should be immunized against influenza because of the interaction of the influenza virus and aspirin that can lead to Reye syndrome.
Women who are pregnant during influenza season have the same complication and hospitalization rate from influenza as persons with chronic diseases and, therefore, should receive the vaccine. This would include women who will deliver from the beginning of October through the end of May. Increased severity of influenza among pregnant women was reported during the pandemics of 1918–1919, 1957–1958, and 2009–2010 . Severe infections among postpartum women also were observed in the 2009–2010 pandemic, and 56 deaths (36 during the third trimester) were reported among 280 pregnant women admitted to intensive care units. Although there are some recommendations that a woman should not receive the influenza vaccine before the 14th week of gestation, the ACIP and the American Congress of Obstetricians and Gynecologists (ACOG) recommend influenza vaccination for all women who are or will be pregnant during the influenza season, regardless of trimester [8,64]. There is a coincidental association of spontaneous abortion, which is common in the first trimester. Also, many practitioners avoid any exposure to vaccines during the first trimester. However, no adverse fetal effects have been associated with influenza immunization [8,65]. Infants born to women who contracted the 1918 flu during their second and third trimesters had higher rates of cardiovascular disease at 60 to 82 years of age . For men this rate of increase was 23.1%; for women it was 17%. In addition, individuals exposed prenatally were less successful economically and educationally. Studies of other influenza pandemics have shown schizophrenia risk is three times higher in those exposed to influenza in utero . This information should help healthcare workers to recognize the importance of immunizing pregnant women.
All children 6 to 59 months of age, especially children 6 to 23 months of age, even without any chronic conditions, should receive the annual influenza immunization because they are at a substantially increased risk for influenza-related hospitalizations . Many of the hospitalizations are due to dehydration that can occur rapidly in a child who has a fever and will not drink fluids. The hospitalization rate in this age group matches the hospitalization rate for other groups at high risk for complications and death from influenza. At this point, these higher hospitalization rates cannot be totally assigned to influenza because RSV circulates at the same time. Since 2003, the Vaccines for Children (VFC) program has covered the cost of the influenza vaccine for all eligible children 6 to 23 months of age and all eligible children 2 to 18 years of age who are household contacts of a child 0 to 23 months of age . The ACIP, the American Academy of Pediatrics, the ACOG, and the American Academy of Family Physicians (AAFP) published the Recommended Immunization Schedule for Persons Age 0 Through 18 Years, which includes a recommended yearly influenza immunization for all children 6 months of age and older [8,67]. Data from two studies showed that a side benefit from the influenza vaccine has been a reduction in otitis media .
Other groups who should receive vaccine during a shortage include American Indians/Alaskan Natives; the morbidly obese (body mass index ≥40); household contacts/caregivers of children younger than 6 months of age for whom there is no vaccine; and persons with medial conditions that put them at higher risk for severe complications from influenza .
Before 2004, influenza-related deaths in children were not on the list of deaths that should be reported. When it became apparent that a significant number of children were dying, the CDC requested that all influenza-related deaths of children younger than 18 years of age be reported to the appropriate state health department. Any postmortem tissue specimens that were collected or autopsy reports that were completed were also asked to be sent to the CDC . However, in the subsequent years there have been even more deaths of children. As noted, in the 2015–2016 flu season, there were 85 deaths among persons younger than 18 years of age . During the 2009 H1N1 pandemic, 32% of hospitalizations and 10% of deaths (approximately 1,250 deaths) were children younger than 18 years of age .
Data from the Internet Panel Survey of healthcare personnel indicated that only 49% of healthcare workers were immunized against influenza, in spite of the fact that vaccination reduced work absenteeism and resulted in fewer deaths among nursing home residents . In the 2011–2012 season, only 67% were immunized. That percentage rose to 72% during the 2012–2013 season and then to 79% in the 2015–2016 season [70,87]. Studies have also shown that ill workers account for as much as 60% of corporate healthcare costs. To respond to these situations, many companies now offer free influenza vaccinations and expanded telecommuting options . The Healthy People 2020 objective is a 90% vaccination rate, but obviously 100% coverage is preferable .
The public continues to follow the example of their healthcare providers. Although approximately 218 million Americans could have benefited from the influenza vaccine in the 2007–2008 flu season, millions of unused doses were destroyed . To emphasize the importance of flu vaccinations, the CDC has established the National Influenza Vaccination Week. In 2016, the week is scheduled for December 4 through 10 . While meaningful improvements in vaccination coverage have been observed in children over the past seven flu seasons (from 44% to 60%), a significant increase has not occurred in the adult population (from 40.4% to 41.7%) .
Persons who provide essential services, such as law enforcement personnel and firefighters, should be immunized. This is especially important in a pandemic situation. Students living in dormitories should receive the vaccine in order to avoid disruption of their studies.
Travelers should be evaluated for influenza immunization when "travel shots" are being recommended. Influenza in temperate climates occurs in the winter months (October through March in the Northern hemisphere; April through September in the Southern hemisphere); it occurs year-round in tropical climates. People taking a cruise could be infected with influenza at any time of the year because many of the service crew members are from tropical areas and a cruise ship is a closed community, which helps to assist in the spread of the virus .
The need for healthcare workers to be immunized against influenza cannot be overemphasized. All healthcare workers should receive the influenza vaccine. Not only does it protect the patient, but it also protects the healthcare worker. Healthcare workers who have been immunized tend to remember to advise their patients to get the immunization. This can strengthen the advice by example and can also provide anecdotal reassurance about the pain or side effects experienced. Studies have shown that residents in long-term care facilities have fewer deaths from influenza when their caregivers have been immunized against influenza .
Persons with a severe allergic reaction to eggs should not be given most types of influenza vaccine . A person with a severe hypersensitivity to eggs may develop an anaphylactic reaction (e.g., sudden sense of great uneasiness or anxiety, pounding headache, hypotension, urticaria, dyspnea). Most influenza vaccines are grown in eggs, and although they go through a purification process, a small amount of egg protein remains. This minute amount could trigger a reaction in those who are severely allergic to eggs. A dislike for eggs, mild gastrointestinal symptoms, or hives (alone, without other, more severe symptoms) following ingestion of eggs is not a contraindication for the inactivated influenza vaccine. Usually, asking a person receiving the influenza vaccine for the first time if they can eat soft-cooked eggs without a problem is a quick screening tool and an adequate precaution. In 2013, the FDA approved the first vaccine that is not grown in eggs, eliminating any risk for those with severe allergic reactions to eggs. The only vaccine considered to be egg-free is Flublok, a trivalent recombinant influenza vaccine; however, this vaccine is only approved for adults 18 years of age and older [8,185].
Persons with acute respiratory or other active infections or illnesses should be advised to wait until they have recovered to receive the vaccine .
Persons with a history of GBS are more prone to another episode of this syndrome . Because GBS is such a rare condition, it is impossible to know if the influenza vaccine is involved in its occurrence. During the 1976 swine flu epidemic, there was an increase of GBS (1 additional case per 100,000 vaccinated) in those who had received the vaccine . However, an increased incidence of GBS following administration of other influenza vaccine formulations since 1976 has extremely low (1 additional case per 1 million vaccinated). According to the package insert for Fluzone, for patients who have recovered from GBS, it is better to err on the side of caution and avoid giving them the influenza vaccine until more information is available . The Epidemiology and Prevention of Vaccine-Preventable Diseases, known as the "Pink Book," states that persons who have developed GBS within six weeks of receiving the influenza vaccine would be wise to avoid a subsequent flu shot [3,8]. However, the recommendation of the ACIP is that recovered GBS persons with risk factors that increase their vulnerability to the complications of influenza should receive the vaccine because the risk of complications is greater than the risk of a recurrence of GBS .
Persons with an allergic reaction to dry natural latex rubber should be evaluated before being given the vaccine because the stopper in some of the vials contains dry natural latex rubber . According to data provided to CDC, Fluvirin and Fluad (manufactured by Seqirus) are the only vials that are expected to possibly contain latex.
Note: Influenza immunization is NOT contraindicated in breastfeeding mothers. In fact, it should be encouraged because the mother could transmit influenza to her vulnerable infant if she gets the disease . She could also be liable to a decreased milk supply because of decreased fluid intake and fever and would have the added burden of infant care and breastfeeding while experiencing exhaustion and other flu symptoms.
Because of antigenic drift, each year the ACIP and the FDA must decide which influenza strains to include in the formulation of the season's vaccine. Because the formulation changes each year to provide protection against the expected circulating strains, an annual influenza immunization is needed. Obviously, the point is to include the strains that will be expected to spread globally. There are two type A strains included in the trivalent formulations, because type A influenza strains are usually those that lead to more complications, hospitalizations, and deaths. The third strain included is always a type B; the quadrivalent formulation includes a second type B strain. In the 2003–2004 influenza season, the expected dominant strain killed the embryonated egg where the virus was grown due to the virulence of the strain . A virus that was close to the expected circulating strain was chosen instead. However, the match was not close enough to the circulating strain for the vaccine to be as effective as it usually is. To the credit of the ACIP, this was only the second mismatch in 15 years [74,75]. In some cases, antibodies produced against one strain can overcome another strain, but the strains must be closely related. Antibodies produced by the strains in the 2003–2004 formulation were not close enough to the dominant circulating strain to destroy it, so people who had received the vaccine still developed influenza. In fact, the choice of which strains to include is based on the current knowledge as to which will be the most virulent strains in circulation. Due to the fact that there are only three strains in the vaccine and there are multiple influenza strains, people who are vaccinated can still develop illness from a strain of influenza virus that was not included in the vaccine.
Another extremely significant factor in the choice of a strain is the ability to grow the strain so that the vaccine can be produced in millions of doses. When vaccine distribution is delayed, it is often due to the fact that one particular strain would not reproduce well or quickly enough. As noted, some strains kill the culture medium.
Trivalent formulations for the 2016–2017 influenza season are A/California/7/2009/(H1N1)-like, A/Hong Kong/4801/2014 (H3N2)-like, and B/Brisbane/60/2008–like (Victoria lineage). Quadrivalent vaccines will include an additional vaccine virus strain, B/Phuket/3073/2013-like (Yamagata lineage) .
Production of influenza vaccine involves the following steps :
The chosen strains of influenza virus are incubated in fertilized chicken eggs.
Fluids containing the virus are harvested.
The virus is inactivated (killed) by formaldehyde.
The virus is concentrated.
The virus is chemically disrupted to produce a "split virus." (All influenza vaccine used in the United States is split virus.)
Further purification of the virus by chemical means is done.
The virus is suspended in sodium phosphate-buffered isotonic sodium chloride solution.
No antibiotics are used in the preparation of influenza vaccine.
Thimerosal is a preservative used in multi-dose vials to inhibit bacterial growth that might occur because of multiple introductions of needles to withdraw individual doses. It is a compound containing 49.6% mercury. Because of the allegation that thimerosal is connected to conditions such as autism and the fact that there have been warnings to avoid fish that has a high mercury content, thimerosal has been removed from most childhood vaccines. Vaccines without thimerosal are packaged in single-dose vials. However, thimerosal is still used in multi-dose vials (5 cc dose vials) and in one brand (Fluvirin) of single-dose prefilled syringes of influenza vaccine . There are 25 mcg of mercury in each 0.5 cc dose of vaccine. One should note that there have been no studies proving any link between mercury poisoning and autism. Thimerosal is made from ethyl mercury, which is different from methyl mercury, the compound named in the government warning about consumption of or exposure to mercury . More influenza vaccine without thimerosal has been made each year and should be used for those who have a severe allergic reaction to thimerosal. One hundred twenty million doses of thimerosal-free vaccine will be available for the 2016–2017 flu season .
These production methods have been used for decades and do not apply some of the modern technology available in the production of vaccines against other organisms, such as hepatitis A or hepatitis B. As noted, most influenza vaccine is incubated in fertilized chicken eggs. It takes one egg to produce one dose. More than 80 million doses are made for annual distribution in the United States alone. The number of chickens and eggs needed for this production is almost beyond comprehension. Also sobering is the thought of what would happen if one or more of the major flocks used for producing the eggs for the vaccine became infected with an avian influenza, which would require destruction of the flock(s).
Another issue involved is the amount of time required to produce the annual influenza vaccine—about six to eight months. Any new strain of influenza could circulate around the world much faster than the vaccine could be produced, resulting in a pandemic. Experimentation is being conducted on faster ways to produce the vaccine. Some companies are experimenting with caterpillar cells to incubate the virus. Experiments have indicated that the vaccine can be produced more quickly and that it would be available to protect people against emerging strains. Phase I trials indicated that the vaccine incubated in caterpillar cells is safe. In a clinical trial of 400 elderly people, the vaccine stimulated the production of nearly twice the number of antibodies as the vaccine produced using eggs. In addition, there were no adverse effects. Phase II trials in 400 elderly participants showed that 97% of them developed antibodies if the highest dose of the vaccine was used [77,78].
Another approach being explored in influenza vaccine production is to genetically engineer cells to replicate continuously. Such a process would lead to faster production and a more consistent vaccine . One example of this is the Flublok vaccine, which uses protein-producing machines to make hundreds of copies of hemagglutinin, the small piece of the influenza virus needed for immunity . Flublok is available for the 2016–2017 influenza season.
Other experimentation is being done using DNA-based approaches to develop a broadly protective vaccine that utilizes influenza virus proteins from multiple strains. Several companies are working to develop new ways to grow the antigens that cause the immune system to fight infection [79,81].
Using the reverse genetics method, in which genomes of the influenza viruses are manipulated in order to transfer genes between viral strains, seed viruses for vaccine manufacture can be rapidly generated. In addition, highly pathogenic influenza viruses can be altered so that they are safer for vaccine manufacturers to handle .
Another method of vaccine development, cell culture, has been well tolerated and has successfully led to antibody development in trials. Some research has shown that vaccines developed based on cell culture have been efficacious against all strains of influenza A, including H5N1 . Using cell-based vaccines creates a more consistent manufacturing process and could reduce production time to 9 to 12 weeks. Although there are some side effects from cell-based vaccines, including headaches and injection site reactions, they appear to have a similar tolerability profile to egg-based vaccines .
In another area, one small study has been conducted that indicates that mild exercise before having a flu shot may make the vaccine more effective. Lifting weights before a flu shot increased antibody response in women but reduced the response in men. However, the cell-mediated response in men was increased by weight lifting. The researchers suggest that exercise increases the number of immune cells in muscle tissues, which in turn increases activity in the lymph nodes and creates a more efficient immune response [29,30].
The following information pertains to the egg-based vaccine in use. As is the case for all vaccines, the package insert should be consulted for proper handling and storage in order to preserve its effectiveness. Influenza vaccine should be stored at a temperature of 36 to 46 degrees F (2 to 8 degrees C) . It should be transported in insulated containers with cold packs; however, it should not be directly in contact with the cold packs nor should it be placed anywhere in a refrigerator where it can be frozen. Freezing destroys the effectiveness of influenza vaccine. The vaccine can tolerate being out of the refrigerator while an influenza clinic is being prepared or conducted. However, only enough vaccine for the first half hour should be taken from the refrigerator at a time. When immunizing individual patients in an office setting, the vaccine vial should be returned to the refrigerator as soon as the dose has been withdrawn.
It is important that the temperature of the vaccine storage refrigerator be checked and recorded each morning before starting to dispense immunizations and each evening before leaving for the day. Older refrigerators can develop cold spots where items can freeze, or they may not maintain a constant temperature. All inactivated vaccines, like influenza vaccine, are destroyed by freezing. Large bottles of water should be kept in the refrigerator at all times to help maintain an even temperature and to preserve cold longer in case of a power outage. Some live vaccines, such as chickenpox and oral polio (no longer used in the United States), must be kept frozen. Vaccine should never be stored on the shelves in the door as the temperature there is erratic.
Recommended vaccines for the 2016–2017 flu season are Fluad, Fluarix Quadrivalent, Flublok, Fluzone High-Dose, Fluzone Intradermal Quadrivalent, Fluzone Quadrivalent, Flucelvax Quadrivalent, Fluvirin, Afluria, and Flulaval Quadrivalent (Table 2). Children younger than 18 years of age should not receive Flublok (IM) or Afluria (jet-injection) . Children younger than 9 years of age should not receive Afluria (IM). FluMist is available but is not recommended for the 2016–2017 flu season .
2016–2017 RECOMMENDED INFLUENZA VACCINES AND TARGET POPULATIONS
|Trade Name||Manufacturer||Supplied As||Mercury||Age Group||Route||Componentsa|
|Fluzone Quadrivalent||Sanofi Pasteur||0.25 mL prefilled syringe||0||6 to 35 months||IM||Inactivated|
|0.5 mL prefilled syringe||0||>36 months||IM||Inactivated|
|0.5 mL vial||0||>36 months||IM||Inactivated|
|25 mcg||>6 months||IM||Inactivated|
|Fluzone High-Dose||Sanofi Pasteur||0.5 mL prefilled syringe||0||>65 years||IM||
|Fluzone Intradermal Quadrivalent||Sanofi Pasteur||0.1 mL prefilled microinjection system||0||18 to 64 years||ID||Inactivated|
|Fluarix Quadrivalent||GlaxoSmithKline||0.5 mL prefilled syringe||0||>3 years||IM||Inactivated|
|Flucelvax||Seqirus||0.5 mL prefilled syringe||0||>4 years||IM||Inactivated, cell culture-based|
|Flulaval Quadrivalent||ID Biomedical Corp. of Quebec (distributed by GlaxoSmithKline)||0.5 mL prefilled syringe||0||>3 years||IM||Inactivated|
|5.0 mL multi-dose vial||<25|
|Fluvirin||Seqirus||0.5 mL prefilled syringe||>1 mcg||>4 years||IM||Inactivated|
|5.0 mL multi-dose vial||25 mcg|
|Afluria||Seqirus||0.5 mL prefilled syringe||0||
|5.0 mL multi-dose vial||24.5 mcg|
|Fluad||Seqirus||0.5 mL prefilled syringe||0||>65 years||IM||Adjuvanted inactivated|
|Flublok||Protein Sciences||0.5 mL single-dose vial||0||>18 years||IM||Recombinant|
Fluad is an adjuvanted trivalent inactivated influenza vaccine that was licensed November 2015 for adults 65 years of age and older . The adjuvant, a squalene based oil-in-water emulsion, effectively boosts the immune response in older individuals.
In May 2016, the FDA licensed Flucelvax Quadrivalent, a cell culture-based inactivated influenza vaccine . The vaccine is prepared from virus propagated in adult canine kidney cells rather than in hen's eggs.
Monitoring the 2010 influenza season in Australia produced data indicating that Afluria (marketed as Fluvax in the Southern Hemisphere) was associated with increased frequency of fever and febrile seizures in children 6 months through 4 years of age when compared to previous years . Although Afluria is FDA-approved for children 5 years of age and older, the CDC and the ACIP recommend that Afluria not be given to children younger than 9 years of age . However, if no other age-appropriate vaccine is available for children 5 to 8 years of age and a child has a medical condition that increases risk of influenza complications, Afluria can be used . Generally, the fever occurs 4 to 24 hours after the vaccine is given . It would be prudent to instruct the parents or caregivers of these children to monitor the child's temperature and give nonaspirin fever-reducing medication as needed. In some public health immunization clinics, parents are instructed to give a dose of a fever-reducing medication to the child as soon as they get home, as a preventive measure. In a 2009 clinical trial in the United States, increased fever was noted among recipients of Afluria 6 months through 8 years of age. For the 2010–2011 influenza season, the U.S. Department of Health and Human Services Vaccine Adverse Event Reporting System (VAERS) and Vaccine Safety Datalink reviewed adverse event reports carefully for febrile seizures in children younger than 9 years of age .
The influenza vaccine discussed in this section is for IM use only; the intranasal and intradermal preparations are discussed later in the course. The IM vaccine is for all people 6 months of age or older. In order to assure that the vaccine is given IM, it is necessary to use needles of the proper length. Vaccine that is administered subcutaneously because of improper technique or a needle that is too short is ineffective.
The recommended site for adults and for children 3 years of age and older is the deltoid muscle . A 1-inch needle will reach the deltoid in most children and adults. Some patients with large arms will need a 1.5-inch needle. One should be careful to make sure that the patient's sleeve can go high enough so that the needle can be inserted in the middle of the arm, about 1.5 inches below the top of the shoulder. Usually the firmness of the deltoid can be felt in that area. In patients who are very thin, it is wise to squeeze the deltoid between the thumb and finger to avoid hitting the bone. Administration of the vaccine distal in the deltoid is more painful. The posterior portion of the arm should not be used.
In children younger than 3 years of age, the deltoid is usually not big enough to receive the vaccine. The vastus lateralis muscle should be used . This is the muscle on the outer aspect of the child's thigh and can usually be palpated. At times, when the infant kicks, the outline of the muscle can be seen. Two key elements to administering an injection to a child are to have the child properly and quickly restrained. An assistant, either the parent or a helper, should position the child so that the leg or arm where the injection will be given will not move. The upper body, the leg not being used for the shot, and the foot of the leg being used should be held tightly by the parent. Young children 3 years of age and older should sit sideways on the parent's lap so that the child's legs can be clamped between the parent's knees. The arm that will not be used for the injection should go around the parent's waist and be clamped under the parent's arm. The hand of the arm being used for the injection should be held by the parent. The person giving the vaccination should have all injections prepared so that they can be administered quickly. It is also good to distract the older child by having them blow, count, or see how loudly they can say "ouch."
Children should receive split-virus vaccine. This is not an issue in the United States as all vaccines are split-virus. Because some influenza vaccine comes in multidose vials, a small amount of thimerosal is in the vaccine . For parents who are unwilling to accept the studies showing no connection between thimerosal and autism or other negative health effects, several thimerosal-free preparations are available [8,65].
FluMist, Fluarix, Flulaval (single-dose), Fluzone (single-dose), and Afluria do not contain thimerosal. There are additional vaccines in use with reduced or no thimerosal. Information on the amount of thimerosal present in each vaccine dose is available on the CDC website .
Children younger than 9 years of age receiving influenza vaccine for the first time should receive two doses, one month apart. The dose for a child is age-related . Children from 6 to 35 months of age should be given 0.25 mL administered IM with a 1-inch needle in the outer aspect of the thigh. If it is the first time the child has received a flu shot, a second 0.25 mL dose IM should be given one month later . The Fluzone quadrivalent vaccine (Sanofi Pasteur) is available in a 0.25 mL single-dose prefilled syringe and contains no thimerosal . In subsequent years, the child will receive only one influenza vaccine each year. Children 3 years of age and older should be given 0.5 mL IM using a 1-inch needle in the deltoid. Children who are 3 to 8 years of age receiving influenza vaccine for the first time will need a second vaccine in one month. These second doses in those not previously immunized against influenza are given to maximize a satisfactory antibody response to all antigens in the vaccine. Preferably, both doses should be given before December [8,36,74]. Late-season immunization is acceptable and should be encouraged for those who have not received the vaccine .
As an inactivated vaccine, influenza can be administered with other vaccines if required. Separate needles and separate sites should always be used. In fact, for patients 65 years of age or older who have never received the immunization against pneumococcal disease, that vaccine should be given at the same visit. This is also an excellent time to check on the status of the patient's tetanus immunization. Tetanus vaccine should be given every 10 years, a fact that is often forgotten in adults, especially older individuals.
All patients or their parent/guardian must receive the Vaccine Information Statement (VIS) appropriate to the vaccine being administered. The patient signs that he or she has read the VIS. The record the patient signs must contain the date that the VIS was provided to the patient. Many people think that they are signing permission for the vaccine to be given. Actually, they are signing that they have read the VIS .
Children younger than 18 years of age should not be given any vaccines without a parent/guardian present. Grandparents who are not legal guardians frequently bring children to immunization clinics. A written permission from the child's parent/guardian should be presented to the staff before the vaccine is administered.
The most common side effect following influenza immunization is a local reaction—soreness, redness, or induration at the injection site—that occurs in 15% to 20% of the recipients. Generally, these effects last only one or two days. Some people (<1%) experience fever, chills, malaise, and myalgias, usually within 6 to 12 hours. This effect occurs most often in those receiving the vaccine for the first time. As with the local reaction, these systemic reactions last only one to two days. In a comparative study with a placebo, the systemic reactions occurred as often with the placebo as with the influenza injection. Neurologic reactions to influenza do occur, but they are rare .
A certain percentage of people will be incubating an influenza virus when they receive the influenza injection. When they have symptoms of influenza within a few days of vaccination, they are certain it is the result of the flu shot. Healthcare workers should try to reassure their patients that the vaccine cannot be responsible because the virus in it is split and dead.
Immediate severe allergic reactions can occur after administration of influenza vaccine. These reactions are probably due to hypersensitivity to a component of the vaccine, usually a severe egg allergy. As noted, this concern may be eliminated with new technologies that have become available. All patients receiving the influenza vaccine, especially for the first time, should be carefully screened for severe egg allergy. If a person has a severe allergic reaction to thimerosal, a thimerosal-free vaccine (e.g., Fluzone, Fluarix) should be used. For those allergic to eggs but who have factors that increase their risk of complications from influenza infection, protocols to vaccinate them are available. Flublok may be used in these patients as it is egg-free . A sheet with the symptoms of anaphylaxis and the dosage of therapeutic epinephrine should be posted near the preloaded epinephrine syringe and should be readily available and known to all staff. In addition, crushable packets of ammonia should be available in any area in which immunizations will be administered. It should be noted that anaphylactic reactions are extremely rare. Patients, especially teenagers, may faint and the crushed ammonia passed quickly under the nose is enough to revive them. Never ignore a patient who verbalizes fear of shots or mentions that they have fainted in the past. Make sure such a patient is seated or lying down if in an exam room. Reassure the patient and administer the vaccine as quickly as possible. Position your body in such a way as to be able to support the patient if he or she begins to faint. Taking time to carefully screen a patient for allergies to the components of the vaccine or other reactions to injections is always wise and saves time in the long run.
Adverse events are any unusual conditions, such as fever, dizziness, behavior change, or serious allergic reactions (e.g., difficulty breathing, hoarseness or wheezing, hives, paleness, weakness, tachycardia), following influenza vaccine. The National Childhood Vaccine Injury Act of 1986 mandates that healthcare providers report adverse events following vaccination to VAERS. Providers are additionally encouraged to report any clinically significant adverse event following vaccination to VAERS . Any person can report an adverse event following the administration of any vaccine by calling VAERS or by obtaining a form online. Adverse events usually occur within 48 hours of vaccine administration. However, GBS may occur as long as six weeks after administration. The VAERS form will ask for detailed information on the vaccine, such as lot number, administration site, administrator, and date. Patients to whom influenza vaccine is administered should be instructed to call a physician if there is an adverse event. Careful investigation follows the receipt of a VAERS report. The provider is notified of the results of the investigation usually several months after the report was made. Therefore, it is important to keep a copy of the report in the patient's file and a copy in a special file for VAERS reports. As the report is investigated, the provider may be contacted for clarification or additional information.
The effectiveness of any vaccine depends upon the age and immunocompetence of the person receiving the vaccine. Most children and young adults receiving the vaccine have a good antibody response to the strains included in the vaccine and develop titers sufficient to protect them against those strains. For healthy adults younger than 65 years of age, if the vaccine strains match the circulating strains, illness will be prevented in 70% to 90% of those adults. In children, various studies have shown that children as young as 6 months of age develop antibodies. Children at high risk to develop complications with influenza may have a lower antibody response than healthy children. Also, children receiving the vaccine in the second year exhibit lower attack rates. Otitis media rates are lowered in some studies but not in others. Overall, because the vaccine is beneficial to children in preventing disease and lowering hospitalization rates, the ACIP recommends a yearly influenza immunization for all children 6 months of age and older [4,8].
In adults 60 years of age and older who are not institutionalized, a randomized trial showed that the vaccine was 58% effective against influenza respiratory illness. Efficacy might be lower in those older than 70 years of age. However, the vaccine appears to be effective in preventing secondary complications, hospitalization, and death among older adults, both those who are healthy and those with chronic medical conditions. Among noninstitutionalized older adults, the vaccine prevented hospitalization for pneumonia and influenza 30% to 70% of the time. Among institutionalized older adults, the vaccine can be 50% to 60% effective in preventing hospitalization or pneumonia and 80% effective in preventing death even though it is only 20% to 40% effective in preventing respiratory illness among this population . Overall, in those 65 years of age and older, influenza immunizations have reduced hospitalization by 70% and death by 85% .
In preventing illness among younger workers, the vaccine may help reduce economic losses caused by absenteeism. Decreasing hospitalization rates of healthy infants and toddlers, of older noninstitutionalized and institutionalized adults, and of persons with chronic conditions is cost-effective. Studies have demonstrated that flu-related hospitalizations are decreased 40% to 42% overall with vaccination, that there is a 25% decrease in antibiotic usage for secondary illness associated with influenza, and that there is possibly a decrease in lost workdays. A 2014 study found that a vaccinated child's risk of being hospitalized due to influenza was reduced 74%; for individuals 50 years of age or older, flu-related hospitalization risk was reduced 57% . These statistics indicate a significant annual savings of healthcare dollars for each person who received influenza vaccine. In an era of escalating healthcare costs and increasing antibiotic resistance, these are important figures .
In 2011, the FDA approved a new version of Fluzone to be administered intradermally via microinjection system . The vaccine is packaged in 0.1 mL single-dose, prefilled syringes, and it contains no preservative [8,39]. The microinjection consists of an ultra-thin needle 0.06 inches (1.5 mm) in length, or less than one-tenth the length of the standard needles used for the traditional IM route . The system deposits the vaccine into the dermal layer of the skin, where dendritic cells generate an immune response. Research indicates that use of the intradermal route results in an immune response as good as or better than IM administration using a lower dose of hemagglutinin (9 mcg of hemagglutinin for each influenza strain compared to 15 mcg) [40,41]. As such, this route may be preferred when sparing vaccine is advised.
Fluzone intradermal is recommended for use in adults 18 to 64 years of age [8,39]. Initial research indicates that it may also be effective in older adults (60 to 95 years of age), but more research is necessary before Fluzone intradermal can be recommended for this group . Potential adverse effects associated with intradermal administration are similar to those seen with IM administration, although local injection site reactions may be more common and more visible [34,40]. The most common injection-site reactions are erythema (>75%), swelling (>50%), induration (>50%), pain (>50%), and pruritus (>40%); all of these reactions occur more often with intradermal than with IM administration, with the exception of pain, which occurs at similar rates in both . Due to the small size of the needle, it may also be useful for patients with fear or anxiety related to injections or needles.
Live attenuated influenza vaccines (LAIVs) have been in development in the United States since the 1960s [43,44]. FluMist (a LAIV trivalent formulation), manufactured by MedImmune, LLC, was originally approved in June 2003. FluMist quadrivalent LAIV contains two subtype A strains and two subtype B strains. It was approved by the FDA in February 2012 and was first available for the 2013–2014 flu season [45,46]. All LAIV available in the United States for the 2016–2017 flu season will be the quadrivalent formulation . FluMist, which is delivered intranasally, is licensed only for healthy, nonpregnant persons 2 to 49 years of age. Live vaccines are unsuitable for healthcare workers that care for immunocompromised patients .
However, LAIV (FluMist) is not recommended by the CDC and the ACIP and should not be used for the 2016–2017 flu season. Data from the 2015–2016 flu season showed a 3% overall efficacy rate (A and B viruses combined) of LAIV in children and adolescents (who were the primary recipients of the vaccine) compared to a 63% efficacy rate of inactivated influenza vaccine . Department of Defense data also showed no significant protection from the FluMist vaccine in children 2 to 17 years of age, particularly against H1N1 and other A-type viruses, which were the most abundant circulating strains in the 2012–2013 and 2015–2016 seasons. Information provided to the CDC/ACIP by the manufacturer for the 2016–2017 season showed that this year's formulation efficacy is expected to be similarly poor . Patients (including children) who received LAIV for the 2016–2017 season should be revaccinated with any other available product at any time (as all other vaccines are inactivated) in order to achieve adequate protection against influenza .
The Healthy People Year 2020 objectives are to :
Increase influenza vaccination levels to 90% or higher among high-risk groups
Have 90% of residents in long-term care facilities receive the vaccine
Increase influenza vaccination levels to 80% among healthy children and adults younger than 65 years of age
Among high-risk people 65 years of age and older, the overall influenza vaccination rate is 67%. However, people of color have much lower rates .
There are several other high-risk groups, discussed previously in this course, that fall far short of the 90% influenza immunization rate goal. According to data from the National Health Interview Survey, only 39% of high-risk people 18 to 64 years of age were immunized against influenza in 2008 . Since 1999, in years without vaccine shortages, immunization levels have ranged between 63% to 66% for high-risk individuals [70,87].
One of the major factors influencing people with conditions that put them at high-risk for complications, hospitalization, and death from influenza is the misconception that the flu shot will give them the flu. This misconception is fueled by the fact that, in such a large cohort receiving the influenza immunization, a certain percentage will already be incubating the flu. When the symptoms of influenza appear one day or so after getting the shot, the natural assumption is that the illness came from the shot. Some take the opposite view that the flu shot will protect them against colds, so they are disappointed the "the flu shot didn't work" when they get a cold .
Another factor is that patients rely on their physician's advice. Unfortunately, physicians may not specifically suggest that their patients get the influenza vaccine. This leads the patient to think that it is not important or it would have been mentioned.
Cost may be a prohibitive factor for those too young for Medicare, which covers influenza and pneumococcal immunizations. Some people may assume that the influenza immunization is effective for several years. Others feel that a healthy person should not take anything, like a flu shot, that might make them sick . Some patients do not realize how effective the influenza vaccine is in preventing complications, hospitalizations, deaths, and actual influenza disease when the vaccine antigens correspond to the circulating antigens.
Probably one of the biggest factors affecting influenza immunization rates is the fact that influenza is so common—a true illustration of "familiarity breeds contempt." Few are aware of the number of hospitalizations and deaths and the economic burden associated with influenza. Media attention focuses on deaths from SARS or other diseases while influenza kills far more each year.
Now that studies have shown that the immunity produced by the vaccine lasts several months, the ACIP recommends that influenza immunizations start as soon as the vaccine is available. Thus patients who are seen infrequently by their healthcare providers can receive the vaccine when they have an appointment and avoid a special visit just for the immunization. Providers should offer the vaccine to all patients, especially children 6 months to 8 years of age, as soon as they have a supply. The CDC also recommends that the offer of the vaccine and its refusal be documented in the patient's medical record .
One of the major factors in increasing the number of administrations of influenza vaccine is the involvement of the medical practitioner providing care in a variety of settings, such as physicians' offices, clinics, outpatient rehabilitation programs, or any place where there is contact between medical providers and their patients. To encourage practitioner involvement, providers should be informed of the reimbursement for the vaccine and its administration by Medicare and Medicaid and should be instructed as to billing methods, especially roster billing.
The majority of flu shots given are administrated by the person's personal healthcare provider, and studies have shown that a healthcare provider's recommendation plays a critical role in a patient's decision to get a seasonal flu vaccine . As many as 75% of patients at high risk for influenza or for death from a complication of influenza have seen a healthcare provider in the last year. One of the most effective methods of encouraging a high-risk patient to receive the flu shot is a verbal recommendation from the patient's physician .
To ensure that high-risk patients receive the recommendation, a variety of reminder techniques might be employed, such as placing stickers on the charts of high-risk patients, creating computer-generated lists of patients not scheduled to be seen, sending reminders via email or regular mail, and telephoning patients. Educational efforts by public health departments through media and personnel could encourage high-risk people to ask their healthcare provider for the flu shot . Beginning in September, emergency rooms and walk-in clinics should display posters and educational materials about the need for the flu shot and either provide the vaccine or provide information about where it may be obtained .
Influenza immunization is also recommended for all people who have contact with high-risk populations. Obviously, this includes all healthcare professionals, a group for which the ACIP recommends annual influenza vaccination . According to results of a survey conducted by the CDC among 2,258 self-selected healthcare personnel, 79% of survey participants reported having had an influenza vaccination for the 2015–2016 season, a significant increase from 67% during the 2011–2012 season [70,87]. Vaccination coverage was highest among hospital-based healthcare personnel (91.2%) and lowest among healthcare personnel at long-term care facilities (69.2%). Coverage was also higher in occupational settings that offered no-cost, onsite vaccination for one or more days compared with settings that did not offer no-cost coverage. Vaccination coverage was 85.8% overall among healthcare personnel in all occupational settings who reported an employer mandate to receive vaccination [70,87].
Immunization lowers worker absenteeism and transmission to vulnerable patients. Those who supervise or manage other healthcare personnel should set an example for their staff and patients by making sure to get a flu shot each year. It seems that those who have received the vaccine are more aware of the need to inform patients of the value of the flu shot, and their example is an encouragement.
As noted, LAIV should not be used to immunize contacts of severely immunocompromised patients unless no contact for seven days following receipt of LAIV can be assured . There have been no reported instances in which a healthcare professional immunized with LAIV has transmitted influenza to a patient. Unvaccinated healthcare workers are more likely to transmit the virus . To encourage more healthcare professionals and allied personnel to get the flu shot, it should be provided at the work site free of charge .
Implementation of standing orders in acute care hospitals is another way to help increase influenza vaccine coverage. Patients who are hospitalized as flu season approaches, or during flu season, should have their records checked for chronic illness that is impacted by influenza and for influenza vaccine status. Those who have risk factors for complications and have not received the influenza immunization should receive the flu shot before discharge, as covered by the standing order. Such standing orders would have to be developed and implemented by the medical board of the hospital. All medical personnel connected with the hospital should be made aware of the standing order and reminded by posters or other means during influenza season. A study of Medicare patients hospitalized during flu season showed that only 31.6% had received the flu vaccine before admission, 1.9% during admission, and 10.6% after admission .
In long-term care facilities, there should be a standing order for each patient to receive a flu shot in October. When a patient is admitted to the facility, the attending medical professional and family member(s) should be informed of the standing order. If there is a reason that the patient should not receive the influenza vaccine, the physician can so order or the family member can so request. All residents should be immunized on the same day, if possible, before flu season. Those admitted after this day should receive the vaccine upon admission . One study showed that only 62% of residents in nursing homes received influenza immunization in spite of its demonstrated effectiveness in preventing complications, hospitalization, and death in long-term care patients. Another study showed that if 80% or more of the residents in the facility were immunized against influenza, hospitalization from all causes was reduced regardless of the vaccination status of the individual resident . As noted, another protective measure for residents of institutions is for the care providers to receive an influenza immunization.
Home healthcare agencies should also have protocols in place to immunize patients under their care during the flu season and to inform the in-home caregivers of their need to be immunized. Staff members with patient contact should also be immunized .
All healthcare providers of patients in hospitals, long-term care facilities, and home health agencies should be aware that the Centers for Medicare and Medicaid Services has removed the physician signature requirement for the administration of influenza and pneumococcal vaccines to patients covered by Medicare and Medicaid .
Religious meeting places are a point of contact for many groups. Patient education materials can be included in the organization's bulletin. In some areas, the local public health department will provide an influenza immunization clinic in conjunction with a religious service.
Reminder posters and educational materials can also be displayed at banks, grocery stores, and community centers. These materials are available from the local public health department or on the CDC website. Organizations such as Lions, Kiwanis, Rotary, and the AARP, that are interested in controlling the cost of health care, should be enlisted to help encourage their friends and neighbors to be immunized against influenza.
Many public health departments provide influenza immunizations in community settings, such as churches, community centers, meetings of minority groups, airports, and malls—any place where a clinic can be temporarily set up. Some even provide "drive-up clinics" where the person does not need to get out of the car to receive the flu shot. These clinics are especially helpful for a person who cannot wait in line or walk easily.
The primary and most effective way to prevent influenza is vaccination. However, in cases when antigens of the vaccine are not close enough to the circulating antigen, when there is a shortage of vaccine, or when a new strain has emerged and is circulating before the vaccine can be made and distributed, people will have to resort to other ways to protect themselves from infection.
Good handwashing is difficult to practice, is rarely known or taught, and is one of the single most effective ways to prevent transmission of many diseases, including influenza. Everyone knows to wash their hands before eating and after using the restroom. However, few do little more than remove obvious dirt. Good handwashing involves removing the skin oils where organisms can remain even when the hands look clean. A quick pass under the water faucet and fast dry with a towel removes visible dirt, but the oils and organisms remain.
To effectively remove the oils and organisms, the process should take at least 20 seconds (e.g., the amount of time that it takes to sing "Twinkle, Twinkle Little Star"). The hands should be soaped and rubbed vigorously for 15 seconds to create a good lather and to assure that all parts of each hand are soaped and rubbed well. Then the hands should be rinsed thoroughly and dried, preferably with a paper towel. The towel should be used to turn off the water and then properly thrown away. Such handwashing removes the oils that harbor the organisms, but 20 seconds can seem like a long time in the busy life of a healthcare provider. If there is no visible dirt or contamination, a waterless hand sanitizer with at least 60% alcohol can be used between patients. However, nothing is as good as washing well with soap and water. Some mistakenly think that hot water must be used to kill the organisms. Water hot enough to kill organisms would be too hot to touch. Warm water mainly adds to comfort and hopefully encourages better washing technique. Careful attention to handwashing and cleansing may result in chapped skin, so the medical professional should find the proper lotions to care for his/her hands [90,91].
The eyes, nose, and mouth are entryways for bacteria and viruses. Everyone tends to unconsciously touch their eyes, nose, and mouth when going about their activities. Because organisms are not visible and hand washing is often less than adequate, infection occurs. Though difficult, the person trying to prevent illness should make a conscious effort to avoid touching his/her face .
Covering a cough or sneeze is of primary importance however it is done . Ideally, disposable paper tissues will be readily available during cold and flu season and used to cover the nose and mouth when coughing or sneezing. Patients and children should be instructed that, when this is not possible, they should cough or sneeze into their upper sleeve or elbow instead of into their hands. This will avoid contaminating the hands with an offending virus or bacteria . In those instances when coughs and sneezes are covered with only the bare hands, the hands should be cleaned with soap and water or with an alcohol-based hand sanitizer as soon as possible to prevent transfer of the organisms to another person. Coughing, sneezing, or blowing nasal secretions into a cloth handkerchief is not recommended as this results in creating a moist, viable culture that is then carried in the pocket or purse, potentially resulting in prolonged episodes of re-infection or transfer from cross-contamination.
During cold and flu season, trips to the store, school, church, and workplace bring contact with those who are coughing and sneezing. If at all possible, avoid close contact. This is an excellent time to consciously work on keeping your hands away from your face. Good handwashing should be done as soon as possible after contact with someone exhibiting symptoms of respiratory illness. Help the immune system to overcome the organisms by getting enough rest, drinking six to eight glasses of water per day, and eating fresh fruits and vegetables . Healthcare providers can lessen the spread of influenza by utilizing proper cough etiquette, providing tissues and safe disposal, using rapid diagnostic tests and antiviral chemoprophylaxis for suspected flu in healthcare workers, and recommending that influenza sufferers stay home .
Antiviral medications can also be used to prevent influenza. Three of the four antiviral drugs used to treat illness due to influenza can also be used to prevent it, although this is complicated by growing resistance to available agents. Amantadine (Symmetrel) and rimantadine (Flumadine) have been approved for treatment and prevention, but both of these agents have also been associated with decreasing effectiveness due to viral resistance and are no longer recommended for these uses [45,96,97]. Oseltamivir (Tamiflu) is an effective treatment of uncomplicated acute illness due to influenza A and B viruses in adults and children older than 2 weeks of age, and it is approved as a preventive treatment in persons 1 year of age and older. In 2007, the Japanese Ministry of Health, Labor, and Welfare issued a warning that oseltamivir may cause psychiatric problems and suicide in patients 10 to 19 years of age . This warning has been the subject of much controversy, and no such warning has been issued in the United States. Zanamivir (Relenza) is approved for prophylaxis in persons 5 years of age and older; ACIP recommends that prophylaxis with zanamivir be considered for individuals at high risk of influenza complications, for unvaccinated healthcare workers exposed to influenza, and for eligible residents of institutions that house high-risk patients when outbreak control is needed .
A physician's order is required to obtain any of the antivirals. In the past, amantadine and rimantadine prevented influenza A illness 70% to 90% of the time . However, the increasing incidence of amantadine- and rimantadine-resistant strains of influenza in the United States has made these medications less effective . Therefore, they are no longer recommended for treatment or prophylaxis of circulating influenza A strains [45,97].
Antiviral medications can make a person less contagious to others, so they are prescribed for contacts of people who are at high risk for complications from the flu. A subclinical infection may develop in a patient taking an antiviral. This allows the body to make antibodies against the virus. If any antiviral medication is to be totally effective, it must be taken as long as influenza is active in the community. Some studies indicate that taking an antiviral during peak influenza activity in a community is also effective. Of course, the less expensive single application vaccine is the best choice in preventing influenza in contacts of high-risk persons. However, in situations in which the individual has a hypersensitivity to one of components of the vaccine, or the needed two weeks to develop immunity are not available before contact, an antiviral medication can be used. Another reason to use an antiviral prophylaxis would be if the available vaccine does not match the circulating virus.
Antivirals are also used in closed environments, such as institutions or cruise ships, to control flu outbreaks. In such cases, it is best to combine the vaccine with an antiviral to provide protection for those exposed but who have not developed illness until the vaccine can stimulate the immune system to make protective antibodies. This also avoids the protracted use of the antiviral medication. The antiviral will not interfere with the antibody response elicited by the vaccine [3,16,99].
The antiviral medications zanamivir and oseltamivir are also used to treat acute illness due to influenza (Table 3). To be effective, any of these medications must be started within 48 hours of symptom onset. Generally, a course of one of these antivirals will reduce the illness by one to two days, prevent serious complications, and make the patient less contagious to others. These medications are effective only against influenza viruses and will not affect the common cold or other ILI of viral origin [16,99,100]. All require a prescription from a physician.
COMPARISON OF ANTIVIRALS USED IN INFLUENZA
|Type of antiviral||Neuraminidase inhibitor||Neuraminidase inhibitor||Neuraminidase inhibitor|
|Effective for type||Influenza types A and B||Influenza types A and B||Influenza types A and Ba|
|Route of administration||Inhaled||Oral||IV|
|Age that can receive||
|Side effects||Throat/tonsil pain, nasal symptoms, diarrhea, nausea, headache, cough||Nausea and vomiting||Diarrhea|
|aPeramivir efficacy is based on clinical trials in which the predominant influenza virus type was influenza A; a limited number of subjects infected with influenza B virus were enrolled.|
Zanamivir belongs to the antiviral group of neuraminidase inhibitors. It is effective against both influenza A and B and was approved in 1999 to treat uncomplicated illness due to influenza virus in adults and children 7 years of age and older. The dosage is 10 mg twice daily by inhalation for five days. Doses should be 12 hours apart. It may also be used to prevent influenza virus in adults and children 5 years of age and older. The dosage is two 10-mg inhalations once daily for seven days after last known exposure [45,101]. Zanamivir can lead to a decrease in respiratory function and bronchospasm. It is not recommended for patients with asthma, obstructive pulmonary disease, or other chronic lung diseases. More common (>10%) side effects include headache, throat/tonsil discomfort or pain, nasal signs and symptoms, and cough. Other effects that occur in less than 10% of patients include diarrhea, nausea, headache, dizziness, nasal infections, sinusitis, and bronchitis . Some allergic responses of oropharyngeal or facial edema have also occurred [16,22,100,102].
Oseltamivir also is a neuraminidase inhibitor and effective against both influenza A and B viruses. It is marketed as Tamiflu, which should not be confused with Theraflu. Like zanamivir, it was approved in 1999. It can be used as treatment in adults and children who have been symptomatic for no more than two days. The treatment dosing for adults and children 13 years of age and older is 75 mg twice daily. The treatment dosing for children younger than 13 year of age is weight dependent :
3 mg twice daily for children aged 2 weeks to younger than one year
30 mg twice daily for children aged 1 year and older who weigh ≤15 kg
45 mg twice daily for children who weigh >15 kg and up to 23 kg
60 mg twice daily for children who weigh >23 and up to 40 kg
75 mg twice daily for children who weigh >40 kg
Oseltamivir can also be used as a preventive in anyone 1 year of age or older, but such usage should be rare . The dose is 75 mg twice daily by mouth for adults and once daily for children and adolescents who weigh more than 40 kg (88 lbs.) . Studies have shown that oseltamivir reduces the incidence of complications that may require antibiotics. Although the neuraminidase inhibitors promote a drug-resistant mutant of the virus, less resistance appears to occur with oseltamivir than with zanamivir. The reported side effects with oseltamivir are nausea and vomiting, which are lessened if the medication is taken with food [8,16,22,100,102].
Since 2005, some resistance to all of the antivirals has been documented. However, the 2009 H1N1 outbreak remained sensitive to oseltamivir except in a few cases . Serious reactions to the four antiviral medications should be reported to the FDA MedWatch program.
Approved in 2014, peramivir is a neuraminidase inhibitor for use in patients 18 years of age or older with acute uncomplicated influenza who have shown symptoms for no longer that two days [45,97]. Peramivir injection preparation is a 200 mg/20 mL single-use vial, stored at 59 to 86 degrees F (15 to 30 degrees C). After being diluted, it should either be administered immediately or refrigerated and administered within 24 hours . Peramivir is typically given in a single 600-mg dose; the dose should be adjusted based on renal function. The most common side effect is diarrhea (8%) . An efficacy study showed that overall symptoms were relieved 21 hours sooner in participants given peramivir compared to those given placebo . Efficacy studies have primarily been conducted in patients with A type influenza viruses, and it is effective for 2009 H1N1 [45,159].
Amantadine was approved in 1966 as a treatment for uncomplicated respiratory tract illness caused by influenza. It belongs to a group of chemically related drugs called adamantanes (tricyclic amines) and is effective only against influenza A viruses. Rimantadine, approved in 1993, is also in the adamantanes group. Therefore, it is also only effective against influenza A. However, circulating influenza A (H3N2) and 2009 H1N1 viruses are resistant to adamantanes. As a result, these medications are no longer recommended for the treatment or prophylaxis of influenza A [45,103].
All treatment with either oseltamivir or zanamivir should begin within 48 hours of symptom onset to be effective . In most individuals without underlying medical conditions, influenza is a self-limiting disease. Recovery usually occurs after one week, although fatigue and malaise may persist two or more weeks. The decision to use an antiviral is influenced by the type of work the patient does. In an epidemic or pandemic, persons providing critical services should be treated because shortening their absence by one or two days is important. For other personnel, the decision should be based on the comparison between the wages that would be lost and the cost of the medication . If an outbreak of influenza occurs in an institution, antiviral medications should be used for both treatment and prophylaxis .
Some people may desire treatment because of upcoming plans or because they do not like to be sick. These individuals should be encouraged to obtain the annual influenza vaccine in the future, as disease that develops in spite of the vaccine is usually milder unless the vaccine strains do not match the circulating strains.
Antiviral treatment is recommended as soon as possible for patients with confirmed or suspected influenza who have severe, complicated, or progressive illness or who require hospitalization. It is also recommended for outpatients with confirmed or suspected influenza who are at higher risk for influenza complications on the basis of their age or underlying medical conditions [96,104]. Antiviral treatment also may be considered on the basis of clinical judgment for any outpatient with confirmed or suspected influenza who does not have known risk factors for severe illness if treatment can be initiated within 48 hours of illness onset.
Pregnancy should not be considered a contraindication to the use of oseltamivir or zanamivir. Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses, and if influenza is confirmed or suspected in these patients, it should be treated with oseltamivir or zanamivir; fever should be treated with acetaminophen. . Because antivirals have a potential but unknown risk during pregnancy, it is important to continue to vaccinate pregnant women. The seasonal flu shot has been given to pregnant women for many years without any harm to the women or their fetuses. Vaccines that contain thimerosal result in exposure to only trace amounts of mercury and are not associated with toxicity .
Family members or friends should be located to care for the high-risk patient who lives alone. With enough community support (e.g., home health, neighbors, "Meals on Wheels"), a patient might be able to remain alone, but it would require careful planning and coordination among all involved. During an epidemic or a pandemic, it may be necessary to set up temporary facilities, such as a shelter for medically fragile patients, to provide care. A normally healthy adult living alone may only need help in the form of shopping.
Points in the care of the patient include: careful observation, providing symptomatic relief, help with activities of daily living, helping the patient remain hydrated, and emotional support (Appendix 1).
Attention should also be given to the person(s) caring for the influenza patient in the home to protect him/her from the disease. This would include influenza immunization, with or without an antiviral medication for two weeks, instruction on effective handwashing, wearing a mask when providing care or when the patient is coughing, getting adequate rest, consuming five to nine or more fruits, fruit juices, and vegetables each day, and drinking eight glasses of water every day (Appendix 2).
Of course, the most important aspect of self-care is obtaining the immunization. However, should one develop influenza and not be at high risk for complications, there are a few general steps to speed recovery and protect others :
Consider obtaining an antiviral if flu is in the first or second day of illness.
Stay home to protect others from infection.
Get plenty of rest.
Drink plenty of liquids.
Do not drink alcohol or use tobacco products.
Consider over-the-counter medications to relieve the symptoms.
Cover coughs and sneezes.
Wash hands well and frequently, especially after coughing or sneezing.
By keeping a written record of observations, a patient's subtle changes become more apparent, and the information will also help a physician. As discussed, there are many diseases that initially present like influenza or conditions that can be complicated by influenza; therefore, each person with influenza should be watched. The patient with influenza usually starts to improve after a few days. Patients and/or caregivers should be given a list of symptoms that indicate when a physician should be notified (Appendix 3). Any difficulty in breathing, a fever that is not responding to antipyretics, change in mental state, inability to maintain hydration, or worsening of symptoms should be reported to a physician, or the patient should be taken to the emergency room if a physician is unavailable.
The healthcare professional should review the following items with influenza patients or their family member(s), so a physician can be notified appropriately and promptly :
High or prolonged fever
Breathing (fast or difficult with retractions in children, or cyanosis, labored breathing, shortness of breath, or pain or pressure in the chest in adults)
Inadequate fluid intake (e.g., fewer wet diapers, darker urine)
Changes in mental status (e.g., hard to arouse, confusion, too irritable to be comforted)
Fainting or near-fainting, seizures
Severe or persistent vomiting
Worsening of a chronic disease
Worsening of influenza symptoms, increasing weakness
Any rash or jaundice
Dry cough that becomes productive
Infection control procedures should be followed carefully as soon as any contact with an influenza patient occurs so that transmission can be prevented. In order to protect staff, posters prominently displayed or warning signs at the sign-in desk should request that the staff be informed if the patient has any respiratory symptoms.
Patient education posters about flu, the vaccine, and cough etiquette should be displayed in emergency rooms, waiting rooms, exam rooms, elevators, and other appropriate traffic areas used by patients and visitors. Messages should be brief but clear. Pictures could also be included for children who cannot read or for non-English speakers. All education materials should be provided in the major languages of the community.
As a result of the evolving racial and immigration demographics in the United States, interaction with patients for whom English is not a native language is inevitable. Because patient education is such a vital aspect of the prevention and treatment of influenza, it is each practitioner's responsibility to ensure that information and instructions are explained in such a way that allows for patient understanding. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.
In this multicultural landscape, interpreters are a valuable resource to help bridge the communication and cultural gap between clients/patients and practitioners. Interpreters are more than passive agents who translate and transmit information back and forth from party to party. When they are enlisted and treated as part of the interdisciplinary clinical team, they serve as cultural brokers, who ultimately enhance the clinical encounter.
Educational materials might include:
Cover your cough.
Use a tissue.
Throw the tissue away in the wastebasket.
Wash your hands.
Tissues and wastebaskets should be easily accessed.
Rub your hands well to make a good lather.
Rub your hands for 15 seconds.
Dry with a paper towel.
Turn off water with a paper towel.
Throw the paper towel in the wastebasket.
If no facilities to wash hands are available, alcohol-based hand cleaner should be available.
When influenza is present in the community, patients who are coughing should be given a mask and asked to sit in a separate area. If a separate area is not available, they should be at least 3 feet away from other people. Masks can be the surgical masks with ties or procedural masks with ear loops. They do not need to be respirator N95 masks.
Staff involved with patients who have respiratory symptoms with fever should follow droplet precautions as developed at their work place. For all patient contact, a mask (surgical or procedural) should be worn. Hands should be washed thoroughly following contact. During an epidemic, staff circulating between floors in the hospital should be limited .
The influenza viruses that are carried by birds, both domesticated and wild, rarely have infected humans. This is partly due to the fact that avian influenza (AI) viruses attach to receptors found on bird cells but not found on human cells. Human viruses prefer the receptors found in the human respiratory tract. Pigs have receptors used by avian, swine, and human influenza viruses and have traditionally been the link between avian and human influenza viruses. Because pigs acquire all three types of viruses, reassortment/antigenic shift of the hemagglutinin and neuraminidase proteins occurs in the pig host, which then transmits the new strain to humans or other pigs [14,107].
However, there now exists evidence that avian influenza can spread directly to humans . In 2004, areas of Asia experienced large-scale outbreaks of avian influenza, specifically the H5N1 virus, in poultry. The virus went on to infect humans, with a high mortality rate. The number of countries, people, and animals affected by the virus reached unprecedented levels. In 2006, the CDC summarized the H5N1 outbreak. Wild birds and poultry had been infected in Asia, parts of Europe, the Middle East, and Africa. Human infections continued to be reported in China, Egypt, Indonesia, Azerbaijan, Cambodia, and Djibouti. There were some probable human-to-human transmissions of H5N1, but these were rare. As of October 2016, there had been more than 850 human cases of H5N1 since 2003, with a continued fatality rate of approximately 53% [108,109]. In 2013, an outbreak of H7N9 virus in China spread to humans, with 14 reported infections and 6 deaths in the first two months . Both the CDC and the WHO have reported that there is a strong threat of a future pandemic of avian influenza and that preparedness is vital [111,112].
Although influenza A viruses can infect all birds, domestic poultry flocks are more vulnerable to infections that can reach epidemic proportions. Generally, domesticated fowl transmit the virus in saliva, nasal secretions, and feces. However, it is thought that the fecal-oral route is the common way the virus is spread among flocks. Wild birds rarely become sick but are a source of infection through their droppings because they carry the virus in their intestines. Free-roaming domestic fowl are at more risk from wild bird droppings than housed flocks. Both food and water supplies can be contaminated by droppings or sharing with wild birds. At first it was thought that wild birds spread the virus from farm to farm, but further study indicated that people and equipment probably spread the virus to domesticated flocks [113,114].
AI viruses are classified as low pathogenic and high pathogenic based on their genetic sequence and the resulting illness in birds. Low pathogenic AI has been detected in wild birds, mostly ducks, geese, and gulls, since 1975 . Low pathogenic AI virus causes only ruffled feathers and a reduction in egg production. Fortunately, most AI viruses are low pathogenic; however, in six to nine months, they can mutate to high pathogenic. High pathogenic AI viruses, first noted in 1878 in Italy, are highly contagious, spread rapidly, and are almost 100% fatal. Fowl can die the same day that they first exhibit symptoms [115,116,117].
Whenever an AI virus infects a human directly, there is much concern. Humans rarely have any immunity to AI viruses. Medical resources around the world quickly mobilize when there is a case of AI that skips reassortment in swine and directly infects a human. Fowl within a 2-mile (3-kilometer) radius of the source bird/flock are killed in order to contain the virus. An AI virus in humans usually produces upper respiratory disease and conjunctivitis. The infected humans and their contacts are watched closely for secondary transmission. For a pandemic to follow, these factors are needed:
Humans do not have immunity to the virus
Direct transmission from bird to human
Sustainable transmission from human to human
Movement of infected/contagious individuals to other geographic locations
Once a new pandemic influenza virus emerges, it generally circulates for many years [113,116]. Researchers at the University of Wisconsin, Madison, have been combining H5N1 with a seasonal flu strain (H3N2). As a result, they have found such reassortment flu viruses are highly pathogenic; 22 were more pathogenic for mice than the original H5N1, and three caused extremely severe disease .
The hemagglutinin antigens that historically have caused human influenza are H1, H2, and H3. Although all known hemagglutinin subtypes occur in birds, H5, H7, and H9 have been implicated more in recent outbreaks. Various combinations with the neuraminidase antigens occur. All of these AI viruses are type A, as B and C do not infect birds. Some of the cases focused on in the past decades have included the following [111,119,120,125]:
H5N1 – Hong Kong, 1997, first documented human infection–18 hospitalized, 6 deaths, 1.5 million chickens culled
H9N2 – Hong Kong, 1999, 2 mild cases in children, several in mainland China
H7N2 – Virginia, 2002, 4.7 million chickens and turkeys culled
H7N7 – Netherlands, 2003, 80 poultry workers, 3 family members infected (79 eye infections, 6 influenza-like), one veterinarian death due to acute respiratory distress syndrome and complications
H5N1 – Hong Kong/China, 2003, 2 ill, death
H9N2 – Hong Kong, 2003, 1 case confirmed in a child
H5N1 – Asia, 2004–2005 (H5N1 had been found in Asian chickens April, 2003), 112 confirmed cases, 57 deaths; too widespread to cull all fowl
H7N3 – British Columbia, 2004, 2 ill
H5N2 – Taiwan, 2004, low pathogenic, no human illness
H7N2 – Delaware, 2004, no human illness
H5N2 – Texas, 2004, no human illness
H5N1 – Russia/Romania/Turkey/Azerbaijan/Egypt, 2006, some human illness, unknown deaths
H7N9 – China, 2013–2017, 1,222 confirmed cases, 40% mortality rate
Fortunately, although in some of these outbreaks bird-to-human transmission did occur, human-to-human transmission has been extremely rare. Limited transmission possibly did occur between humans in the Netherlands, but no sustainable transmission occurred, so an epidemic or pandemic did not follow. There were 14 cases and 12 deaths (11 children) from H5N1 virus in Vietnam. The viruses isolated from those who expired in Vietnam were mostly resistant to amantadine and rimantadine. Studies are continuing as to the effectiveness of oseltamivir and zanamivir against H5N1 viruses. There is some evidence that the 2004 H5N1 virus in Asia is sensitive to oseltamivir [113,114,116,121]. However, some evidence of resistance to oseltamivir has been reported in highly pathogenic avian influenza H5N1 viruses isolated from human cases . Most of the 2004 H5N1 outbreaks were controlled by veterinarian officials or spontaneously died out. However, H5N1 continues to fulminate in poultry in Egypt .
Most cases of AI in humans have resulted from contact with infected poultry or contaminated surfaces. It is also possible for the virus to become aerosolized and then land on exposed surfaces of the mouth, nose, or eyes. Aerosolized virus could also be inhaled directly into the lungs. Eating poultry products has not been associated with the development of AI. Influenza viruses are destroyed by adequate heat. Because of the pathogens found in poultry, all patients should be reminded to cook all poultry, including eggs, thoroughly. Chicken should be cooked until the internal temperature reaches 180 degrees F. All utensils and surfaces that have come in contact with raw poultry should be washed well with soap and water immediately following use. A separate cutting board should be used to cut raw poultry. In order to retard bacterial or viral replication, all poultry products should be defrosted in the refrigerator, not at room temperature.
Some patients might become concerned about contaminated poultry products from other countries entering our food supply. Some countries will not permit poultry to be imported from countries in which there were detections of AI, such as China's ban of U.S. chicken in 2015. However, the risk of AI spreading through the global chicken industry is low because most chickens on the international market are killed and frozen or chilled. All documented transmission to date has been from live birds [124,125].
Humans have no immunity to AI viruses, so illness tends to be severe and the fatality rate high. Prevention is difficult because the viruses tend to be highly contagious. Because of the mobile nature of people and efficient, rapid transport, any virus can spread quickly around the world. The current manufacturing process of influenza vaccine requires several months. The elements are all in place for a pandemic.
In 2007, a team of scientists at the National Institute of Allergy and Infectious Diseases reported that it had developed a way to generate vaccines and therapeutic antibodies that could target constantly mutating influenza viruses, such as H5N1. The team focused on mutations that enable H5N1 hemagglutinin protein to better recognize and enter human cells and those mutations that will elicit antibodies. This information will enable researchers to consider how to design potential vaccines that will protect people from future emerging AI virus mutants, possibly helping to contain a pandemic in its early stages .
In order to understand how influenza viruses mutate, researchers have been working to synthesize the hemagglutinin responsible for the 1918 influenza ("Spanish flu") pandemic. The success of this endeavor was reported in 2004, and scientists have since discovered how subtle alterations enabled the virus to move from birds to people .
The H5N2 avian influenza virus continues to be monitored around the world by scientists. It is highly virulent but has not been transmitted person to person yet [4,112]. In 2015, H5N2 avian influenza virus (along with H5N8 and H5N1) were found in more than 200 bird samples, indicating the likelihood that 40 million farm and backyard birds have been infected in 20 states .
As with the development of all vaccines, the first step is to isolate the organism. In the case of AI, various research centers and companies around the world are working to make a vaccine. The first step is to isolate the virus (e.g., the H5N1 influenza A virus in 2004). Next, the virus is dismantled so the most virulent elements can be excluded. Then the virus is reassembled without those virulent elements, and attempts are made to produce it . As noted, the virus has been isolated and the virulent elements have been identified to allow vaccine development to proceed. In 2006, a new recombinant H5N1 virus became available for distribution to companies interested in pandemic vaccine development . In 2007, GlaxoSmithKline received a contract from the U.S. Department of Health and Human Services to manufacture 22.5 million doses of AI vaccine in addition to the 5 million doses ordered in 2006 . Research to find novel media or methods (rather than using eggs) is ongoing .
In 2007, the FDA approved the first human vaccine for the AI virus H5N1 . This vaccine is intended for individuals 18 to 64 years of age who could be at an increased risk of exposure to the H5N1 influenza virus. The vaccine is not available commercially, but rather has been purchased by the federal government to be distributed if necessary. The vaccine consists of two 1-mL IM doses given 21 to 35 days apart (optimum: 28 days). There is thimerosal in this vaccine [45,131]. Because this vaccine has been approved by the FDA and found to be safe and effective, it is no longer considered experimental. Therefore, it can be used during a pandemic without the time-consuming protocol and signed informed consent necessary for an experimental drug or vaccine . In 2013, the first adjuvanted H5N1 vaccine, Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted, was approved for individuals 18 year of age and older. The vaccine is not for commercial use, but at least 20 million doses are stocked at the Strategic National Stockpile for emergency release .
Another plan is to gather a supply of effective antiviral medications to use not only to treat AI but also to use as a preventive treatment if a vaccine is not available. As discussed, some testing of the four antivirals available has been done with the H5N1 virus, which produced mass illness in Asia in 2004. So far, only oseltamivir was shown to be effective. More research is needed . Some have suggested combining probenecid and oseltamivir to enhance effectiveness and to stretch limited oseltamivir supplies .
It is not known if other AI strains will be sensitive to oseltamivir or to any of the other antivirals. The suggestion has been made to stockpile antivirals so they would be available in a pandemic. Logically, it would make sense to include the effective antiviral medications in the Strategic National Stockpile and use the same distribution system and overall protocol in managing them .
Because of the rapid spread of avian influenza among flocks in Asia in the spring of 2004, the need for more involvement and communication between animal and human experts became apparent. No reporting of animal diseases is required by the WHO. However, the Global Early Warning System combines and coordinates the disease intelligence mechanisms of the United Nations Food and Agriculture Organization, the World Organization for Animal Health, and the WHO to provide the international community with information about the prediction, prevention, and control of animal disease threats . In addition, the World Organization for Animal Health monitors avian influenza outbreaks in its member countries (including the United States) . Human medical practitioners are not trained in the subtle indications of animal illnesses, nor are they usually aware of early indications that an epidemic is developing. Veterinarian expertise is also needed to institute the best measures for containing the illness and limiting transmission not only to animals but to humans as well .
During the outbreaks of AI in poultry in Asia during 2003–2004, people were not restricted from traveling to outbreak areas because of the limited transmission to humans. However, the following recommendations were sent to embassies and Americans living abroad :
Practice frequent and careful handwashing with soap and water or with a hand cleanser if soap and water are unavailable.
Avoid bird markets and poultry yards where AI is most likely to be transmitted.
All poultry and eggs should be cooked well as influenza virus is destroyed by heat.
Masks and other personal protective equipment in public areas are not recommended.
Travelers should be immunized with the current influenza vaccine against human influenza strains before traveling and should be reminded that winter (i.e., flu season) occurs in the Southern Hemisphere when the Northern Hemisphere is experiencing summer.
The CDC has developed guidelines for airline personnel with a suspected case of AI on board an international flight originating in an area in which AI has been reported :
As much as possible, airline staffs are to keep the sick person separated from close contact with others.
A surgical or procedural mask should be provided to limit the amount of droplets coughed into the air. If the passenger cannot wear the mask, anyone assisting him/her should be masked.
Staff should teach the passenger cough etiquette if it is not being practiced.
Disposable gloves are to be worn for any contact with body fluids, and hands are to be washed well when gloves are removed.
The captain is to report the illness to the nearest U.S. Quarantine Station if the aircraft is coming to the United States. The Quarantine Station will coordinate appropriate medical assistance when the plane lands and will notify the appropriate CDC staff.
In addition, general precautions of handwashing and covering coughs are, as always, important. Should flight personnel or ground staff become ill and believe they have been exposed to AI, they should notify their employer. If they are away from home, they should obtain local medical help. On any visit to a medical practitioner, they should inform the staff of the possible exposure to AI .
The major way to limit disease and transmission among domesticated fowl is to destroy all diseased birds and their flockmates. Because the virus appears to be carried by people and machines, possibly on shoes and tires, to surrounding areas, the recommendation is that all fowl in a 2-mile (3-kilometer) radius of the diseased flock be culled. Obviously, no shipping of live poultry from the infected areas should occur.
Those culling the flocks are vulnerable to infection because they will be dealing with diseased birds, exposed to their feces, or inhaling dust/dirt contaminated with the feces. Therefore, cullers must have personal protective equipment: coveralls or a surgical gown with long sleeves and an impermeable apron, heavy duty rubber gloves or disposable nitrile or vinyl gloves, rubber boots or disposable shoe covers, N95 respirator masks, and safety goggles. Frequent effective handwashing is important. All cullers should have received the current influenza vaccine so they will not acquire the circulating influenza and provide an opportunity for reassortment with the AI strain. Cullers should be monitored by the local health department and be provided information on the ways to prevent infection. They should be instructed when to call the practitioner and to always tell the practitioner that they have been exposed to AI. Persons who are at high risk for complications from influenza should not be employed as cullers. Medical personnel who have contact with cullers should make sure that the cullers have received the current influenza vaccine, understand the symptoms of the flu, realize that eye infections are common, and understand the importance of following the protective guidelines, including how to effectively wash their hands. The CDC states that treatment with an antiviral may be considered for workers involved with culling flocks of known infected birds, but does not recommend routine use of chemoprophylaxis of workers involved in culling non-infected birds as a preventative measure [31,138]. Whether personal protective equipment was used correctly, the type of exposure, and risk of complications from illness should be part of clinical decision making. Oseltamivir or zanamivir (one dose twice daily) is recommended versus the typical antiviral regimen (once daily dose) for exposed individuals who require chemoprophylaxis .
Those who dispose of the carcasses and those who are cleaning and disinfecting the environment where the flocks were housed are also at risk. The viruses can survive for varying periods of time, in some cases up to weeks or months, depending upon the temperature and humidity. For personal protection, those who dispose of the carcasses should follow the same recommendations as the cullers [31,138].
All workers involved in eradication efforts should be monitored for respiratory symptoms, fever, and conjunctivitis for one week after the last involvement with the diseased birds or their environment. If they seek medical care, they should be instructed to tell the practitioner that they were working with birds that had AI. Other than seeing the practitioner, all symptomatic personnel should stay home until their temperature has been normal for 24 hours. To protect their families, they should cover all coughs and dispose of the tissues safely, wash their hands well, and try to limit any face-to-face contact with others .
In handling environmental cleanup, it is important to note that the virus is killed by heating to 56 degrees C (132.8 degrees F) for three hours or to 60 degrees C (140 degrees F) for 30 minutes. Formalin and iodine compounds will also kill AI. When the temperature is cool, the virus can survive for three months in contaminated manure. It can survive for four days at 22 degrees C (71.6 degrees F) in water and for more than 30 days at 0 degrees C (32 degrees F) .
The culling of millions of birds has an economic impact on the owners and countries in which the culling must be done. However, the more widespread the virus is in any country or countries, the more opportunity there is for transmission to humans. Each AI in a human increases the possibility that co-infection with a human influenza virus can occur leading to reassortment of the antigens and a new virulent influenza virus that can be transmitted person-to-person .
If a patient is known to have or suspected of having respiratory AI, he or she should be segregated in the waiting room, be provided with a surgical or procedural mask, be given tissues and a way to dispose them, and not be kept in the waiting room for an extended period.
A nasopharyngeal swab or aspirate should be collected and sent to the local public health laboratory. It is important to keep the local health authorities aware of any such suspected illness so that the full use of available resources can be made, if necessary. The specimen should then be forwarded to the state laboratory for reverse transcription-polymerase chain reaction (RT-PCR) for influenza A analysis and, if possible, for H1 and H3 analysis. Should the state not have the capacity to perform these tests, or if the tests are positive, the specimen should be sent to the CDC. Only a level 3+ laboratory should attempt to isolate the virus. Blood should be collected and stored locally for an acute (within one week of symptom onset) and convalescent (after three weeks of symptom onset) specimen to test for AI antibodies .
Medical practitioners should also be alert to ask all patients with respiratory symptoms and fever if they have traveled to any area in which AI is reported .
Early detection is another way to handle AI so that proper containment procedures can be initiated as soon as possible. As discussed, both the CDC and the WHO are working to increase surveillance in countries around the world [134,140]. Hopefully, all countries will be able to detect and acknowledge the presence of a disease before it becomes widespread and the death toll escalates .
As discussed, pigs represent an important link in the interspecies transmission of influenza and in the creation of new virus types. In addition, swine influenza has the potential to cause significant disease in humans, although it is difficult to predict the potential impact of swine influenza in humans. Because most individuals, with the possible exception of those with regular contact with pigs, do not have immunity to these viruses, the potential for pandemic exists.
Swine influenza is usually caused by the H1N1 subtype, but other swine influenza A viruses do occur, including H1N2, H3N1, and H3N2 . Although swine flu viruses do not normally infect humans, sporadic human infections have occurred. When this occurs, these viruses are called "variant viruses" and are denoted by adding the letter "v" to the virus subtype designation. Human infections with H1N1v, H3N2v, and H1N2v viruses have been detected in the United States . Pigs may become infected with more than one virus subtype simultaneously; in these cases, genes from the viruses may mix and create a new "reassortment" virus . The main swine influenza viruses circulating in U.S. pigs in the past decade include triple reassortant (tr) H1N1, trH3N2, and trH1N2 .
Among pigs, swine influenza is a highly contagious acute respiratory disease. In many countries, including the United States, swine populations are routinely vaccinated against the prevalent subtypes. Vaccination of pigs, while not sufficient to produce sterilizing immunity, can reduce the levels of virus shed by the animals and reduce the potential for human exposure and infection .
In 2009, an outbreak of H1N1 influenza A (hereafter referred to as 2009 H1N1), popularly referred to as the "swine flu," occurred. Tests showed this virus was similar to influenza viruses normally occurring in pigs in North America. However, with more extensive testing, scientists learned that there were two genes present that typically occur in pigs in Europe and Asia. In addition, there were also avian and human genes. A quadruple reassortment virus was the result [11,144].
It should be noted that the so-called Spanish Influenza of 1918–1919 was also an H1N1 virus. The hemagglutinin gene in 2009 H1N1 influenza apparently descended from the avian-origin 1918 pandemic influenza virus; however, laboratory testing showed that 2009 H1N1 did not have any 1918-like markers that had been associated with increased risk of severe disease, nor did it have genetic markers that were previously associated with high death rates in people infected with the avian influenza A (H5N1) virus in other countries .
The 2009 H1N1 virus was first detected in the United States in April 2009. Laboratory testing at the CDC confirmed infection with the virus in two patients, 8 and 10 years of age, who lived 130 miles apart, who had no contact with pigs, and who had no known connection to one another. Sporadic reports of human infection with North American-lineage swine influenza virus in the United States had been reported from December 2005 to January 2009, but the detection of infection in the two children raised concern that a novel swine-origin influenza virus had made its way into the human population and that human-to-human transmission of the virus had occurred. By September 2009, more than 99% of the circulating viruses were 2009 H1N1 .
The 2009 H1N1 virus was not a new subtype, but many humans had no pre-existing antibody to it (especially those younger than 65 years of age). The virus quickly spread worldwide, and on June 11, 2009, the WHO declared it a worldwide pandemic . The 2009 H1N1 virus remained the predominant circulating virus for the entire 2009–2010 influenza season [11,145]. On June 23, 2010, the public health emergency for 2009 H1N1 expired in the United States, and the WHO declared the pandemic over on August 10, 2010 .
Data from past pandemics show that influenza activity occurs in waves. A second wave of 2009 H1N1 occurred in the fall of 2010 and peaked in the first three weeks of October . Experts believe that 2009 H1N1 will continue to circulate for some time as a typical winter flu, as it did extensively in 2012–2013 and 2015–2016. It is included in the formulation of the 2016–2017 vaccine .
Like all flu viruses, 2009 H1N1 is mainly spread among people by coughing, sneezing, talking, and occasionally via fomites. It is not spread by food or by eating pork or pork products. There have been no cases acquired from influenza-contaminated drinking water. Chlorine treatment of drinking water has been shown to inactivate the highly pathogenic H5N1 virus, and H1N1 would be similarly affected. A documented case of influenza from any water exposure (drinking or recreational) has not occurred.
Pets, such as dogs, cats, and ferrets, can be infected with H1N1 from close contact with a sick human. All available information indicates that H1N1-infected dogs, cats, and ferrets do not transmit the illness to humans. So far, there is no H1N1 vaccine for animals. Most recover with supportive care .
When a swine influenza virus does become a source of widespread human illness, the transmission patterns change. Instead of being mainly limited to swine contact, the virus will spread by human-to-human contact. According to the CDC, available data indicate that the 2009 H1N1 virus is transmitted in ways similar to other influenza viruses, primarily via large-particle respiratory droplet transmission . Because humans have little to no immunity to influenza viruses of swine origin, transmission may be common.
H1N1 survives on surfaces, including kitchen counters, door knobs, desk tops, and other fomites, for two to eight hours. Individuals can pick up the virus when they touch contaminated objects and unconsciously then touch their eyes, mouth, or nose. Thus it is vital for people to learn to keep their hands away from their mouths, eyes, and nose and to frequently wash their hands well with soap and water or use an alcohol-based hand sanitizer. An alcohol-based product, bleach solution, or hot, soapy water can be used to clean surfaces . One positive result of the H1N1 pandemic, as indicated in a study conducted in Hong Kong, was that people were washing their hands more frequently and wearing face masks when having ILI or in public areas .
A major transmission concern with 2009 H1N1 was regarding newborns whose mothers had the virus. The CDC and State Health Departments strongly recommended vaccination for this population because of demonstrated risks to both infants and pregnant women. However, many disregarded the recommendation. It was then decided that infant and mother should be separated until the mother had been on antivirals for at least 48 hours, was afebrile for 24 hours without antipyretics, and could control her cough and respiratory secretions. Before visiting the infant, the mother was instructed to clean her hands well with soap and water or an alcohol-based hand sanitizer, wear a face mask, and observe respiratory/cough etiquette. If her gown had been contaminated with byproducts of coughing or sneezing, she was instructed to change to a fresh gown. Following these guidelines, the mother was then allowed to hold, feed, and care for the infant .
Like seasonal influenza, vaccination is the most important preventive measure. Other common sense preventive steps (e.g., appropriate cough cover, correct disposal of used tissues, adequate rest, good fluid intake, staying home when ill) should also be practiced.
Persons who live with or provide care for infants younger than 6 months of age
Healthcare and emergency medical services personnel
Children and young adults 6 months to 24 years of age
Persons 25 to 64 years of age at higher risk for influenza-related complications
The ACIP also recommended that local public health authorities and healthcare practitioners have flexibility to determine how quickly and when to expand vaccination to other groups . The priority patients were vaccinated as soon as the vaccine was available. The CDC recommended that children younger than 10 years receive two doses of influenza vaccine . For the 2016–2017 flu season, the ACIP recommends that children 6 months through 8 years of age who are receiving influenza vaccine for the first time be given two doses at least four weeks apart .
Similar to seasonal flu, H1N1 symptoms include chills, fever, myalgia, fatigue, headache, cough, sore throat, and rhinitis. But unlike seasonal flu, there may be vomiting and diarrhea in some people. Others may have respiratory symptoms without fever [11,152].
Unless it becomes a pandemic, swine influenza infection in humans generally goes undistinguished from typical human influenza as a result of the overlapping flu seasons and the relatively mild clinical presentation. The disease is diagnosed by analysis of a sputum sample collected in the first four to five days of illness, when an individual is most likely to be shedding the virus . In June 2010, the FDA authorized the CDC Influenza 2009 A (H1N1)pdm Real-Time RT-PCR panel (IVD) to detect human infections with 2009 H1N1. This test replaced the previous real-time RT-PCR diagnostic test authorized by the FDA in April 2009, just as the WHO declared that a pandemic was imminent [144,154]. There are now several RT-PCT and other molecular assays available to differentiate 2009 H1N1 .
In the case of the 2009 H1N1 virus, the CDC recommends that clinicians not routinely test for the virus when it is known to occur in the community, but that testing be prioritized in people who are hospitalized with suspected flu and in people for whom a diagnosis of flu would help their physician make decisions about their care . As the 2009–2010 H1N1 epidemic progressed, it became apparent that those younger than 65 years of age were at greatest risk (Table 4) .
While most swine influenza cases were sufficiently mild to resolve spontaneously, antiviral medications were used if treatment was indicated. The specifically recommended agents were determined based on clinical and epidemiologic assessment of the virus. For example, in the case of the 2009 H1N1 outbreak in North America, the virus's susceptibility profile indicated that the preferred antivirals would be oseltamivir or zanamivir .
During the 2009–2010 H1N1 pandemic, the CDC recommended antiviral treatment for all persons with suspected or confirmed influenza requiring hospitalization . In addition, early empiric treatment with oseltamivir or zanamivir was considered for persons with suspected or confirmed influenza who were at higher risk for complications, including :
Children younger than 2 years of age
Persons 65 years of age or older
Pregnant women and women up to two weeks postpartum (including following pregnancy loss)
Persons of any age with certain chronic medical or immunosuppressive conditions
Persons younger than 19 years of age who are receiving long-term aspirin therapy
The recommended treatment for adult and adolescent patients was either 75 mg oseltamivir twice per day or 10 mg (two 5-mg inhalations) of zanamivir twice daily [45,145]. Children 7 years of age and older may be treated with the adult dose of zanamivir. However, calculating oseltamivir doses for children is more complicated and has been the source of medical errors . It is important to note that while healthcare providers in the United States generally write prescriptions for liquid medications in milliliters, oseltamivir is dosed in milligrams . For infants 2 weeks of age or older, the oseltamivir dosage is 3 mg/kg twice daily . For children between 1 and 12 years of age, dosage is based on weight [45,145]:
<15 kg (<33 lbs.): 30 mg twice daily
>15 kg to 23 kg (>34 lbs. to 51 lbs.): 45 mg twice daily
>23 kg to 40 kg (>51 lbs. to 88 lbs.): 60 mg twice daily
>40 kg (>88 lbs.): 75 mg twice daily
Treatment should continue for five days . Pregnancy is not considered a contraindication to the use of oseltamivir or zanamivir.
As of 2015, 2009 H1N1 was susceptible to both oseltamivir and zanamivir, with a few exceptions [96,103]. Those resistant to oseltamivir have been sensitive to zanamivir. Sporadic oseltamivir-resistant 2009 H1N1 virus infections have been identified, but the public health impact has been limited . As of 2015, no evidence existed of ongoing transmission of oseltamivir-resistant 2009 H1N1 virus strains worldwide .
A study at Utah State University examined the use of oseltamivir combined with T-705 (favipiravir), an antiviral in late-stage development by Toyama Chemical of Japan, on mice [158,160]. This combination was effective against H1N1, N3N2, and H5N1 influenzas. The study indicated that two antivirals may be a better strategy for treatment of humans with influenza. Favipiravir is a viral RNA polymerase inhibitor with a novel mechanism of action, inhibiting viral gene replication within infected cells to prevent their propagation .
Should methods for containment of a new avian or swine influenza virus fail, a worldwide epidemic or pandemic could follow. Because the population has no immunity to the new strain, millions of people could be infected and several million could die. The 1918 pandemic afflicted 20% to 40% of the world's population and caused 50 million deaths, at least 675,000 of which were in the United States . As a comparison, "seasonal" flu generally affects less than 20% of the population . The WHO estimates that there would be 233 million outpatient visits, 5.2 million hospitalizations, and 7.4 million deaths globally within a very short period of time were a pandemic to occur . Waves of the outbreak could occur in any given community for approximately six to eight weeks, then reoccur months later, affecting the global population for one to two years . The resulting strain on resources would be far more severe than a terrorist attack that is localized to one or a few areas and lasting from a few minutes to hours. However, planning for a bioterrorist attack and an influenza pandemic have many similarities, and each can enhance the other .
As became clear in 2009, the government has decided that it will not close our borders if pandemic flu occurs elsewhere. Challenges to closing the borders are numerous, and the disease will inevitably infect the United States regardless of border closures. In the event of a pandemic, attempts will be made to limit those who might be infected from entering the country .
Medical practitioners, emergency departments, and clinics, especially walk-in facilities, will be the first contacts in a pandemic. Having a high index of suspicion is vital to help slow the spread of the disease. Checking the CDC weekly influenza reports will help to clarify suspicions . Experience during the 2004 SARS outbreak in Toronto showed that, once SARS was recognized, infection control measures worked well to protect the medical community and facilities. The public health infrastructure was active, strong, and responsive, ensuring that public health in a major urban center was also protected .
The WHO has defined phases for a pandemic that reflect a global risk assessment of each influenza virus with pandemic potential :
Interpandemic phase: The period between influenza pandemics
Alert phase: Influenza caused by a new subtype has been identified in humans, and the population has little or no immunity to the virus. This may be a precursor to a pandemic.
Pandemic phase: A period of global spread of human influenza caused by a new subtype with sustained person-to-person transmission. Multiple cases occur in the same geographic area.
Transition phase: As assessed global risk reduces, de-escalation of global actions may occur, and reduction in response activities may be appropriate.
The CDC has developed guidelines for public response in a pandemic situation. These stress that people should stay away from crowds, avoid close contact with anyone at work or school, stay home if they or anyone in the household is sick, wash hands frequently, practice covering all coughs and sneezes, and dispose of tissues safely.
Many people think they will be protected in a crowd if they wear a mask, but there is little scientific data proving that masks protect against the flu. Industrial masks/N95 respirators should be considered for caregivers. N95 masks must fit closely (no air leaks) to be effective. Masks that become damp or wet cease to be protective. Proper disposal of a mask is imperative, as it has the potential to become a source of infection rather than protection [106,169].
In planning for the inevitable pandemic, five areas should be covered. These include: surveillance and laboratory issues, communication, community services, medical care, and vaccines and drugs. In September 2006, the California Department of Health Services developed the Pandemic Influenza Preparedness and Response Plan . The plan was then revised in 2007. The 2007 plan includes sections on pandemic influenza surveillance and epidemiology, laboratory testing capacity, healthcare planning, infection control in the healthcare setting, case management, vaccine programs, antiviral drug programs, community disease control and prevention, and risk communication. These sections cover the responsibilities of the medical community (health practitioners, hospitals, and clinics) and public health departments and include prevention and mitigation plans .
This area includes establishing global and local data collection systems in order to determine expected disease rates in humans and animals so that an increase is recognized as quickly as possible. It also includes developing laboratory infrastructure and expertise to handle specimens correctly and accurately. The CDC is a WHO Collaborating Center that plays a major role in identifying antigenically drifted seasonal and novel influenza A viruses that possibly have pandemic potential . The CDC's Influenza Division conducts surveillance throughout the year and collects and analyzes influenza viruses from around the world for antigenic (immune response), antiviral susceptibility, epidemiology, and genetic characterizations.
The second planning area is communication among all those who will be involved in a response on local, state, and federal levels. The Federal Emergency Management Agency requires that all planning for various hazards/disasters/terrorist acts follow the Incident Command System (ICS) . This system provides a structure for the flow of information to the participants providing the response and back to those in authority. An influenza pandemic would require multiple agencies, organizations, and community groups to effectively respond, so in many areas, they would be under the local ICS.
In addition, communication includes relaying accurate, frequent, concise, and timely information to the public by a primary spokesperson. Health experts should use interactions with media personnel to provide educational points about the transmission, prevention, and symptoms of influenza. Such points, referred to as "sound bites," are brief, accurate, in common language, and important.
Another area of communication is between individual healthcare providers and patients. Having patient educational materials prepared before the flu season will assist patients to remember what they have been told and increase their participation in preventing the flu, as well as caring for themselves or someone else with the flu. The U.S. Chamber of Commerce has also developed a pamphlet for business owners that lists steps that can be taken to protect employees and to help keep businesses operating in the case of an outbreak .
One of the facets of a pandemic is the social disruption caused by the illness of so many employees. Therefore, the third area in any preparedness plan is maintenance of community services from healthcare providers, ambulance personnel, police, fire fighters, utility workers, and truck drivers—all the services that are called on daily to maintain life in our communities. This may involve providing vaccine first to healthcare professionals and those responsible for essential services in the community. Some services and work may be done via telecommuting so that more people can stay at home and lessen their exposure to the influenza virus.
Medical care is the fourth area that will be heavily impacted in a pandemic. The local health officer in most jurisdictions has the legal authority to isolate those with symptoms and quarantine those who have been exposed, as needed, to slow the spread of the disease. Equipment and care may have to be prioritized. In a pandemic, multiple geographic areas are impacted, so obtaining help from another area probably will not be possible. Some hospitals, health departments, and other medical facilities are developing lists of physicians and nurses who are either retired or no longer practicing but who would be available to assist during a crisis if needed . Starting in the 2000–2001 flu season, Ontario, Canada, offered influenza vaccine to all its residents to lessen the impact on hospitals. This universal vaccination program reduced the number of cases by 61% and influenza mortality by 28% .
If all available hospital beds in the area are in use, it may be necessary to set up a shelter for medically fragile people. Local health departments have plans and agreements with the American Red Cross and other organizations to establish shelters. Normally, these shelters are for people who have been displaced/evacuated because of a natural event (e.g., fire, flood, earthquake). A shelter for medically fragile people has additional equipment and staffing needs. Such a shelter would be for people who require help with medical treatment, such as wound care, medications, and IVs. People who are too sick to care for themselves and who have no one to care for them would be appropriate referrals for a medically fragile shelter .
The final area to be addressed is the supply and delivery of vaccines and drugs. The objectives of planning are to reduce morbidity and mortality, make sure essential services are available, reduce the economic impact, and equitably distribute the resources . Those with high risk of complications from the flu are generally the first to receive the vaccine if a shortage is anticipated or production is slow. In a pandemic, the decision may be made that healthcare professionals and others providing essential services would be the first recipients of vaccine. Because the vaccine would be completely new to a person's immune system, two doses 30 days apart may be needed to produce immunity, as is the current practice for children 6 months through 8 years of age receiving influenza vaccine for the first time .
During the influenza pandemic in 1918, large public gatherings continued to be permitted in some areas, most notably in Philadelphia, which served to spread the epidemic and led to a death rate of 719 per 100,000. Cities that had enforced a shutdown of schools, churches, and other gatherings slowed the spread and experienced a death rate of 347 per 100,000. Quarantine, school closings, and public meeting bans cut peak death rates 30% to 50% .
In 2007, the federal government established that, in the case of a severe influenza outbreak, schools should be closed for up to three months; sports events, movies, church, and other public gatherings and events should be canceled; working hours should be staggered to decrease the number of commuters using public transportation at any one time; and the use of public transport should be discouraged . Sick people and their families, even healthy members, should stay home 7 to 10 days. Issues of other gathering places, such as daycare centers and malls, will also need to be addressed. Parents should prevent their children from gathering. Measures of isolation (isolating ill patients) and quarantine (isolating exposed persons) should be used to slow the spread of influenza . State borders and airports would not be closed because of the need to transport food and other supplies [177,178].
In New York City, the plan emphasizes the importance of early detection. A monitoring system that tracks 60,000 pieces of information (e.g., ambulance runs, emergency room visits, pharmacy sales) has been developed .
A cooperative research project between Azusa Pacific University in California and National Chung Sing University in Taiwan is researching traditional Chinese herbal treatments and their effects on influenza virus subunits to develop alternative treatments, especially for countries in which vaccines or pharmaceutical treatments will be unavailable in a pandemic .
For medical care providers, an influenza epidemic presents many challenges. These would be compounded by the increased number of cases in a pandemic. A group in Los Angeles studied the impact on emergency departments and outpatient facilities during seven influenza epidemics. Some of the lessons learned in order to better cope with an increased number of patients were that :
Elective surgery should be reduced or eliminated.
Facilities should work with licensing agencies, fire marshals, and other regulators to relax staff-patient ratios and/or bed capacity limitations.
Additional staff resources for epidemics should be developed.
Walk-in influenza clinics should be established to triage and treat patients at lower cost.
Methods to identify additional needed equipment should be developed.
During the SARS outbreak, nurses at Stanford University Medical Center set up receiving areas to prescreen hundreds of patients before they entered the emergency department. Those with ILI were diverted to negative pressure rooms for further testing. Screening questions were used to triage the patients . Table 5 provides a list of questions that could be asked of patients to elicit extra information that may assist in a more rapid diagnosis. These questions should be asked in the receiving area of the hospital, clinic, or office in order to minimize the introduction of highly contagious organisms.
ASSESSMENT OF A PATIENT WITH INFLUENZA-LIKE ILLNESS
When asking a patient or family member when a symptom began, or other information that depends on recalling one's activities, it is helpful to have a calendar and to refer any symptom to some event that would be easily remembered; for example, "Your sister visited on Tuesday. Did you have the fever then?"
This receiving area would also be a place where educational materials could be provided for the "worried well." In an office situation, it might be possible to set up a small table outside the office door to screen patients and distribute masks and educational materials. Some public health department plans include supplying public health staff to emergency rooms to help answer questions and educate the worried well, allowing the hospital staff to assist in the care of those critically ill.
Influenza, with its complication, pneumonia, is the only infectious disease that remains one of the top 10 killers in the United States. An effective vaccine to prevent influenza has been available for decades but is underused by both the general public and healthcare professionals. As a result, the economic burden of influenza is billions of dollars, including the inefficient use of healthcare resources.
The threat of biologic weapons has made the control of influenza imperative as many of the possible biologic agents initially may be misdiagnosed as influenza because of similar symptoms. Added to the perils facing the world is the expected pandemic of influenza as the result of the introduction of an avian or swine influenza virus to which humans have no immunity.
Antigenic drift: Change in an influenza virus that allows it to resist the immunity developed against it. Antigenic drift is a factor behind the need for an annual influenza vaccine.
Antigenic shift: Reassortment of RNA segments involving hemagglutinin and neuraminidase antigens from two different influenza A types in one host cell to create a new influenza type.
Antiviral: A medication that will kill or weaken a virus.
Avian, or bird, influenza (AI): Influenza caused by viruses that occur naturally among wild birds. The low pathogenic variety is common in birds and causes few problems. High pathogenic AI is deadly to domestic fowl and may be transmitted to humans, resulting in high morbidity and mortality rates due to lack of immunity.
Case definition: A standardized precise description of a disease to assist in accurate data collection. Generally, there are 3 levels in a case definition: suspect, probable, and confirmed. Description for each level is particular to the disease being defined based on clinical symptoms and laboratory findings.
Epidemic: An increase in the expected number of cases of a particular disease. The amount of increase needed to declare an epidemic depends upon the disease involved.
Hemagglutinin: A surface antigen on the influenza A virus indicated in the name of the virus by a capital H followed by the subtype number.
Influenza: Respiratory illness with fever.
Isolation: Separation of a person with a contagious disease from the public.
Neuraminidase: A surface antigen on the influenza A virus indicated in the name of the virus by a capital N followed by the subtype number.
Quarantine: Restriction of a well person who has been exposed to a known infectious organism.
Pandemic: Epidemic of a disease that is worldwide.
Split virus: Chemical alteration of a virus for use in a vaccine. All influenza vaccine in the United States is split virus.
|Association for Professionals in Infection Control and Epidemiology|
|Association of State and Territorial Health Officials|
|Centers for Disease Control and Prevention|
|National Institute of Allergy and Infectious Diseases|
|U.S. Food and Drug Administration|
|U.S. Food and Drug Administration/MedWatch|
|Vaccine Adverse Event Reporting System|
|World Health Organization Global Influenza Programme|
1. Monitor the patient for improvement or worsening of symptoms. Write down the date and time of all observations: temperature, coughing, sneezing, amount the patient has had to drink and eat.
2. Supportive care
Over-the-counter medicines that bring fever down (no aspirin in anyone younger than 8 years of age)
Pain relievers (e.g., medications, carefully monitored heating pads)
Back or leg rubs
Cough medications, as ordered and needed
Cool cloth to the head
Limited light in the room
An encouraging, positive, but not overly exuberant attitude
3. Maintain the patient's fluid intake with water, juices, popsicles, ice cubes, tea, coffee, or broths. Milk may be appealing to some patients.
4. Provide any foods that are appealing to the patient. However, fluid intake is more critical than solid food intake.
5. Provide tissues and a disposal place that the patient can reach, such as a wastebasket or paper bag pinned to the bed.
6. Assist the patient to the bathroom, if needed.
7. Continue any routine medications, if possible. Check with the physician if the patient cannot take or vomits the medications or if the medication needs to be taken with food and the patient is not eating.
8. Persons on insulin should have their blood sugar carefully monitored. Blood sugar may go up because of the disease process or go down because of poor food intake.
9. Keep the patient oriented as to time of day and date by telling him/her the time (and day, if needed) whenever they awake. Napping can lead to disorientation, especially in the elderly patient. Some patients may also need to be reminded where they are.
10. Provide a way for the patient to summon help, such as a bell, whistle, or some other method.
1. Get the flu shot.
2. Wash your hands frequently. Use soap, make a good lather, rub lather all over your hands for 15 seconds, rinse well, and dry with a paper towel or with your own towel at home. The process should take at least 20 seconds and should be completed:
After shaking hands
After being around someone who is coughing/sneezing
After caring for someone who is sick
As soon as you get home
3. Avoid touching your mouth, nose, or eyes.
4. Wear a mask when you take care of someone with the flu.
5. Get 7 to 8 hours rest in 24 hours.
6. Drink at least 6 to 8 glasses of water each day. Sodas do not count. If one is tiring of water, putting it in a colored glass may help. Also, room temperature water is easier to drink in quantities than cold water.
7. Eat at least 5 or more servings of fruits and vegetables each day.
8. If caring for someone, get away from the house for a period of time each day, even just to go to the store or take a walk.
9. Avoid alcohol and tobacco.
Phone Number ___________________________________________
Usually the person with the flu gets very sick suddenly, stays very sick for a few days, and then starts to feel better. The flu can cause other problems. Below is a list of symptoms and signs that indicate that a person needs help from a physician.
As you take care of the person, write down the date and time when you take the temperature or notice a new sign or symptom. If you are having trouble getting the patient to drink fluids, write down the time the person had a drink and how much they drank. The following signs should be reported to a physician immediately.
The temperature stays above 102 degrees F in spite of the person taking medicine to bring the fever down. (Never give aspirin to anyone younger than 18 years of age.)
The person says or looks like he or she is having trouble breathing. The person is short of breath. The child is breathing very fast. The chest between the ribs or above the collar bone retracts when the child takes a breath. The person, especially if a child, looks a little blue.
The person will not drink water, juice, or any fluid or suck popsicles or ice. The infant has less than 6 wet diapers in 24 hours. The urine is very dark and there is not much of it. If the skin on the forearm is pinched up, it slowly returns to normal. The eyes are sunken in and the mouth is dry. The person keeps vomiting or retching.
The person is hard to wake up. No matter what you try, the child/infant cannot be comforted. The person is confused or seeing things. The person has fainted or nearly fainted. The person has a convulsion.
Any worsening of the flu symptoms, as individuals with the flu will start to feel better after 3 to 5 days. Any worsening of any health problem (e.g., chest pain, swelling of the feet).
1. Centers for Disease Control and Prevention. CDC Study Confirms Variability of Flu. Available at http://www.cdc.gov/flu/about/disease/us_flu-related_deaths.htm. Last accessed October 13, 2016.
2. Centers for Disease Control and Prevention. Seasonal Influenza-Associated Hospitalizations in the United States. Available at http://www.cdc.gov/flu/about/qa/hospital.htm. Last accessed October 13, 2016.
3. Atkinson W, Hamborsky J, Wolfe C (eds). Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Public Health Foundation; 2015.
4. Centers for Disease Control and Prevention. Licensure of a high-dose inactivated influenza vaccine for persons aged ≥65 years (Fluzone high-dose) and guidance for use—United States, 2010. MMWR. 2010;59(16):485-486.
5. Mao L, Yang Y, Qiu Y, Yang Y. Annual economic impacts of seasonal influenza on U.S. counties: spatial heterogeneity and patterns. Int J Health Geographics. 2012;11:16.
6. Science Daily. Universal Influenza Vaccine Tested Successfully in Humans. Available at http://www.sciencedaily.com/releases/2008/01/080124185522.htm. Last accessed October 13, 2016.
8. Centers for Disease Control and Prevention. Prevention and control of influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices—United States, 2016–17 influenza season. MMWR. 2016:65(5);1-54.
9. Centers for Disease Control and Prevention. Summary of the 2015–2016 Influenza Season. Available at http://www.cdc.gov/flu/about/season/flu-season-2015-2016.htm. Last accessed October 20, 2016.
10. Centers for Disease Control and Prevention. Influenza activity—United States, 2012–2013 season and composition of the 2013–2014 influenza vaccine. MMWR. 2013;62(23):473-479.
11. Centers for Disease Control and Prevention. 2009 H1N1 Flu ("Swine Flu") and You. Available at http://www.cdc.gov/h1n1flu/qa.htm. Last accessed October 13, 2016.
12. Centers for Disease Control and Prevention. Influenza activity United States and worldwide: 2007–08 Season. MMWR. 2008;57(25):692-697.
13. National Commission on Prevention Priorities. Preventive Care: A National Profile on Use, Disparities, and Health Benefits. Available at http://www.rwjf.org/content/dam/farm/reports/reports/2007/rwjf13325. Last accessed October 13, 2016.
14. Olsen C. Influenza: Pigs, People and Public Health. Available at http://www.montanahelp.org/2004_NPB_swine_flu_factsheet.pdf. Last accessed October 13, 2016.
15. National Institutes of Health. Interregional Spread of Influenza through United States Described by Virus Type, Size of Populations and Commuting Rates and Distance. Available at https://www.nih.gov/news-events/news-releases/interregional-spread-influenza-through-united-states-described-virus-type-size-population-commuting-rates-distance. Last accessed October 13, 2016.
16. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2012–13 influenza season. MMWR. 2012;61(32):613-618.
17. Bowser A. Serious Influenza Complications Common in Children. Available at http://www.medscape.com/viewarticle/474175. Last accessed October 13, 2016.
19. Centers for Disease Control and Prevention. Seasonal Influenza: Flu Basics. Available at http://www.cdc.gov/flu/about/disease.htm. Last accessed October 13, 2016.
20. Centers for Disease Control and Prevention. Key Facts about Influenza (Flu) and Flu Vaccine. Available at http://www.cdc.gov/flu/keyfacts.htm. Last accessed October 13, 2016.
21. Centers for Disease Control and Prevention. Notice to readers: considerations for distinguishing influenza-like illness from inhalational anthrax. MMWR. 2001;50(44):984-986.
22. Centers for Disease Control and Prevention. Clinical Description and Lab Diagnosis of Influenza. Available at http://www.cdc.gov/flu/professionals/diagnosis/index.htm. Last accessed October 13, 2016.
23. Centers for Disease Control and Prevention. Rapid Diagnostic Testing for Influenza. Available at http://www.cdc.gov/flu/professionals/diagnosis/rapidclin.htm. Last accessed October 13, 2016.
24. Centers for Disease Control and Prevention. Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection. Available at http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm. Last accessed October 13, 2016.
25. Centers for Disease Control and Prevention. Update: influenza-associated deaths reported among children aged <18 years—United States, 2003–Influenza Season. MMWR. 2003;52(Dispatch):1-2.
26. Rogawski E, McGrath L, Vielot N, Westreich D. Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study. Heart. 2014;100(6):517-518.
27. Medical News Today. Baxter Reveals Interim Results on Pandemic Flu Vaccine Clinical Trial. Available at http://www.medicalnewstoday.com/articles/66602.php. Last accessed October 13, 2016.
28. World Organization for Animal Health. Update on Highly Pathogenic Avian Influenza in Animals (Type H5 and H7). Available at http://www.oie.int/animal-health-in-the-world/update-on-avian-influenza/2016/. Last accessed October 20, 2016.
29. Edwards KM, Burns VE, Allen LM, et al. Eccentric exercise as an adjuvant to influenza vaccination in humans. Brain Behav Immun. 2007;21(2):209-217.
30. Kohut ML, Arntson BA, Lee W, et al. Moderate exercise improves antibody response to influenza immunization in older adults. Vaccine. 2004;22(17-18):2298-2306.
31. Centers for Disease Control and Prevention. Interim Guidance on Influenza Antiviral Chemoprophylaxis of Persons Exposed to Birds with Avian Influenza A Viruses Associated with Severe Human Disease or with the Potential to Cause Severe Human Disease. Available at http://www.cdc.gov/flu/avianflu/guidance-exposed-persons.htm. Last accessed October 13, 2016.
32. U.S. Food and Drug Administration. FDA Approves Rapivab to Treat Flu Infection. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm427755.htm. Last accessed October 13, 2016.
33. Centers for Disease Control and Prevention. Update: recommendations of the Advisory Committee on Immunization Practices (ACIP) regarding use of CSL seasonal influenza vaccine (Afluria) in the United States during 2010–11. MMWR. 2010;59(31):989-992.
34. Sanofi Pasteur. Fluzone Intradermal (Influenza Virus Vaccine): Facts at a Glance. Available at http://multivu.prnewswire.com/mnr/sanofipasteur/49833/docs/49833-Fluzone_ID_Fact_Sheet.pdf. Last accessed October 13, 2016.
35. Centers for Disease Control and Prevention. General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(RR02):1-60.
36. U.S. health officials call for vigilance against influenza: vaccine supplies predicted to be ample. Nation's Health. 2003;33(9).
37. Centers for Disease Control and Prevention. Vaccine Information Statements (VIS): Inactivated Influenza VIS. Available at http://www.cdc.gov/vaccines/hcp/vis/vis-statements/flu.html. Last accessed October 13, 2016.
38. Centers for Disease Control and Prevention. Interim Guidance on Testing, Specimen Collection, and Processing for Patients with Suspected Infection with Novel Influenza A Viruses with the Potential to Cause Severe Disease in Humans. Available at http://www.cdc.gov/flu/avianflu/severe-potential.htm. Last accessed October 13, 2016.
39. U.S. Food and Drug Administration. May 9, 2011 Approval Letter—Fluzone Intradermal. Available at http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm255160.htm. Last accessed October 13, 2016.
40. Holland D, Booy R, De Looze F, et al. Intradermal influenza vaccine administered using a new microinjection system produces superior immunogenicity in elderly adults: a randomized controlled trial. J Infect Dis. 2008;198(5):650-658.
41. Kenney RT, Frech SA, Muenz LR, Villar CP, Glenn GM. Dose sparing with intradermal injection of influenza vaccine. N Engl J Med. 2004;351(22):2295-2301.
42. Paccalin M, Weinberger B, Nicolas J-F, Van Damme P, Mégard Y. The intradermal vaccination route—an attractive opportunity for influenza vaccination in the elderly. Eur Geriatr Med. 2010;1(2):82-87.
43. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2005;55(RR8):1-40.
44. Centers for Disease Control and Prevention. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR. 2008;57(RR7):1-60.
45. LexiComp Online. Available at http://online.lexi.com. Last accessed October 13, 2016.
46. Daily Med. FluMist Quadrivalent (Influenza Vaccine Live Intranasal) Spray. Available at https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=64f300d3-e1ba-40bc-a25f-4203ffdb27cf. Last accessed October 13, 2016.
47. Centers for Disease Control and Prevention. Questions and Answers: Antiviral Drugs 2009–2010 Flu Season. Available at http://www.cdc.gov/h1n1flu/antiviral.htm. Last accessed October 13, 2016.
48. Centers for Disease Control and Prevention. Bird Infections with Highly-Pathogenic Avian Influenza A (H5N2), (H5N8), and (H5N1) Viruses: Recommendations for Human Health Investigations and Response. Available at https://emergency.cdc.gov/han/han00378.asp. Last accessed October 13, 2016.
49. Treanor J. Influenza vaccine: outmaneuvering antigenic shift and drift. N Engl J Med. 2004;350(3):218-220.
50. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children.N Engl J Med. 2007;356(7):685-696.
51. Zangwill KM, Belshe RB. Safety and efficacy of trivalent inactivated influenza vaccine in young children: a summary for the new era of routine vaccination. Pediatr Infect Dis J. 2004;23(3):189-197.
52. Bergen R, Black S, Shinefield H, et al. Safety of cold-adapted live attenuated influenza vaccine in a large cohort of children and adolescents. Pediatr Infect Dis J. 2004;23(2):138-144.
53. U.S. Department of Health and Human Services. FDA approves first adjuvanted vaccine for prevention of H5N1 avian influenza. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm376444.htm. Last accessed October 13, 2016.
55. Semchuk KM, Love EJ, Lee RG. Parkinson's disease: a test of the multifactorial etiologic hypothesis. Neurology. 1993;43(6):1173-1180.
56. Casals J, Elizan TS, Yahr MD. Postencephalitic parkinsonism: a review. J Neural Transm. 1998;105(6-7):645-676.
57. Pahwa R, Koller WC. Defining Parkinson's disease and parkinsonianism. In: Ellenberg JH, Keller WC, Langston JW (eds). Etiology of Parkinson's Disease. New York, NY: Marcel Dekker; 1995: 1-54.
58. Reid AH, McCall S, Henry JM, Taubenberger JK. Experimenting on the past: the enigma of von Economo's encephalitis lethargica. J Neuropathol Exp Neurol. 2001;60(7):663-670.
59. Brydak LB. Neurological complication of influenza infections. Przegl Epidemiol. 2002;56(suppl 1):16-30.
60. Takahashi M, Yamada T. A possible role of influenza A virus infection for Parkinson's disease. Adv Neurol. 2001;86:91-104.
61. Advisory Committee on Immunization Practices. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices (ACIP)—United States, 2013–2014. MMWR. 2013;62(7):1-43.
62. Fiore AE, Shay DK, Haber P, et al. Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR. 2007;56(RR-6):1-54.
63. Advisory Committee on Immunization Practices. ACIP Meeting Minutes Archive: June 2007 Minutes. Available at http://www.cdc.gov/vaccines/acip/meetings/minutes-archive.html#07. Last accessed October 13, 2016.
64. Centers for Disease Control and Prevention. Flu Vaccination Coverage Among Pregnant Women – United States, 2015–16 Flu Season. Available at https://www.cdc.gov/flu/fluvaxview/pregnant-coverage_1516estimates.htm. Last accessed October 20, 2016.
65. Sanofi Pasteur. Fluzone Intradermal: Highlights of Prescribing Information. Available at https://www.vaccineshoppe.com/image.cfm?pi=fluID&image_type=product_pdf. Last accessed October 13, 2016.
66. Mazunder B, Almoord D, Park K, Crimmins EM, Finch CE. Lingering prenatal effects of the 1918 influenza pandemic on cardiovascular disease. J Dev Orig Health Dis. 2010;1(1):26-34.
67. Centers for Disease Control and Prevention. Recommended Immunization Schedule for Persons Age 0 through 18 Years. Available at http://www.cdc.gov/vaccines/schedules/hcp/imz/child-adolescent.html. Last accessed October 13, 2016.
68. Shrestha SS, Swerdlow DL, Borse RH, et al. Estimating the burden of 2009 pandemic influenza A (H1N1) in the United States (April 2009–April 2010). Clin Infect Dis. 2011;52(Suppl 1):S75-S82.
69. Caban-Martinez AJ, Lee DJ, Davila EP, et al. Sustained low influenza vaccination rates in US healthcare workers. Prev Med. 2010;50:210-212.
70. Centers for Disease Control and Prevention. Health Care Personnel and Flu Vaccination, Internet Panel Survey, United States, November 2014. Available at http://www.cdc.gov/flu/fluvaxview/hcp-ips-nov2014.htm. Last accessed October 13, 2016.
71. Goetzel RZ, Long SR, Ozminkowski RJ, Hawkins K, Wang S, Lynch W. Health, absence, disability, and presenteeism cost estimates of certain physical and mental health conditions affecting U.S. employers. J Occup Environ Med. 2004;46(4): 398-412.
72. Associated Press. 10 Million Doses of Flu Shot to be Thrown Away: Annual Expiration Date Ensures Up-to-Date Vaccine, but at a Huge Cost. Available at http://www.msnbc.msn.com/id/17708169. Last accessed October 13, 2016.
73. Centers for Disease Control and Prevention. National Influenza Vaccination Week. Available at http://www.cdc.gov/flu/nivw. Last accessed October 13, 2016.
74. Brown D. For health officials flu shot is an annual gamble. Washington Post. January 12, 2004:A3. Available at https://www.highbeam.com/doc/1P2-149155.html. Last accessed October 13, 2016.
75. Bartlett J. Infectious Diseases: February 15, 2004. Available at http://www.medscape.com/viewarticle/467518. Last accessed October 13, 2016.
76. Centers for Disease Control and Prevention. Seasonal Influenza Vaccine Supply for the U.S. 2016-2017 Influenza Season. Available at http://www.cdc.gov/flu/about/qa/vaxsupply.htm. Last accessed October 13, 2016.
77. Hathaway W. Trial Flu Vaccine Produced from Caterpillar Cells. Available at http://articles.courant.com/2004-05-04/features/0405040254_1_vaccine-production-new-vaccine-flu. Last accessed October 13, 2016.
78. Hathaway W. An Insect Alternative Helps to Fight the Flu. Available at http://articles.courant.com/keyword/avian-flu/featured/5. Last accessed October 13, 2016.
79. Rojahn SY. Synthetic Biology Could Speed Flu Vaccine Production. Available at https://www.technologyreview.com/s/514661/synthetic-biology-could-speed-flu-vaccine-production/. Last accessed October 13, 2016.
80. U.S. Food and Drug Administration. FDA Approves New Seasonal Influenza Vaccine Made Using Novel Technology. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm335891.htm. Last accessed October 13, 2016.
81. Milián E, Kamen AA. Current and emerging cell culture manufacturing technologies for influenza vaccines. Biomed Res Int. 2015;2015:504831.
82. U.S. Department of Health and Human Services. Healthy People 2020. Available at http://www.healthypeople.gov/2020/default.aspx. Last accessed October 13, 2016.
83. Immunization Action Coalition. Ask the Experts: Diseases & Vaccines. Availalable at http://www.immunize.org/askexperts/experts_inf.asp. Last accessed October 13, 2016.
84. Centers for Disease Control and Prevention. Key Facts about Seasonal Flu Vaccine. Available at http://www.cdc.gov/flu/protect/keyfacts.htm. Last accessed October 13, 2016.
85. American Academy of Ambulatory Care Nursing. Health Care Providers are the Key to Influenza Vaccination. Available at http://www.aaacn.org/news/health-care-providers-are-key-influenza-vaccination. Last accessed October 13, 2016.
86. Centers for Disease Control and Prevention. Seasonal Influenza (Flu): Free Resources. Available at http://www.cdc.gov/flu/freeresources/index.htm. Last accessed October 13, 2016.
87. Black CL, Yue X, Ball SW, et al. Influenza vaccination coverage among health care personnel—United States, 2015–16 influenza season. MMWR. 2016;65:1026-1031.
88. Pearson ML, Bridges CB, Harper SA. Influenza vaccination of health care professionals. MMWR. 2006;55(RR2):1-16.
89. Bowser A. Vaccines Effective in Nursing Home Residents. Available at http://www.medscape.com/viewarticle/474119. Last accessed October 13, 2016.
90. Hennepin County Community Health Department. Infectious Diseases in Childcare Settings and Schools Manual. Available at http://www.hennepin.us/childcaremanual. Last accessed October 13, 2016.
91. Centers for Disease Control and Prevention. Handwashing: Clean Hands Save Lives. Available at http://www.cdc.gov/handwashing. Last accessed October 13, 2016.
92. Centers for Disease Control and Prevention. How Flu Spreads. Available at http://www.cdc.gov/flu/about/disease/spread.htm. Last accessed October 13, 2016.
93. Centers for Disease Control and Prevention. Cover Your Cough. Available at http://www.cdc.gov/flu/protect/covercough.htm. Last accessed October 13, 2016.
94. Centers for Disease Control and Prevention. CDC Says "Take 3" Actions to Fight the Flu. Available at http://www.cdc.gov/flu/protect/preventing.htm. Last accessed October 13, 2016.
95. Centers for Disease Control and Prevention. Prevention Strategies for Seasonal Influenza in Healthcare Settings. Available at http://www.cdc.gov/flu/professionals/infectioncontrol/healthcaresettings.htm. Last accessed October 13, 2016.
96. Centers for Disease Control and Prevention. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(RR1):1-24.
97. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Available at http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Last accessed October 13, 2016.
99. Aoki FY, Allen UD, Stiver HG, Evans GA. The use of antiviral drugs for influenza: guidance for practitioners 2012/2013. Can J Infect Dis Med Microbiol. 2012;23(4):e79-e92.
100. Rothberg M, He S, Rose DN. Management of influenza symptoms in healthy adults: cost effectiveness of rapid testing and antiviral therapy. J Gen Intern Med. 2003;10(18):808-815.
101. Centers for Disease Control and Prevention. Dosage: Guidance on the Use of Influenza Antiviral Agents. Available at http://www.cdc.gov/flu/professionals/antivirals/antiviral-dosage.htm#Tab1. Last accessed October 13, 2016.
102. Centers for Disease Control and Prevention. Treatment: Antiviral Drugs. Available at http://www.cdc.gov/flu/antivirals/whatyoushould.htm. Last accessed October 13, 2016.
103. Centers for Disease Control and Prevention. Antiviral Drug Resistance among Influenza Viruses. Available at http://www.cdc.gov/flu/professionals/antivirals/antiviral-drug-resistance.htm. Last accessed October 13, 2016.
104. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary for Clinicians. Available at http://www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm. Last accessed October 13, 2016.
105. Centers for Disease Control and Prevention. Other Important Information for People Sick with Flu. Available at http://www.cdc.gov/flu/faq/what-to-do.htm. Last accessed October 13, 2016.
106. Centers for Disease Control and Prevention. Respiratory Hygiene/Cough Etiquette in Healthcare Settings. Available at http://www.cdc.gov/flu/professionals/infectioncontrol/resphygiene.htm. Last accessed October 13, 2016.
107. Centers for Disease Control and Prevention. Transmission of Influenza A Viruses between Animals and People. Available at http://www.cdc.gov/flu/avianflu/virus-transmission.htm. Last accessed October 13, 2016.
108. World Health Organization. Cumulative Number of Confirmed Human Cases of Avian Influenza A(H5N1) Reported to WHO, 2003–Available at http://www.who.int/influenza/human_animal_interface/2016_10_03_tableH5N1.pdf?ua=1. Last accessed October 20, 2016.
109. Centers for Disease Control and Prevention. Highly Pathogenic Avian Influenza A (H5N1) in People. Available at http://www.cdc.gov/flu/avianflu/h5n1-people.htm. Last accessed October 13, 2016.
110. Centers for Disease Control and Prevention. Human Infections with Novel Influenza A (H7N9) Viruses. Available at https://emergency.cdc.gov/HAN/han00344.asp. Last accessed October 13, 2016.
111. World Health Organization. Avian Influenza: Assessing the Pandemic Threat. Available at http://whqlibdoc.who.int/hq/2005/WHO_CDS_2005.29.pdf. Last accessed October 13, 2016.
112. Centers for Disease Control and Prevention. Public Health Threat of Highly Pathogenic Avian Influenza A (H5N1) Virus. Available at http://www.cdc.gov/flu/avianflu/h5n1-threat.htm. Last accessed October 13, 2016.
113. Centers for Disease Control and Prevention. Avian Influenza in Birds. Available at http://www.cdc.gov/flu/avianflu/avian-in-birds.htm. Last accessed October 13, 2016.
114. Hitt E. Avian Flu: What Clinicians Need to Know. Available at http://www.medscape.com/viewarticle/468007. Last accessed October 13, 2016.
115. U.S. Department of Agriculture. Low Pathogenic H5N1 vs. Highly Pathogenic H5N1: Latest Update. Available at http://www.usda.gov/wps/portal/usda/usdahome?contentidonly=true&contentid=2006/08/0296.xml. Last accessed October 13, 2016.
116. World Health Organization. Frequently Asked Questions on Human Infection Caused by the Avian Influenza A(H7N9) Virus. Available at http://www.who.int/influenza/human_animal_interface/faq_H7N9/en/. Last accessed October 13, 2016.
117. Centers for Disease Control and Prevention. Update: influenza activity—United States 2003–2004 season. MMWR. 2004;53(13): 284-287.
118. Li C, Hatta M, Nidom CA, et al. Reassortment between avian H5N1 and human H3N2 influenza viruses creates hybrid viruses with substantial virulence. Proc Natl Acad Sci USA. 2010;107(10):4687-4692.
119. Centers for Disease Control and Prevention. Interim Guidance for Protection of Persons Involved in U.S. Avian Influenza Outbreak Disease Control and Eradication Activities. Available at http://www.cdc.gov/flu/avian/professional/protect-guid.htm. Last accessed February 23, 2017.
120. World Health Organization. H5N1 Avian Influenza: Timeline of Major Events. Available at http://www.who.int/influenza/H5N1_avian_influenza_update_20121217b.pdf. Last accessed October 13, 2016.
121. Centers for Disease Control and Prevention. Interim Report: Human Infection with Avian H7 Influenza Viruses, North America. Available at http://www.cdc.gov/flu/avian/interim-report.htm. Last accessed October 13, 2016.
122. Centers for Disease Control and Prevention. Prevention and Treatment of Avian Influenza A Viruses in People. Available at http://www.cdc.gov/flu/avianflu/prevention.htm. Last accessed October 13, 2016.
123. Kayali G, Kandeil A, El-Shesheny R, et al. Avian influenza A(H5N1) virus in Egypt. Emerg Infect Dis. 2016;22(3).
124. Crispin SW, Cohen M, Mapes T. Bird-flu outbreak revives concerns stirred by SARS. Wall Street Journal. January 28, 2004. Available at http://online.wsj.com/article/SB107524207391913268.html. Last accessed October 13, 2016.
125. Centers for Disease Control and Prevention. Outbreaks of Avian Influenza in North America. Available at http://www.cdc.gov/flu/avianflu/outbreaks.htm. Last accessed February 23, 2017.
126. National Institutes of Health. NIH Scientists Target Future Pandemic Strains of H5N1 Avian Influenza. Available at https://www.nih.gov/news-events/news-releases/nih-scientists-target-future-pandemic-strains-h5n1-avian-influenza. Last accessed October 13, 2016.
127. Gamblin SJ, Haire LF, Russell RJ, et al. The structure and receptor binding properties of the 1918 influenza hemagglutinin. Science. 2004;303(5665):1838-1842.
128. World Health Organization. Availability of New Recombinant H5N1 Vaccine Virus. Available at http://www.who.int/influenza/resources/documents/H5N1virusJune/en/. Last accessed October 13, 2016.
129. GlaxoSmithKline. GlaxoSmithKline Receives New HHS Order for H5N1 Bulk Antigen. Available at http://www.biopharminternational.com/glaxosmithkline-receives-new-hhs-order. Last accessed October 13, 2016.
130. International Federation of Pharmaceutical Manufacturers and Associations. IFPMA Supports Principles of Pandemic Influenza Preparedness Decision. Available at http://www.ifpma.org/resource-centre/ifpma-supports-principles-of-pandemic-influenza-preparedness-decision. Last accessed October 13, 2016.
131. U.S. Food and Drug Administration. FDA Approves First U.S. Vaccine for Humans against the Avian Influenza Virus H5N1. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108892.htm. Last accessed October 13, 2016.
132. He G, Massarella J, Ward P. Clinical pharmacokinetics of the prodrug oseltamivir and its active metabolite Ro 64-0802. Clin Pharmacokinet. 1999;37(6):471-484.
134. Global Early Warning System. About GLEWS. Available at http://www.glews.net/about-glews/. Last accessed October 13, 2016.
135. Altman LK. As bird flu spreads global health weaknesses are exposed. New York Times. February 3, 2004. Available at http://www.nytimes.com/2004/02/03/health/the-doctor-s-world-as-bird-flu-spreads-global-health-weaknesses-are-exposed.html?pagewanted=all&src=pm. Last accessed October 13, 2016.
136. Centers for Disease Control and Prevention. Guidelines and Recommendations: Interim Guidance about Avian Influenza (H5N1) for U.S. Citizens Living Abroad. Available at http://wwwnc.cdc.gov/travel/page/avian-flu-americans-abroad. Last accessed October 13, 2013.
137. Centers for Disease Control and Prevention. Interim Guidance for Airline Flight Crews and Persons Meeting Passengers Arriving from Areas with Avian Influenza (Updated). Available at http://wwwnc.cdc.gov/travel/page/avian-flu-arriving-from-areas. Last accessed October 13, 2016.
138. World Health Organization. WHO Interim Recommendations for the Protection of Persons Involved in the Mass Slaughter of Animals Potentially Infected with Highly Pathogenic Avian Influenza Viruses. Available at http://www.wpro.who.int/emerging_diseases/documents/docs/WHOinterimrecommendation26012004.pdf. Last accessed October 13, 2016.
139. California Department of Health Services Division of Communicable Disease Control. Avian Influenza (H5N1) Update as of January 29, 2004.
140. Centers for Disease Control and Prevention. Influenza Division International Program. Available at http://www.cdc.gov/flu/international/program/index.htm. Last accessed October 13, 2016.
141. Centers for Disease Control and Prevention. Key Facts about Human Infections with Variant Viruses. Available at http://www.cdc.gov/flu/swineflu/keyfacts-variant.htm. Last accessed October 13, 2016.
142. World Health Organization. Avian Influenza Update: Implications of H5N1 Infections in Pigs in China. Available at http://www.who.int/csr/don/2004_08_25/en/. Last accessed October 13, 2016.
143. Centers for Disease Control and Prevention. What People who Raise Pigs Need to Know about Influenza (Flu). Available at http://www.cdc.gov/flu/swineflu/people-raise-pigs-flu.htm. Last accessed October 13, 2016.
144. Centers for Disease Control and Prevention. The 2009 H1N1 Pandemic: Summary highlights, April 2009–April 2010 (Archive). Available at http://www.cdc.gov/h1n1flu/cdcresponse.htm. Last accessed October 13, 2016.
145. Centers for Disease Control and Prevention. Updated Interim Recommendations for the Use of Antiviral Medications in the Treatment and Prevention of Influenza for the 2009–2010 Season (Archive). Available at http://www.cdc.gov/h1n1flu/recommendations.htm. Last accessed October 13, 2016.
146. World Health Organization. H1N1 in Post-Pandemic Period. Available at http://www.who.int/mediacentre/news/statements/2010/h1n1_vpc_20100810/en/. Last accessed October 13, 2016.
147. Leighty J. Code zebra: on the frontlines, California EDs brace for action against infectious disease and bioterrorism. Nurse Week. 2004;13-15.
148. U.S. Department of Health and Human Services. FLU.gov: Prevention. Available at http://www.flu.gov/prevention-vaccination/index.html. Last accessed October 13, 2016.
149. Lau JTF, Griffiths S, Choi K-C, Lin C. Prevalence of preventive behaviors and associated factors during early phase of the H1N1 influenza epidemic. Am J Infect Control. 2010;38(5):374-380.
150. Centers for Disease Control and Prevention. Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices, 2009. MMWR. 2009;58(RR10):1-8.
151. Centers for Disease Control and Prevention. Interim Guidance on Follow-up of Close Contacts of Persons Infected with Novel Influenza A Viruses Associated with Severe Human Disease and on the Use of Antiviral Medications for Chemoprophylaxis. Available at http://www.cdc.gov/flu/avianflu/novel-av-chemoprophylaxis-guidance.htm. Last accessed October 13, 2016.
152. Centers for Disease Control and Prevention. Flu Symptoms and Severity. Available at http://www.cdc.gov/flu/about/disease/complications.htm. Last accessed October 13, 2016.
153. Centers for Disease Control and Prevention. Influenza Symptoms and the Role of Laboratory Diagnostics. Available at http://www.cdc.gov/flu/professionals/diagnosis/labrolesprocedures.htm. Last accessed October 13, 2016.
154. Centers for Disease Control and Prevention. New CDC Test to Detect Human Infections with the 2009 H1N1 Influenza Virus Authorized for Use by FDA. Available at http://www.cdc.gov/media/pressrel/2010/r100622.htm. Last accessed October 13, 2016.
155. Centers for Disease Control and Prevention. Guidance for Clinicians on the Use of RT-PCR and Other Molecular Assays for Diagnosis of Influenza Virus Infection. Available at http://www.cdc.gov/flu/professionals/diagnosis/molecular-assays.htm. Last accessed October 13, 2016.
156. World Health Organization. Pandemic (H1N1) 2009: Frequently Asked Questions. Available at http://www.who.int/csr/disease/swineflu/frequently_asked_questions/en/. Last accessed October 13, 2016.
157. U.S. Food and Drug Administration. FDA Public Health Alert: Potential Medication Errors with Tamiflu for Oral Suspension. Available at http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm183649.htm. Last accessed October 13, 2016.
158. Smee DF, Hurst BL, Wong MH, et al. Effects of the combination of favipiravir (T-705) and oseltamivir on influenza A virus infections in mice. Antimicrob Agents Chemother. 2010;54(1):126-133.
159. U.S. Food and Drug Administration. Emergency Use Authorization of Peramivir IV: Fact Sheet for Health Care Providers. Available at http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM187811.pdf. Last accessed October 13, 2016.
160. Toyama Chemical. The New Drug Application Approval of "AVIGAN® Tablet 200mg" in Japan for the Anti-influenza Virus Drug. Available at https://www.toyama-chemical.co.jp/eng/news/news140324e.html. Last accessed October 13, 2016.
161. U.S. Department of Veterans Affairs. About Pandemic Flu. Available at http://www.publichealth.va.gov/flu/pandemic/. Last accessed October 13, 2016.
162. Centers for Disease Control and Prevention. Seasonal Influenza (Flu). Available at http://www.cdc.gov/flu/index.htm. Last accessed October 13, 2016.
163. World Health Organization. WHO Checklist for Influenza Pandemic Preparedness Planning. Geneva: World Health Organization, Department of Communicable Disease, Surveillance and Response, Global Influenza Programme; 2005.
164. Hearne SA, Davis M, Segal LM, et al. Ready or not? Protecting the public's health in the age of bioterrorism. Biosecur Bioterror. 2004;2(1):47-50.
165. U.S. Department of Health and Human Services. FLU.gov: About Pandemics. Available at http://www.flu.gov/pandemic/about. Last accessed October 13, 2016.
166. Centers for Disease Control and Prevention. Situation Update: Summary of Weekly FluView. Available at http://www.cdc.gov/flu/weekly/summary.htm. Last accessed October 13, 2016.
167. Galvani AP. Emerging infections: what have we learned from SARS? Emerg Infect Dis. 2004;10(7):1351-1352.
168. World Health Organization. Pandemic Influenza Risk Management: WHO Interim Guidance. Geneva: World Health Organization; 2013.
169. Centers for Disease Control and Prevention. Interim Guidance for the Use of Masks to Control Influenza Transmission. Available at http://www.cdc.gov/flu/professionals/infectioncontrol/maskguidance.htm. Last accessed October 13, 2016.
170. California Department of Public Health. Pandemic Influenza Preparedness and Response Plan. Available at http://www.bepreparedcalifornia.ca.gov/Documents/PandemicPlan.pdf. Last accessed October 13, 2016.
171. Centers for Disease Control and Prevention. CDC's World Health Organization (WHO) Collaborating Center for Surveillance, Epidemiology and Control of Influenza. Available at http://www.cdc.gov/flu/weekly/who-collaboration.htm. Last accessed October 13, 2016.
172. Federal Emergency Management Agency. Incident Command System. Available at https://www.fema.gov/incident-command-system-resources. Last accessed October 13, 2016.
173. U.S. Chamber of Commerce. It's Not Flu as Usual: What Businesses Need to Know about Pandemic Flu Planning. Available at https://www.uschamber.com/its-not-flu-usual. Last accessed October 13, 2016.
174. Gensheimer KF, Meltzer MI, Postema AS, Strikas RA. Influenza pandemic preparedness. Emerg Infect Dis. 2003;9(12):1645-1648.
175. California Emergency Medical Services Agency. Shelter Medical Group Toolkit: Local Emergency Preparedness Planners Guide for the Care and Sheltering of the Medically Fragile. Available at http://www.emsa.ca.gov/Media/Default/PDF/TOOLKIT.pdf. Last accessed October 13, 2016.
176. Bakalar N. How (and how not) to battle flu: a tale of 23 cities. The New York Times. April 17, 2007. Available at http://www.nytimes.com/2007/04/17/health/17flu.html. Last accessed October 13, 2016.
177. Centers for Disease Control and Prevention. Ethical Guidelines in Pandemic Influenza: Recommendations of the Ethics Subcommittee of the Advisory Committee to the Director, Centers for Disease Control and Prevention. Available at http://www.cdc.gov/od/science/integrity/phethics/panflu_ethic_guidelines.pdf. Last accessed October 13, 2016.
178. Markel H, Lipman HB, Navarro JA, et al. Nonpharmaceutical interventions implemented by U.S. cities during the 1918–1919 influenza pandemic. JAMA. 2007;298(6):644-654.
179. New York City Department of Health and Mental Hygiene. NYC DOHMH Pandemic Influenza Preparedness and Response Plan. Available at https://www1.nyc.gov/assets/em/downloads/pdf/hazard_mitigation/nycs_risk_landscape_chapter_4.9_pandemic_flu.pdf. Last accessed October 13, 2016.
181. Centers for Disease Control and Prevention. Influenza A (H3N2) Variant Virus. Available at http://www.cdc.gov/flu/swineflu/h3n2v-cases.htm. Last accessed October 13, 2016.
182. Centers for Disease Control and Prevention. Frequently Asked Flu Questions 2016–2017 Influenza Season. Available at http://www.cdc.gov/flu/about/season/flu-season-2016-2017.htm. Last accessed October 13, 2016.
183. National Center for Health Statistics. Influenza. Available at http://www.cdc.gov/nchs/fastats/flu.htm. Last accessed October 13, 2016.
184. Centers for Disease Control and Prevention. Flu Vaccination Coverage, United States, 2015–2016 Influenza Season. Available at http://www.cdc.gov/flu/fluvaxview/coverage-1516estimates.htm. Last accessed October 13, 2016.
185. Centers for Disease Control and Prevention. Flublok Seasonal Influenza (Flu) Vaccine. Available at http://www.cdc.gov/flu/protect/vaccine/qa_flublok-vaccine.htm. Last accessed October 13, 2016.
1. National Center for Immunization and Respiratory Diseases. General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011;60(2):1-64. Summary retrieved from the National Guideline Clearinghouse at https://guideline.gov/summaries/summary/25633. Last accessed October 25, 2016.
2. Nordin J, Anderson R, Anderson R, et al. Immunizations. Bloomington, MN: Institute for Clinical Systems Improvement; 2012. Summary retrieved from the National Guideline Clearinghouse at https://guideline.gov/summaries/summary/36813. Last accessed October 25, 2016.
3. Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza: recommendations of the Advisory Committee on Immunization Practices. MMWR Surveill Summ. 2011;60(1):1-24. Summary retrieved from the National Guideline Clearinghouse at https://guideline.gov/summaries/summary/25627. Last accessed October 25, 2016.
Mention of commercial products does not indicate endorsement.