By Paul A. Granato, Ph.D.
Influenza is a seasonal viral respiratory disease that has likely caused human infections since antiquity. The first major documented outbreak of influenza was in 1918 and caused pandemic disease resulting in an estimated 50 million deaths worldwide. Since that time, there have been periodic epidemics, the most recent being the outbreak of the “swine” flu in 2009. Given the severity of disease and the high incidence of influenza that the United States is currently experiencing, the purpose of this article is to provide a brief overview of the last century of influenza disease, the viruses responsible for infection, and public health measures to prevent or at least minimize the severity of the disease.
The Spanish Flu – 1918
A century ago, a third of the world’s population, or around 500 million people, came down with a disease that was dubbed the Spanish flu. The disease got its name when the king of Spain, Alfonso XIII, his prime minister, and several cabinet members came down with the disease. Worldwide, at least 50 million and perhaps as many as 100 million people died from the disease with more than two thirds of them dying in a single 10-week period in the autumn of 1918. In the United States, 675,000 people died in about a year, which is the same number of individuals who died from AIDS over the last four decades.
The first confirmed case of flu in the 1918 outbreak occurred in a mess cook stationed at an Army training facility in Kansas. The military camp, with its crowded conditions and over 100,000 troops in transit, served as a “perfect storm” for the transmission of disease. These soldiers were then shipped to Europe to fight WWI where the infection was transmitted throughout Europe and subsequently around the world, producing the resultant global pandemic. By the end of 1918, flu had killed at least 57,000 American soldiers – 4,000 more than those killed in combat.
It is of interest that influenza was first mistakenly thought to be caused by a bacterium, Haemophilus influenzae, an opportunistic organism that commonly accompanies influenza infections. It was not until 1931 that Dr. Ernest Goodpasture, an American pathologist, discovered that influenza was actually caused by a virus. From that initial Spanish flu outbreak of mistaken identity, the influenza virus got its name.
Other Flu Epidemics
Since the 1918 flu pandemic, periodic outbreaks of influenza A disease have been documented throughout the world. Some of the notable U.S. outbreaks occurred in 1976 and 1988 and, most recently, the swine flu outbreak in 2009. All of these outbreaks were caused by influenza A H1N1. Worldwide influenza A outbreaks have also been documented. Some of the more notable outbreaks have originated in Hong Kong (1968, influenza A H3N2), in the Philippines (2007, influenza A H1N1), in Northern Ireland (2009, influenza A H1N1), in Nepal (2015, influenza A H1N1), and in India (2015 and 2017, influenza A H1N1). During the current 2017 to 2018 flu outbreak, most of the infections occurring in the U.S. are caused by influenza A H3N2.
There are four types of influenza viruses: type A, type B, type C, and type D. Influenza D viruses primarily infect cattle and are not known to cause infections in humans while influenza C can cause infections in both humans and pigs. However, infections in humans are generally mild and rarely diagnosed or documented.
Influenza A viruses are of the greatest significance to public health because of their potential to cause epidemic and pandemic outbreaks. The influenza A viruses are classified into subtypes according to the combinations of two major virus surface glycoproteins, called hemagglutinin (HA) and neuraminidase (NA). To date, there are at least 18 different hemagglutinin subtypes and 11 different neuraminidase subtypes. Depending on the host origin, influenza A viruses can be classified as avian influenza, swine influenza, or other types of animal influenza viruses. Some examples include avian influenza or “bird flu” virus subtypes A H5N1 and A H9N2, or swine influenza or “swine flu” virus subtypes A H1N1 and A H3N2.
Influenza B viruses circulate among humans and can cause seasonal epidemics. Some studies have shown that seals can also be infected by influenza B virus.
Epidemiology and Transmission
Influenza causes seasonal epidemics in geographical areas with temperate climates but, in tropical climates, seasonality is less apparent with influenza infections occurring throughout the year. In temperate regions of the United States, epidemics generally occur between December and April. The year 2017 has been unusual for influenza because, according to Laboratory Alliance’s Microbiology Department, which began documenting influenza infections in September, the numbers are significantly increasing with each succeeding month. Concerns exist that the influenza epidemic has yet to peak. As of mid-February, at least 84 pediatric deaths alone have already been documented in the U.S. Sadly, this number will likely increase with each passing day until the flu season “runs its course” and finally ends.
According to the World Health Organization, in a typical year, seasonal influenza epidemics cause three to five million severe cases and 300,000 to 500,000 deaths globally each year. In the U.S., influenza accounts for 140,000 to 710,000 influenza-related hospitalizations and 12,000 to 56,000 deaths each year with the highest burden of disease occurring in the very young, the very old, and individuals with coexisting underlying medical conditions.
Influenza viruses are transmitted from person to person primarily via droplets generated by sneezing, coughing, and speaking. Direct and indirect contact with inanimate objects contaminated with secretions and small particle aerosols are other potential routes of transmission. Following exposure to influenza, the typical incubation period before the development of symptomatic disease is one to four days, but may be as long as two weeks. Influenza A and B virus infections spread rapidly through the community with clinical attack rates as high as 70% following a common source exposure in an enclosed space.
Symptoms of Disease
Influenza A and B virus infections typically cause a febrile respiratory illness characterized by fever, cough, upper respiratory tract symptoms including sore throat, runny nose, and nasal congestion. Systemic symptoms of headache, muscle aches, and malaise may also be present. During the Spanish flu outbreak, the disease was often called the “grippe.” The fever generally lasts three to five days, but the symptoms of dry cough and malaise may persist for several or more weeks. Complications may include otitis media in children, sinusitis, lower respiratory infection with secondary bacterial pneumonia, exacerbation of underlying cardiac or pulmonary disease, myositis, and neurologic complications of seizures, acute encephalitis, and death. In contrast, influenza C viruses cause very mild respiratory illnesses that are indistinguishable from the common cold, which is one reason they are rarely diagnosed.
Early diagnosis of infection is important for the prompt administration of an appropriate antiviral agent. Many clinical microbiology laboratories, such as Laboratory Alliance of Central New York, offer a molecular gene amplification (PCR) assay that can establish the laboratory diagnosis of influenza infection within 60 minutes of specimen receipt. This laboratory service is offered by Laboratory Alliance’s three hospital Rapid Response Laboratories, as well as Laboratory Alliance’s Operations Center. The service is available 24 hours per day, seven days per week.
A few antiviral agents, such as Tamiflu (Oseltamivir) and Relenza (Zanamivir), are available for the treatment of influenza. These antiviral agents, however, do not cure the disease but minimize the severity of symptoms and reduce the period of viral shedding.
Vaccination is the most effective way to prevent influenza infection. Even though vaccines are not always effective in preventing disease, the immunity that develops following vaccination can minimize the symptoms of infection and the serious life-threatening complications that can result.
A factor that can alter vaccine effectiveness is the manner in which they are manufactured. In the United States, most influenza-vaccine viruses are propagated in eggs. During this egg-based production process, the vaccine virus may undergo changes in the HA glycoprotein that facilitates replication in eggs. Since the influenza HA glycoprotein is the primary target for the neutralizing humoral antibodies that are produced following vaccination and are necessary to prevent infection, small modifications in the HA glycoprotein can cause minor changes in the virus which may decrease vaccine effectiveness. Because of this, efforts are currently underway to develop a universal vaccine which will offer protection against the majority of influenza viruses by inactivating the virus by influenza-specific T-cells instead of humoral antibodies. The universal influenza vaccine is not yet commercially available.
Other useful personal protective measures include: frequent washing of hands with soap and water or with alcohol-based hand sanitizers; good respiratory hygiene (covering one’s mouth and nose when coughing or sneezing); imposing self-isolation by staying home when feeling unwell, feverish, and having symptoms of the flu; avoiding close contact with influenza infected people; and, avoiding touching one’s eyes, nose or mouth as such contact may facilitate virus entry into the body resulting in infection.
Despite the best efforts of public health officials to combat influenza and to develop effective vaccines, it is likely that the influenza viruses will continue to cause disease each year for the foreseeable future. In some years, the vaccines available may be less effective because the influenza A virus has the unique ability to undergo spontaneous re-assortment of its H and N surface glycoproteins. When this happens, as has been the case this year, the vaccines may offer only partial immunity against infection. Despite this, individuals must be encouraged to receive the vaccine because partial immunity is better than none at all.
Perhaps, our yearly battle with influenza can best be summarized by the words spoken by Nobel Laureate, Dr. Joshua Lederberg, as he was discussing the AIDS epidemic in the early 1990s, “The 1990s have been marked by a renewed recognition that our human species is still locked in a Darwinian struggle with our microbial and viral predators.”
Paul A. Granato, PhD, DABMM, is director of microbiology / scientific director, clinical microbiology at Laboratory Alliance of Central New York.
Granato has served as the chief of microbiology at the Syracuse Veterans Affairs Medical Center, clinical microbiologist at Crouse Hospital, and consultant clinical microbiologist for the Onondaga County Department of Health and Centrex Clinical Laboratories.
He was on the faculty at SUNY Upstate Medical University for more than 35 years and is currently professor emeritus in the Department of Pathology. Granato has also served on two microbiology editorial boards and many national committees. He has authored three textbooks and over 100 book chapters, scientific articles and abstracts. He serves as the director of microbiology for Laboratory Alliance, is a Diplomate of the American Board of Medical Microbiology and is an elected Fellow by the American Academy of Microbiology.
Granato graduated from Le Moyne College, earned his doctoral degree in microbiology and molecular biology from Syracuse University, and completed a post-doctoral fellowship in clinical microbiology and infectious diseases at Columbia University, College of Physicians and Surgeons in New York City.