Epidemics, Pandemics, and Outbreaks
I have written several articles on the coronavirus and on masks and healthcare issues. A series of links have been provided at the bottom of this article for your convenience. This article will, however address a different aspect of the virus or on healthcare issues in general.
You probably know that COVID-19, the illness caused by the new coronavirus SARS-CoV-2, is a pandemic. But what’s the difference between a pandemic, an epidemic, and an outbreak? And when does a disease become a public health concern? Here are the basics of the spread of serious diseases and what you can do to protect yourself, your family, and your community.
Let’s start with the meanings of each word.
An outbreak is when an illness happens in unexpected high numbers. It may stay in one area or extend more widely. An outbreak can last days or years. Sometimes, experts consider a single case of a contagious disease to be an outbreak. This may be true if it’s an unknown disease, if it’s new to a community, or if it’s been absent from a population for a long time.
An epidemic is when an infectious disease spreads quickly to more people than experts would expect. It usually affects a larger area than an outbreak.
A pandemic is a disease outbreak that spreads across countries or continents. It affects more people and takes more lives than an epidemic. The World Health Organization (WHO) declared COVID-19 to be a pandemic when it became clear that the illness was severe and that it was spreading quickly over a wide area.
The number of lives lost in a pandemic depends on:
- How many people are infected
- How severe of an illness the virus causes (its virulence)
- How vulnerable certain groups of people are
- Prevention efforts and how effective they are
The WHO’s pandemic alert system ranges from Phase 1 (a low risk) to Phase 6 (a full pandemic):
- Phase 1: A virus in animals has caused no known infections in humans.
- Phase 2: An animal virus has caused infection in humans.
- Phase 3: There are scattered cases or small clusters of disease in humans. If the illness is spreading from human to human, it’s not broad enough to cause community-level outbreaks.
- Phase 4: The disease is spreading from person to person with confirmed outbreaks at the community level.
- Phase 5: The disease is spreading between humans in more than one country of one of the WHO regions.
- Phase 6: At least one more country, in a different region from Phase 5, has community-level outbreaks.
Prevention: Slowing the Spread of Pandemic Disease
There’s no sure way to prevent the spread of disease during an outbreak, epidemic, or pandemic. It might take scientists a long time to make a vaccine. But it’s easier to make specific vaccines more quickly now than it was several years ago. Once a vaccine is ready, people and groups who are more likely to become ill will get it first.
In the meantime, you can take other steps to stay healthy:
- Wash your hands often with soap and water. If that’s not an option, use an alcohol-based hand cleaner or gel sanitizer. Rub it on your hands until they’re dry.
- Don’t touch your mouth, nose, and eyes unless you’ve just washed your hands.
- When you cough or sneeze, cover your mouth and nose with a tissue. Then throw the tissue in the trash. Wash your hands afterward.
- Avoid crowded places. Stay home if you can.
- Clean and disinfect household surfaces every day.
If you get sick:
- Stay home and away from other people. If you want to talk to your doctor, call before you go to their office. But if you have severe symptoms like trouble breathing, call 911 or go to an emergency room right away.
- Wear a face mask if you have to go out for medical care. Avoid public transportation, ride-hailing, and taxis.
- Have only one person care for you, if possible.
- Wash your hands often, and keep household surfaces clean and disinfected.
A pandemic causes economic and social problems because so many people are ill or can’t work.
Here are a few things you can do to help your family and your community before and during a pandemic:
- Make an emergency contact list.
- Find local aid organizations in case you need information, support, or health services.
- Find out whether you can work from home.
- Plan home learning activities in case school is closed.
- Store extra water, food, medicine, and supplies.
- Stay as healthy as you can by getting rest, managing stress, eating right, and exercising.
- Help seniors and neighbors by sharing information and resources.
For more information on what to do in a pandemic, call the CDC Hotline at 800-CDC-INFO (800-232-4636) or go to http://www.cdc.gov.
Many diseases are so common that we barely think about them. You might hear experts use one of these terms to describe them:
- Sporadic means cases are rare and happen unevenly.
- Endemic means a disease is constant and happens about as often as expected.
- Hyperendemic means an illness is constant but people are getting sick at a higher rate.
Cases can also come in a cluster, a group of illnesses in a certain place and time.
Notable Past Pandemics
The list of the deadliest pandemics in world history includes:
- The Black Death. Experts think the plague, sparked by bacteria called Yersinia pestis, is to blame for the illness that tore through Europe in 1347-51. An estimated 25 million people died.
- The influenza pandemic of 1918. At least 50 million people around the world died of flu during the outbreak of 1918-19. It’s often called the “Spanish flu,” not because the virus started there but because Spain was one of the first countries to announce cases.
- Smallpox. The smallpox pandemic stretched over hundreds of years. Experts estimate that it killed as many as 300 million people in the 20th century alone. Thanks to widespread vaccine use, it was declared eradicated in 1980.
- HIV and AIDS. The human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS), and related illnesses have killed about 32 million people around the world.
Flu also killed millions of people worldwide in other pandemics:
- 1957 (1.1 million)
- 1968 (1 million)
- 2009 (up to 575,000)
Prevention and Treatment of Viral Infections
Viruses cause a variety of diseases in animals, including humans, ranging from the common cold to potentially fatal illnesses like meningitis (Figure 1). These diseases can be treated by antiviral drugs or by vaccines; however, some viruses, such as HIV, are capable both of avoiding the immune response and of mutating within the host organism to become resistant to antiviral drugs.
Vaccines for Prevention
The primary method of controlling viral disease is by vaccination, which is intended to prevent outbreaks by building immunity to a virus or virus family (Figure 2). Vaccines may be prepared using live viruses, killed viruses, or molecular subunits of the virus. Note that the killed viral vaccines and subunit viruses are both incapable of causing disease, nor is there any valid evidence that vaccinations contribute to autism.
Live viral vaccines are designed in the laboratory to cause few symptoms in recipients while giving them protective immunity against future infections. Polio was one disease that represented a milestone in the use of vaccines. Mass immunization campaigns in the 1950s (killed vaccine) and 1960s (live vaccine) significantly reduced the incidence of the disease, which caused muscle paralysis in children and generated a great amount of fear in the general population when regional epidemics occurred. The success of the polio vaccine paved the way for the routine dispensation of childhood vaccines against measles, mumps, rubella, chickenpox, and other diseases.
The issue with using live vaccines (which are usually more effective than killed vaccines), is the low but significant danger that these viruses will revert to their disease-causing form by back mutations. Live vaccines are usually made by attenuating (weakening) the “wild-type” (disease-causing) virus by growing it in the laboratory in tissues or at temperatures different from what the virus is accustomed to in the host. Adaptations to these new cells or temperatures induce mutations in the genomes of the virus, allowing it to grow better in the laboratory while inhibiting its ability to cause disease when reintroduced into conditions found in the host. These attenuated viruses thus still cause infection, but they do not grow very well, allowing the immune response to develop in time to prevent major disease. Back mutations occur when the vaccine undergoes mutations in the host such that it readapts to the host and can again cause disease, which can then be spread to other humans in an epidemic. This type of scenario happened as recently as 2007 in Nigeria where mutations in a polio vaccine led to an epidemic of polio in that country.
Some vaccines are in continuous development because certain viruses, such as influenza and HIV, have a high mutation rate compared to that of other viruses and normal host cells. With influenza, mutations in the surface molecules of the virus help the organism evade the protective immunity that may have been obtained in a previous influenza season, making it necessary for individuals to get vaccinated every year. Other viruses, such as those that cause the childhood diseases measles, mumps, and rubella, mutate so infrequently that the same vaccine is used year after year.
Vaccines and Antiviral Drugs for Treatment
In some cases, vaccines can be used to treat an active viral infection. The concept behind this is that by giving the vaccine, immunity is boosted without adding more disease-causing virus. In the case of rabies, a fatal neurological disease transmitted via the saliva of rabies virus-infected animals, the progression of the disease from the time of the animal bite to the time it enters the central nervous system may be two weeks or longer. This is enough time to vaccinate individuals who suspect that they have been bitten by a rabid animal, and their boosted immune response is sufficient to prevent the virus from entering nervous tissue. Thus, the potentially fatal neurological consequences of the disease are averted, and the individual only has to recover from the infected bite. This approach is also being used for the treatment of Ebola, one of the fastest and most deadly viruses on Earth. Transmitted by bats and great apes, this disease can cause death in 70 to 90 percent of infected humans within two weeks. Using newly developed vaccines that boost the immune response in this way, there is hope that affected individuals will be better able to control the virus, potentially saving a greater percentage of infected persons from a rapid and very painful death.
Another way of treating viral infections is the use of antiviral drugs. Because viruses use the resources of the host cell for replication and the production of new virus proteins, it is difficult to block their activities without damaging the host. However, we do have some effective antiviral drugs, such as those used to treat HIV and influenza. Some antiviral drugs are specific for a particular virus and others have been used to control and reduce symptoms for a wide variety of viral diseases. For most viruses, these drugs can inhibit the virus by blocking the actions of one or more of its proteins. It is important to note that the targeted proteins be encoded by viral genes and that these molecules are not present in a healthy host cell. In this way, viral growth is inhibited without damaging the host.
Antivirals have been developed to treat genital herpes (herpes simplex II) and influenza. For genital herpes, drugs such as acyclovir can reduce the number and duration of episodes of active viral disease, during which patients develop viral lesions in their skin cells. As the virus remains latent in nervous tissue of the body for life, this drug is not curative but can make the symptoms of the disease more manageable. For influenza, drugs like Tamiflu (oseltamivir) (Figure 3) can reduce the duration of “flu” symptoms by one or two days, but the drug does not prevent symptoms entirely. Tamiflu works by inhibiting an enzyme (viral neuraminidase) that allows new virions to leave their infected cells. Thus, Tamiflu inhibits the spread of virus from infected to uninfected cells. Other antiviral drugs, such as Ribavirin, have been used to treat a variety of viral infections, although its mechanism of action against certain viruses remains unclear.
By far, the most successful use of antivirals has been in the treatment of the retrovirus HIV, which causes a disease that, if untreated, is usually fatal within 10 to 12 years after infection. Anti-HIV drugs have been able to control viral replication to the point that individuals receiving these drugs survive for a significantly longer time than the untreated.
Anti-HIV drugs inhibit viral replication at many different phases of the HIV replicative cycle (Figure 4). Drugs have been developed that inhibit the fusion of the HIV viral envelope with the plasma membrane of the host cell (fusion inhibitors), the conversion of its RNA genome into double-stranded DNA (reverse transcriptase inhibitors, like AZT), the integration of the viral DNA into the host genome (integrase inhibitors), and the processing of viral proteins (protease inhibitors).
Unfortunately, when any of these drugs are used individually, the high mutation rate of the virus allows it to easily and rapidly develop resistance to the drug, limiting the drug’s effectiveness. The breakthrough in the treatment of HIV was the development of HAART, highly active anti-retroviral therapy, which involves a mixture of different drugs, sometimes called a drug “cocktail.” By attacking the virus at different stages of its replicative cycle, it is much more difficult for the virus to develop resistance to multiple drugs at the same time. Still, even with the use of combination HAART therapy, there is concern that, over time, the virus will develop resistance to this therapy. Thus, new anti-HIV drugs are constantly being developed with the hope of continuing the battle against this highly fatal virus.
The study of viruses has led to the development of a variety of new ways to treat non-viral diseases. Viruses have been used in gene therapy. Gene therapy is used to treat genetic diseases such as severe combined immunodeficiency (SCID), a heritable, recessive disease in which children are born with severely compromised immune systems. One common type of SCID is due to the lack of an enzyme, adenosine deaminase (ADA), which breaks down purine bases. To treat this disease by gene therapy, bone marrow cells are taken from a SCID patient and the ADA gene is inserted. This is where viruses come in, and their use relies on their ability to penetrate living cells and bring genes in with them. Viruses such as adenovirus, an upper-respiratory human virus, are modified by the addition of the ADA gene, and the virus then transports this gene into the cell. The modified cells, now capable of making ADA, are then given back to the patients in the hope of curing them. Gene therapy using viruses as carriers of genes (viral vectors), although still experimental, holds promise for the treatment of many genetic diseases. Still, many technological problems need to be solved for this approach to be a viable method for treating genetic disease.
Another medical use for viruses relies on their specificity and ability to kill the cells they infect. Oncolytic viruses are engineered in the laboratory specifically to attack and kill cancer cells. A genetically modified adenovirus known as H101 has been used since 2005 in clinical trials in China to treat head and neck cancers. The results have been promising, with a greater short-term response rate to the combination of chemotherapy and viral therapy than to chemotherapy treatment alone. This ongoing research may herald the beginning of a new age of cancer therapy, where viruses are engineered to find and specifically kill cancer cells, regardless of where in the body they may have spread.
A third use of viruses in medicine relies on their specificity and involves using bacteriophages in the treatment of bacterial infections. Bacterial diseases have been treated with antibiotics since the 1940s. However, over time, many bacteria have evolved resistance to antibiotics. A good example is methicillin-resistant Staphylococcus aureus (MRSA, pronounced “mersa”), an infection commonly acquired in hospitals. This bacterium is resistant to a variety of antibiotics, making it difficult to treat. The use of bacteriophages specific for such bacteria would bypass their resistance to antibiotics and specifically kill them. Although phage therapy is in use in the Republic of Georgia to treat antibiotic-resistant bacteria, its use to treat human diseases has not been approved in most countries. However, the safety of the treatment was confirmed in the United States when the U.S. Food and Drug Administration approved spraying meats with bacteriophages to destroy the food pathogen Listeria. As more and more antibiotic-resistant strains of bacteria evolve, the use of bacteriophages might be a potential solution to the problem, and the development of phage therapy is of much interest to researchers worldwide.
Pathogenesis is the process by which an infection leads to disease. Pathogenic mechanisms of viral disease include (1) implantation of virus at the portal of entry, (2) local replication, (3) spread to target organs (disease sites), and (4) spread to sites of shedding of virus into the environment. Factors that affect pathogenic mechanisms are (1) accessibility of virus to tissue, (2) cell susceptibility to virus multiplication, and (3) virus susceptibility to host defenses. Natural selection favors the dominance of low-virulence virus strains.
Direct cell damage and death from viral infection may result from (1) diversion of the cell’s energy, (2) shutoff of cell macromolecular synthesis, (3) competition of viral mRNA for cellular ribosomes, (4) competition of viral promoters and transcriptional enhancers for cellular transcriptional factors such as RNA polymerases, and inhibition of the interferon defense mechanisms. Indirect cell damage can result from integration of the viral genome, induction of mutations in the host genome, inflammation, and the host immune response.
Viral affinity for specific body tissues (tropism) is determined by (1) cell receptors for virus, (2) cell transcription factors that recognize viral promoters and enhancer sequences, (3) ability of the cell to support virus replication, (4) physical barriers, (5) local temperature, pH, and oxygen tension enzymes and non-specific factors in body secretions, and (6) digestive enzymes and bile in the gastrointestinal tract that may inactivate some viruses.
Implantation at the Portal of Entry
Virions implant onto living cells mainly via the respiratory, gastrointestinal, skin-penetrating, and genital routes although other routes can be used. The final outcome of infection may be determined by the dose and location of the virus as well as its infectivity and virulence.
Local Replication and Local Spread
Most virus types spread among cells extracellularly, but some may also spread intracellularly. Establishment of local infection may lead to localized disease and localized shedding of virus.
Dissemination from the Portal of Entry
Viremic: The most common route of systemic spread from the portal of entry is the circulation, which the virus reaches via the lymphatics. Virus may enter the target organs from the capillaries by (1) multiplying in endothelial cells or fixed macrophages, (2) diffusing through gaps, and (3) being carried in a migrating leukocyte.
Neural: Dissemination via nerves usually occurs with rabies virus and sometimes with herpesvirus and poliovirus infections.
The incubation period is the time between exposure to virus and onset of disease. During this usually asymptomatic period, implantation, local multiplication, and spread (for disseminated infections) occur.
Multiplication in Target Organs
Depending on the balance between virus and host defenses, virus multiplication in the target organ may be sufficient to cause disease and death.
Shedding of Virus
Although the respiratory tract, alimentary tract, urogenital tract and blood are the most frequent sites of shedding, diverse viruses may be shed at virtually every site.
Infection of the fetus as a target “organ” is special because the virus must traverse additional physical barriers, the early fetal immune and interferon defense systems may be immature, transfer of the maternal defenses are partially blocked by the placenta, the developing first-trimester fetal organs are vulnerable to infection, and hormonal changes are taking place.Go to:
Pathogenesis is the process by which virus infection leads to disease. Pathogenic mechanisms include implantation of the virus at a body site (the portal of entry), replication at that site, and then spread to and multiplication within sites (target organs) where disease or shedding of virus into the environment occurs. Most viral infections are subclinical, suggesting that body defenses against viruses arrest most infections before disease symptoms become manifest. Knowledge of subclinical infections comes from serologic studies showing that sizeable portions of the population have specific antibodies to viruses even though the individuals have no history of disease. These inapparent infections have great epidemiologic importance: they constitute major sources for dissemination of virus through the population, and they confer immunity (see Ch. 48).
Many factors affect pathogenic mechanisms. An early determinant is the extent to which body tissues and organs are accessible to the virus. Accessibility is influenced by physical barriers (such as mucus and tissue barriers), by the distance to be traversed within the body, and by natural defense mechanisms. If the virus reaches an organ, infection occurs only if cells capable of supporting virus replication are present. Cellular susceptibility requires a cell surface attachment site (receptor) for the virions and also an intracellular environment that permits virus replication and release. Even if virus initiates infection in a susceptible organ, replication of sufficient virus to cause disease may be prevented by host defenses (see Chs. 49 and 50).
Other factors that determine whether infection and disease occur are the many virulence characteristics of the infecting virus. To cause disease, the infecting virus must be able to overcome the inhibitory effects of physical barriers, distance, host defenses, and differing cellular susceptibilities to infection. The inhibitory effects are genetically controlled and therefore may vary among individuals and races. Virulence characteristics enable the virus to initiate infection, spread in the body, and replicate to large enough numbers to impair the target organ. These factors include the ability to replicate under certain circumstances during inflammation, during the febrile response, in migratory cells, and in the presence of natural body inhibitors and interferon. Extremely virulent strains often occur within virus populations. Occasionally, these strains become dominant as a result of unusual selective pressures (see Ch. 48). The viral proteins and genes responsible for specific virulence functions are only just beginning to be identified.
Fortunately for the survival of humans and animals (and hence for the infecting virus), most natural selective pressures favor the dominance of less virulent strains. Because these strains do not cause severe disease or death, their replication and transmission are not impaired by an incapacitated host. Mild or inapparent infections can result from absence of one or more virulence factors. For example, a virus that has all the virulence characteristics except the ability to multiply at elevated temperatures is arrested at the febrile stage of infection and causes a milder disease than its totally virulent counterpart. Live virus vaccines are composed of viruses deficient in one or more virulence factors; they cause only inapparent infections and yet are able to replicate sufficiently to induce immunity.
The occurrence of spontaneous or induced mutations in viral genetic material may alter the pathogenesis of the induced disease, e.g. HIV. These mutations can be of particular importance with the development of drug resistant strains of virus.
Disease does not always follow successful virus replication in the target organ. Disease occurs only if the virus replicates sufficiently to damage essential cells directly, to cause the release of toxic substances from infected tissues, to damage cellular genes or to damage organ function indirectly as a result of the host immune response to the presence of virus antigens.
As a group, viruses use all conceivable portals of entry, mechanisms of spread, target organs, and sites of excretion. This abundance of possibilities is not surprising considering the astronomic numbers of viruses and their variants (see Ch. 43).Go to:
Direct cell damage and death may result from disruption of cellular macromolecular synthesis by the infecting virus. Also, viruses cannot synthesize their genetic and structural components, and so they rely almost exclusively on the host cell for these functions. Their parasitic replication therefore robs the host cell of energy and macromolecular components, severely impairing the host’s ability to function and often resulting in cell death and disease.
Pathogenesis at the cellular level can be viewed as a process that occurs in progressive stages leading to cellular disease. As noted above, an essential aspect of viral pathogenesis at the cellular level is the competition between the synthetic needs of the virus and those of the host cell. Since viruses must use the cell’s machinery to synthesize their own nucleic acids and proteins, they have evolved various mechanisms to subvert the cell’s normal functions to those required for production of viral macromolecules and eventually viral progeny. The function of some of the viral genetic elements associated with virulence may be related to providing conditions in which the synthetic needs of the virus compete effectively for a limited supply of cellular macromolecule components and synthetic machinery, such as ribosomes.
Most viruses have an affinity for specific tissues; that is, they display tissue specificity or tropism. This specificity is determined by selective susceptibility of cells, physical barriers, local temperature and pH, and host defenses. Many examples of viral tissue tropism are known. Polioviruses selectively infect and destroy certain nerve cells, which have a higher concentration of surface receptors for polioviruses than do virus-resistant cells. Rhinoviruses multiply exclusively in the upper respiratory tract because they are adapted to multiply best at low temperature and pH and high oxygen tension. Enteroviruses can multiply in the intestine, partly because they resist inactivation by digestive enzymes, bile, and acid. The cell receptors for some viruses have been identified. Rabies virus uses the acetylcholine receptor present on neurons as a receptor, and hepatitis B virus binds to polymerized albumin receptors found on liver cells. Similarly, Epstein-Barr virus uses complement CD21 receptors on B lymphocytes, and human immunodeficiency virus uses the CD4 molecules present on T lymphocytes as specific receptors.
Viral tropism is also dictated in part by the presence of specific cell transcription factors that require enhancer sequences within the viral genome. Recently, enhancer sequences have been shown to participate in the pathogenesis of certain viral infections. Enhancer sequences within the long terminal repeat (LTR) regions of Moloney murine leukemia retrovirus are active in certain host tissues. In addition, JV papovavirus appears to have an enhancer sequence that is active specifically in oligodendroglia cells, and hepatitis B virus enhancer activity is most active in hepatocytes.
Sequence of Virus Spread in the Host
Implantation at Portal of Entry
Viruses are carried to the body by all possible routes (air, food, bites, and any contaminated object). Similarly, all possible sites of implantation (all body surfaces and internal sites reached by mechanical penetration) may be used. The frequency of implantation is greatest where virus contacts living cells directly (in the respiratory tract, in the alimentary tract, in the genital tract, and subcutaneously). With some viruses, implantation in the fetus may occur at the time of fertilization through infected germ cells, as well as later in gestation via the placenta, or at birth.
Even at the earliest stage of pathogenesis (implantation), certain variables may influence the final outcome of the infection. For example, the dose, infectivity, and virulence of virus implanted and the location of implantation may determine whether the infection will be inapparent (subclinical) or will cause mild, severe, or lethal disease.
Local Replication and Local Spread
Successful implantation may be followed by local replication and local spread of virus (Fig. 45-1). Virus that replicates within the initially infected cell may spread to adjacent cells extracellularly or intracellularly. Extracellular spread occurs by release of virus into the extracellular fluid and subsequent infection of the adjacent cell. Intracellular spread occurs by fusion of infected cells with adjacent, uninfected cells or by way of cytoplasmic bridges between cells. Most viruses spread extracellularly, but herpesviruses, paramyxoviruses, and poxviruses may spread through both intracellular and extra cellular routes. Intracellular spread provides virus with a partially protected environment because the antibody defense does not penetrate cell membranes.
Spread to cells beyond adjacent cells may occur through the liquid spaces within the local site (e.g., lymphatics) or by diffusion through surface fluids such as the mucous layer of the respiratory tract. Also, infected migratory cells such as lymphocytes and macrophages may spread the virus within local tissue.
Establishment of infection at the portal of entry may be followed by continued local virus multiplication, leading to localized virus shedding and localized disease. In this way, local sites of implantation also are target organs and sites of shedding in many infections (Table 45-1). Respiratory tract infections that fall into this category include influenza, the common cold, and parainfluenza virus infections. Alimentary tract infections caused by several gastroenteritis viruses (e.g., rotaviruses and picornaviruses) also may fall into this category. Localized skin infections of this type include warts, cowpox, and molluscum contagiosum. Localized infections may spread over body surfaces to infect distant surfaces. An example of this is the picornavirus epidemic conjunctivitis shown in Figure 45-2; in the absence of viremia, virus spreads directly from the eye (site of implantation) to the pharynx and intestine. Other viruses may spread internally to distant target organs and sites of excretion (disseminated infection). A third category of viruses may cause both local and disseminated disease, as in herpes simplex and measles.
Dissemination from the Portal of Entry
Dissemination in the Bloodstream
At the portal of entry, multiplying virus contacts pathways to the blood and peripheral nerves, the principal routes of widespread dissemination through the body. The most common route of systemic spread of virus involves the circulation (Fig. 45-3 and Table 45-2). Viruses such as those causing poliomyelitis, smallpox, and measles disseminate through the blood after an initial period of replication at the portal of entry (the alimentary and respiratory tracts), where the infection often causes no significant symptoms or signs of illness because the virus kills cells that are expendable and easily replaced. Virus progeny diffuse through the afferent lymphatics to the lymphoid tissue and then through the efferent lymphatics to infect cells in close contact with the bloodstream (e.g., endothelial cells, especially those of the lymphoreticular organs). This initial spread may result in a brief primary viremia. Subsequent release of virus directly into the bloodstream induces a secondary viremia, which usually lasts several days and puts the virus in contact with the capillary system of all body tissues. Virus may enter the target organ from the capillaries by replicating within a capillary endothelial cell or fixed macrophage and then being released on the target organ side of the capillary. Virus may also diffuse through small gaps in the capillary endothelium or penetrate the capillary wall through an infected, migrating leukocyte. The virus may then replicate and spread within the target organ or site of excretion by the same mechanisms as for local dissemination at the portal of entry. Disease occurs if the virus replicates in a sufficient number of essential cells and destroys them. For example, in poliomyelitis the central nervous system is the target organ, whereas the alimentary tract is both the portal of entry and the site of shedding. In some situations, the target organ and site of shedding may be the same.
Dissemination in Nerves
Dissemination through the nerves is less common than bloodstream dissemination, but is the means of spread in a number of important diseases (Fig. 45-4). This mechanism occurs in rabies virus, herpesvirus, and, occasionally, poliomyelitis virus infections. For example, rabies virus implanted by a bite from a rabid animal replicates subcutaneously and within muscular tissue to reach nerve endings. Evidence indicates that the virus spreads centrally in the neurites (axons and dendrites) and perineural cells, where virus is shielded from antibody. This nerve route leads rabies virus to the central nervous system, where disease originates. Rabies virus then spreads centrifugally through the nerves to reach the salivary glands, the site of shedding. Table 45-2 shows other examples of nerve spread.
During most virus infections, no signs or symptoms of disease occur through the stage of virus dissemination. Thus, the incubation period (the time between exposure to virus and onset of disease) extends from the time of implantation through the phase of dissemination, ending when virus replication in the target organs causes disease. Occasionally, mild fever and malaise occur during viremia, but they often are transient and have little diagnostic value.
The incubation period tends to be brief (1 to 3 days) in infections in which virus travels only a short distance to reach the target organ (i.e., in infections in which disease is due to virus replication at the portal of entry). Conversely, incubation periods in generalized infections are longer because of the stepwise fashion by which the virus moves through the body before reaching the target organs. Other factors also may influence the incubation period. Generalized infections produced by togaviruses may have an unexpectedly short incubation period because of direct intravascular injection (insect bite) of a rapidly multiplying virus. The mechanisms governing the long incubation period (months to years) of persistent infections are poorly understood. The persistently infected cell is often not lysed, or lysis is delayed. In addition, disease may result from a late immune reaction to viral antigen (e.g., arenaviruses in rodents), from unknown mechanisms in slow viral infections during which no immune response has been detected (as in the scrapie-kuru group), or mutation in the host genetic material resulting in cellular transformation and cancer.
Multiplication in Target Organs
Virus replication in the target organ resembles replication at other body sites except that (1) the target organ in systemic infections is usually reached late during the stepwise progression of virus through the body, and (2) clinical disease originates there. At each step of virus progression through the body, the local recovery mechanisms (local body defenses, including interferon, local inflammation, and local immunity) are activated. Thus, when the target organ is infected, the previously infected sites may have reached various stages of recovery. Figure 45-2 illustrates this staging of infection and recovery in different tissues during a spreading surface infection. Circulating interferon and immune responses probably account for the termination of viremia, but these responses may be too late to prevent seeding of virus into the target organ and into sites of shedding. Nevertheless, these systemic defenses can diffuse in various degrees into target organs and thereby help retard virus replication and disease.
Depending on the balance between virus and host defenses, virus multiplication in the target organ may be sufficient to produce dysfunction manifested by disease or death. Additional constitutional disease such as fever and malaise may result from diffusion of toxic products of virus replication and cell necrosis, as well as from release of lymphokines and other inflammatory mediators. Release of leukotriene C4 during respiratory infection may cause bronchospasm. Viral antigens also may participate in immune reactions, leading to disease manifestations. In addition, impairment of leukocytes and immunosuppression by some viruses may cause secondary bacterial infection.
Shedding of Virus
Because of the diversity of viruses, virtually every possible site of shedding is utilized (Table 45-2); however, the most frequent sites are the respiratory and alimentary tracts. Blood and lymph are sites of shedding for the arboviruses, since biting insects become infected by this route. HIV is shed in blood and semen. Milk is a site of shedding for viruses such as some RNA tumor viruses (retroviruses) and cytomegalovirus (a herpesvirus). Several viruses (e.g., cytomegaloviruses) are shed simultaneously from the urinary tract and other sites more commonly associated with shedding. The genital tract is a common site of shedding for herpesvirus type 2 and may be the route through which the virus is transmitted to sexual partners or the fetus. Saliva is the primary source of shedding for rabies virus. Cytomegalovirus is also shed from these last two sites. Finally, viruses such as tumor viruses that are integrated into the DNA of host cells can be shed through germ cells.
Infection of the fetus is a special case of infection in a target organ. The factors that determine whether a target organ is infected also apply to the fetus, but the fetus presents additional variables. The immune and interferon systems of the very young fetus are immature. This immaturity, coupled with the partial placental barrier to transfer of maternal immunity and interferon, deprive the very young fetus of important defense mechanisms. Another variable is the high vulnerability to disruption of the rapidly developing fetal organs, especially during the first trimester of pregnancy. Furthermore, susceptibility to virus replication may be modulated by the undifferentiated state of the fetal cells and by hormonal changes during pregnancy. Although virus multiplication in the fetus may lead to congenital anomalies or fetal death, the mother may have only a mild or inapparent infection.
To cause congenital anomalies, virus must reach the fetus and multiply in it, thereby causing maldeveloped organs. Generally, virus reaches the fetus during maternal viremia by infecting or passing through the placenta to the fetal circulation and then to fetal target organs. Sufficient virus multiplication may disrupt development of fetal organs, especially during their rapid development (the first trimester of pregnancy). Although many viruses occasionally cause congenital anomalies, cytomegalovirus and rubella virus are the most common offenders. Virus shedding by the congenitally infected newborn infant may occur as a result of persistence of the virus infection at sites of shedding.
Phases of a Pandemic
Whether it’s COVID-19, swine flu, or smallpox, we hear the word pandemic used in a variety of ways. What does pandemic really mean, and when is the term really warranted?
A pandemic refers to an illness that has spread over several countries or continents, usually affecting a large number of people. It takes into account where it is located and how it is spreading. Most recently, the World Health Organization (WHO) declared COVID-19 a pandemic.
Phases of a Pandemic
The Centers Disease for Disease Control and Prevention (CDC) currently has Pandemic Intervals Framework (PIF) in place for tracking the phases of an influenza pandemic. That framework is being applied to COVID-19.
Phase 1: Investigation Interval
A new type of virus is identified and investigated—in animals or humans anywhere in the world—that is thought to have implications for human health.
Phase 2: Recognition Interval
Increased cases, or clusters of cases, are identified, along with an increased potential for person-to-person transmission.
Phase 3: Initiation Interval
Cases of the virus are confirmed with both efficient and sustained person-to-person transmission.
Phase 4: Acceleration Interval
The new virus infects susceptible people. Public health officials may take measures such as closing schools, encouraging social distancing, and offering antivirals or vaccines—if available.
Phase 5: Deceleration Interval
There is a consistently decreasing rate of cases in the United States.
Phase 6: Preparation Interval
Even after the pandemic has subsided, public health officials continue to monitor the virus and brace for another wave of illness.
The Origin and Prevention of Pandemics
Despite the fact that most emerging diseases stem from the transmission of pathogenic agents from animals to humans, the factors that mediate this process are still ill defined. What is known, however, is that the interface between humans and animals is of paramount importance in the process. This review will discuss the importance of the human-animal interface to the disease emergence process. We also provide an overview of factors that are believed to contribute to the origin and global spread of emerging infectious diseases and offer suggestions that may serve as future prevention strategies, such as social mobilization, public health education, behavioral change, and communication strategies. Because there exists no comprehensive global surveillance system to monitor zoonotic disease emergence, the intervention measures discussed herein may prove effective temporary alternatives.
Contemporary pandemics and outbreaks of disease, such as the current H1N1 influenza pandemic, as well as the emergence of H5N1 influenza virus and severe acute respiratory syndrome (SARS)-associated coronavirus, serve as poignant reminders of our global vulnerability to emergent threats to human health and our current inability to predict or prevent such events. However, despite the seemingly unpredictable nature of disease emergence, there are lessons to be learned from the origins of recently emerged diseases as well as those that have their origins in the more distant past, lessons that may offer clues as to how future infectious disease outbreaks and pandemics may be prevented. The challenge lies in using the accumulated, albeit incomplete, knowledge gained from emergent diseases of our past to identify practical solutions and strategies aimed at detecting and halting future threats.
Here, we review the field’s current understanding of the origins of infectious diseases and the factors that contribute to their emergence. In particular, we highlight the importance of the zoonotic transmission of pathogenic agents from animals to humans, the favored mechanism by which emergent diseases have come to afflict humans throughout history. Indeed, one key lesson from past pandemics is the pivotal importance of the human-animal interface. Improving our understanding of this interface will be crucial to future pandemic prevention efforts.
Zoonotic Disease Emergence
The majority of all human infectious diseases and pandemics have originated through the cross-species transmission of microorganisms from animals to humans, overwhelmingly in the Old World. However, because most animal pathogens are not readily transmitted to humans, it follows that for an animal pathogen to become a specialized pathogen in humans, multiple variables must combine in a dynamic and as yet not fully understood process of cross-species transmission. For an animal pathogen to become a successful human pathogen, it must evolve into a pathogen capable of not only infecting humans, but maintaining long-term human-to-human transmission without the need for reintroduction from the original animal host. This process can be categorized into five progressive stages. Stage 1 involves animal microbes that are not present in humans under natural conditions, such as most malarial plasmodia. When a pathogen evolves such that it can be transmitted to a human under natural conditions but cannot support sustained human-tohuman transmission, it has entered stage 2. Examples of such pathogens include tularemia bacilli, Nipah, rabies, and West Nile viruses. Transition from stage 2 and into stage 3 is defined by secondary transmission between humans. Stage 3 includes pathogens that undergo only a few cycles of secondary transmission between humans, such as Ebola, Marburg, and human monkeypox viruses, whereas stage 4 includes diseases that exist in animals but which undergo long sequences of secondary human-to-human transmission without the involvement of animal hosts, such as influenza A, Vibrio cholerae, and dengue virus. Stage 5, in contrast, represents diseases that are exclusive to humans. Agents responsible for some of history’s most troubling diseases belong to stage 5 and include pathogens such as human immunodeficiency virus (HIV) infection, smallpox, and tuberculosis.
The Human and Animal Interface
The disease emergence model above provides a construct for how pathogens emerge from animals and illustrates the continuum of animal pathogen infectivity in the human population. However, relatively little is known about the factors that mediate transition from one stage to the next as a pathogen of animal origin scales the stages of this paradigm, ever increasing its ability to reside in the human population and be transmitted throughout it. What is known, however, is that the interface between humans and animals is of paramount importance in the process. As we increase our interactions with animals through hunting, the trading of animal foods, animal husbandry practices, wet markets, and the domestication of animals or exotic pets, the probability of cross-species transmission dramatically increases.
Zoonotic disease emergence model outlining the 5 stages of pathogen emergence from animals to humans.
It is now generally accepted that the hunting and butchering of wild nonhuman primates in the early 20th century led to the introduction of simian immunodeficiency virus into the human population, giving rise to our modern day HIV pandemic. In our own work, we have demonstrated that the traditional practice of hunting and butchering nonhuman primates continues to be a gateway for the zoonotic transmission of retroviruses. For instance, among central Africans reporting contact with nonhuman primate blood and body fluids through hunting, butchering, and keeping primate pets, we identified a wide array of primate T lymphotropic viruses, including 2 novel viruses: one that is distinct from all other known primate T-lymphotropic viruses, now designated human T lymphotropic virus subtype 4 (HTLV-4), and a second that is similar to other nonhuman primate T lymphotropic virus subtype 3 viruses that had not previously been described as infecting humans. These results demonstrate that entry of pathogens into the human population via contact with nonhuman primates is an ongoing, dynamic process. In fact, zoonotic transmission of viruses occurs on an astonishingly regular basis. In a serological survey of >1000 rural Cameroonian villagers with reported exposure to primates, we found that 1% had antibodies to simian foamy virus, suggesting that populations exposed to animal reservoirs of disease are constantly assailed by zoonotic agents. Presumably, the likelihood of any one zoonotic agent becoming a human pathogen is dependent upon a number of factors. Multiple introductions into the human population may be necessary before a zoonotic agent establishes itself as a human pathogen and the determinants of cross-species tropism are still ill defined, as are the factors that influence whether infection causes disease. However, the frequency with which the human population is exposed to a potential zoonotic agent is likely to be an important determinant in disease emergence.
The course that a pathogen of animal origin takes into the human population varies. The SARS outbreak originated from bats of the genus Rhinolophus, and its human emergence is believed to have been facilitated through intermediate hosts in the wet markets of southern China. The current H1N1 influenza epidemic appears to have arisen in North America primarily through the reassortment of viruses of swine origin. The species of animal that harbors the pathogen, the nature of human interaction with that animal, and the frequency of these interactions all likely modulate the risk of zoonotic transmission. Understanding this complex process will be important to combating future disease emergence. Therefore, further investigation into the interactions that humans have with animals (as a potential reservoir of disease), and conditions that influence this interaction, is warranted. As an example, despite the fact that chimpanzees have an extremely small population size and human contact with them is infrequent, their close phylogenetic relationship to our own species likely played an important role in our acquiring HIV from chimpanzees, as did the nature of our relationship with them. Presumably, the odds of contracting HIV would have been much lower had humans not been engaged in hunting chimpanzees, a practice that offers many opportunities for exposure to zoonotic agents through contact with biological fluids and tissue.
The human-animal interface is fluid and our interaction with other species, and any potential zoonotic agents they may possess, is variable. The frequency and type of human-animal interaction fluctuates in response to other external factors that, in turn, influence the potential for transmission of zoonotic agents. For instance, socioeconomic factors are hypothesized to be a major determinant of the spatial distribution of emerging infectious disease events. Socioeconomic pressures influence bushmeat hunting, a practice that is believed to be a major contributor to disease emergence, by obliging some populations to hunt to meet basic nutritional requirements in response to food availability. Similarly, studies of Lassa fever in Guinea and Sierra Leone directly correlate the risk of infection with Lassa fever, a viral hemorrhagic fever caused by an arenavirus transmitted by rodents, with poor housing and food storage conditions in refugee camps and other desperately poor communities. Other factors are also thought to have the potential to influence zoonotic disease emergence. For instance, the loss of biodiversity is believed to be an important contributing factor to zoonosis, and studies conducted in the Congo Basin and Rift Valley suggest that deforestation and climate change play important roles in the risk of zoonotic transmission from wildlife to humans. Likewise, deforestation and climate change are hypothesized to have been causal events that led to the 1998 emergence of Nipah virus from fruit bats to pig livestock and, subsequently, to the farm workers within the Kinta district of Perak state in Peninsular Malaysia, resulting in hundreds of reported cases of acute viral encephalitis. However, the precise causal relationship between these human-animal interface factors and how they influence the dynamics of zoonotic disease emergence is not fully elucidated, nor is the interconnectedness of the various factors (eg, socioeconomic factors and deforestation) well understood. Defining cause and effect relationships may provide valuable clues as to how would-be emergent diseases might be prevented.
Prevention of Disease Emergence and Pandemics
Current global disease control focuses almost exclusively on responding to pandemics after they have already spread globally. Nevertheless, dramatic failures in pandemic control, such as the ongoing lack of success in HIV vaccine development 25 years into the pandemic, have shown that this wait-and-respond approach is not sufficient and that the development of systems to prevent novel pandemics before they are established should be considered imperative to human health. Had we had such mature systems in place, we may have averted the H1N1 influenza pandemic that is currently unfolding. The early detection of emergent threats to human health is all the more important given the speed with which disease causing agents are now capable of being distributed around the globe through air travel and the global trade of animals as potential reservoirs of disease. Because the success of a pathogen depends on its ability to spread from human to human and on the number of susceptible humans, our ability to cross continents in a single day poses a unique new challenge to emerging infectious disease control. Past studies have highlighted the importance of global travel to the spread of pandemic disease, and the recent emergence and subsequent global spread of H1N1 influenza virus eloquently illustrates how our global interconnectedness can affect the worldwide distribution of a new virus, one that may otherwise have remained a regional phenomena in an era before global transit.
The Committee on Achieving Sustainable Global Capacity for Surveillance and Response to Emerging Diseases of Zoonotic Origin was convened by the Institute of Medicine and the National Research Council to assess the feasibility, needs, and challenges of developing a future and sustainable global disease surveillance program. As the committee’s report comprehensively expresses, our current disease surveillance system and our ability to identify emergent diseases early are inadequate. Implementing all of the committee’s recommendations would represent a significant step forward in achieving a well-integrated zoonotic disease surveillance system, but we are still far from realizing this goal. Given the fact that more than one-half of emerging infectious diseases have resulted from zoonotic transmission and that the human-animal interface is so pivotal to the process of disease emergence, it stands to reason that the most effective strategy in terms of early detection of an emergent pathogenic threat would focus on conducting surveillance of humans highly exposed to animals and within the animal populations to which they are routinely exposed. Despite this, there exists no systematic global effort to monitor for pathogens emerging from animals to humans in “at-risk” populations, and we are probably years from having such a system in place.
Although a global surveillance system for pandemic prevention is still far from reality, there may be more immediate, interim measures that may be taken to mitigate the risk of zoonotic transmission, even in the absence of a global surveillance effort. In situations where humans and animals are in close contact, behavioral change approaches may be a preventative step to reducing the risk of zoonotic transmission. Behavioral modification campaigns have previously been used in combating outbreaks of known infectious diseases. For instance, a behavioral modification campaign was launched in Sierra Leone to reduce cases of Lassa fever. The intervention involved incidence mapping, contact tracing to warn relatives of the dangers of secondary infection, and education to exposed populations in methods of avoiding exposure to rodents, the reservoir of the disease. Prevention posters included graphic depictions to instruct villagers in techniques for protecting food from rodents, trapping rodents, dealing safely with carcasses of dead rats, and symptom recognition. As part of the campaign, local musicians were even commissioned to write and perform songs about routes of transmission of Lassa fever and preventative measures. These outreach activities were an attempt to increase awareness of the disease and to promote behavior change aimed at reducing incident cases of Lassa fever through reducing the risk of exposure to animals, in this case rodents.
We have implemented similar risk-reduction measures in our own work with Cameroonian bushmeat hunters through “healthy hunter” education sessions. These sessions are designed to encourage hunters to reduce their contact with wild animal blood and body fluids. We educate hunters in this program on pathogens that can be found in wild animals, which species are believed to pose the greatest risk with regard to the transmission of zoonotic agents, and what steps can be taken to avoid possible infections. Although it is important to explain that the best way to avoid infections is to not handle animals and to limit one’s exposure to animal blood and body fluids, for many people, hunting and butchering represent an essential part of daily food preparation. Thus, the focus of this intervention is on reducing the risk of zoonotic infection and not necessarily the practice of bushmeat hunting itself. With this in mind, the interactive education sessions are meant to inform individuals of precautions that may be taken to reduce the risk of being infected with a zoonotic agent when engaged in highrisk practices such as hunting and butchering. Such precautions include avoiding the hunting of nonhuman primates, because they share many diseases and infections with humans; avoiding butchering or handling animal meat if there are injuries on the hands or arms; immediately washing any bites, scratches, cuts, or injuries obtained during hunting or butchering, preferably with soap; and avoiding contact with animal carcasses found in the forest.
More research is needed to determine the efficacy of reducing disease spread through social mobilization, public health education, behavioral change, and communication strategies. Although it is challenging to measure behavioral change efficacy in reducing the risk of transmission of potential pathogens, program evaluation will be important in defining replicable behavioral change and communication models that are useful in emerging infectious disease “hot spots,” those regions that have disproportionately given rise to the majority of human diseases. If they prove to be effective, behavior modification measures may have an enormous impact on curtailing disease emergence and progression in conjunction with other strategies.
The Future of Pandemics
The ongoing global HIV pandemic, the recent outbreaks of pathogens such as SARS and the H5N1 influenza virus, as well as the current H1N1 influenza pandemic, the global consequences of which are still to be determined, demonstrate our continued vulnerability to emerging infectious diseases. The most recent example, H1N1 influenza, and its dramatic spread also reminds us that we have entered into a new age of global pandemics, largely because of the rapidity with which newly emergent pathogens are capable of being transmitted around the world. Because of our continued vulnerability and the challenges that global travel poses to pandemic control, it is now more important than ever that we identify emerging infectious diseases early. Although it is still difficult to predict the agent that will pose the next pandemic threat, when it will occur or where it will begin, it will likely be the result of cross-species transmission from animals to humans. This likelihood argues in favor of developing a system aimed at detecting the transmission of potentially pathogenic agents from animals to humans early in the zoonotic disease emergence process and identifying ways by which we can diminish the risk of transmission, especially in populations that are highly exposed to animals and their potentially zoonotic agents.
My intention in this article was to discuss the natural progression of a viral epidemic. Some viruses just disappear on their own. Some viruses like Small pox and polio are eradicated by vaccines. Other viruses like the flu become endemic and never truly go away. We simply learn to live with them. The vast majority of people who die from the flu are either very young children who haven’t developed a more mature immune system or the elderly who have weakened immune systems or people that are in poor health and malnourished. The vast majority of viral pandemics mutate to less deadly forms, like the original SARS virus. It is postulated that the COVID-19 virus will become less deadly and will evolve into an endemic state. In which case an acceptable number of deaths will occur each year and we will have the option of getting the vaccination like we do the flu vaccine every year. We are already seeing this take place as exhibited by the most recent mutation the Omicron variant. Evolution is survival of the fittest. We have evolved to the top of the food chain, so our only enemy is either ourselves or infectious agents.
webmd.com, “Epidemics, Pandemics, and Outbreaks.” By Jennifer Robinson, MD; pressbooks.com, “103 Prevention and Treatment of Viral Infections;” ncbi.nlm.nih.gov, “Viral Pathogenesis.” By Samuel Baron, Michael Fons, and Thomas Albrecht; verywellhealth.com, “Phases of a Pandemic.” By Trisha Torrey; ncbi.nlm.nih.gov, “The Origin and Prevention of Pandemics.” By James M. Hughes; washingtonpost.com, “‘The 1918 flu is still with us’: The deadliest pandemic ever is still causing problems today.” By Teddy Amenabar; qz.com, “Has Covid-19 gone from pandemic to endemic?” By Sarah Todd;
‘The 1918 flu is still with us’: The deadliest pandemic ever is still causing problems today
In 1918, a novel strand of influenza killed more people than the 14th century’s Black Plague.
At least 50 million people died worldwide because of that H1N1 influenza outbreak. The dead were buried in mass graves. In Philadelphia, one of the hardest-hit cities in the country, priests collected bodies with horse-drawn carriages.
In the middle of today’s novel coronavirus outbreak, some are turning to the conclusion of past pandemics to discern how and when life might “return to normal.” The Washington Post has received a few dozen questions from readers who want historical context for our current epidemic. But how did the deadliest pandemic ever recorded come to an end?
Over time, those who contracted the virus developed an immunity to the novel strand of influenza, and life returned to normal by the early 1920s, according to historians and medical experts. Reports at the time suggest the virus became less lethal as the pandemic carried on in waves.
But the strand of the flu didn’t just disappear. The influenza virus continuously mutated, passing through humans, pigs and other mammals. The pandemic-level virus morphed into just another seasonal flu. Descendants of the 1918 H1N1 virus make up the influenza viruses we’re fighting today.
“The 1918 flu is still with us, in that sense,” said Ann Reid, the executive director of the National Center for Science Education who successfully sequenced the genetic makeup of the 1918 influenza virus in the 1990s. “It never went away.”
It’s not clear exactly how or where the 1918 influenza outbreak began, but, at some point, the novel H1N1 virus passed from birds to humans.
From start to finish, the flu could burn through a town or city in a matter of weeks. Very few people had ever contended with a concoction of influenza like this before, which is why it was so potent, Reid said.
Even President Woodrow Wilson contracted the virus while negotiating the end of World War I.
Seasonal influenza tends to kill the oldest and youngest in a society but in 1918, roughly half of those who died were men and women in their 20s and 30s. People were getting sick and dying in the prime of their lives.
“As many as 8 to 10 percent of all young adults then living may have been killed by the virus,” historian John M. Barry wrote in his best-selling book “The Great Influenza.”
All the while, World War I continued. The bloody trench warfare across Europe left 8.5 million or more soldiers dead. The tight quarters during the war only aided the spread of the virus, said Howard Markel, a physician and medical historian at the University of Michigan.
The 1918 outbreak has been called the Spanish flu because Spain, which remained neutral during World War I, was the first country to publicly report cases of the disease. China, France and the United States already had cases of the flu, but wartime censorship largely kept the outbreaks out of the newspapers.
Then, the king of Spain — Alfonso XIII — and several other members of his government contracted the flu. This series of unfortunate events left a permanent mark, tying the country to the deadly outbreak.
“There was a very common habit, which has persisted to this day, of blaming an epidemic on one country or one group of people,” Markel said. “It goes back centuries.”The debate surrounding reopening too soon amid the coronavirus pandemic is striking an eerily familiar tone. (The Washington Post)
The longer the influenza virus existed in a certain community, the less lethal the sickness was. An epidemiological study cited by Barry in “The Great Influenza” noted that “the virus was most virulent or most readily communicable when it first reached the state, and thereafter it became generally attenuated.”
Experts say there’s this natural progression where a virus often — but not always — becomes less lethal as time wears on. It’s in the best interest of the virus for it to spread before killing the host.
“The natural order of an influenza virus is to change,” Barry told The Post. “It seems most likely that it simply mutated in the direction of other influenza viruses, which is considerably milder.”
By 1920, the influenza virus was still a threat, but fewer people were dying from the disease. Some scientists at the time started to move on to other research. Barry wrote that William Henry Welch, a famous pathologist from Johns Hopkins who was studying the virus, found it “humiliating” that the outbreak was passing away without experts truly understanding the underlying cause of the disease.
What Welch didn’t predict was that the virus never truly went away. In 2009, David Morens and Jeffery Taubenberger — two influenza experts at the National Institutes of Health — co-authored an article with Anthony S. Fauci explaining how the descendants of the 1918 influenza virus have contributed to a “pandemic era” that has lasted the past hundred years. At the time the article was published, the H1N1 influenza virus in public circulation was a fourth-generation descendant of the novel virus from 1918.
“All those pandemics that have happened since — 1957, 1968, 2009 — all those pandemics are derivatives of the 1918 flu,” Taubenberger told The Post. “The flu viruses that people get this year, or last year, are all still directly related to the 1918 ancestor.”
Because of this, the 1918 influenza outbreak doesn’t come with a neat bookend. Society moved on, but the virus continued in some form or fashion.
“We are living in a pandemic era that began around 1918,” Taubenberger wrote with Fauci and Morens back in 2009 for the New England Journal of Medicine. “Ever since 1918, this tenacious virus has drawn on a bag of evolutionary tricks to survive.”
We continue to turn back to the 1918 outbreak as a point of comparison, said Jeremy Greene, a historian of medicine at Johns Hopkins. Some of the public health measures a hundred years ago are still put in place today. To “flatten the curve,” cities and towns have more or less shut down. That said, Greene cautions against drawing the parallels “too closely.”
There are similarities to draw between today’s pandemic and the influenza outbreak a hundred years ago. Both come from winged animals — one from birds and the other from bats. Both are respiratory viruses. Both led people to wear masks in public. Both forced cities and schools to shut down for periods of time. And, finally, in both cases, the country’s leaders exacerbated problems by ignoring the early warning signs.
Despite all that, influenza viruses and coronaviruses are not the same. There’s very little someone can draw from influenza to then provide treatment for the infectious disease named covid-19, said Paul Offit, the director of the Vaccine Education Center at Children’s Hospital of Philadelphia.
“They’re really different viruses,” Offit added.
Influenza is consistent and relatively quick when compared with the novel coronavirus. If you get exposed to the flu, you’ll start showing symptoms in one to four days after the infection. According to the Centers for Disease Control and Prevention, it tends to take five days for those infected with SARS-CoV-2 to start showing symptoms of covid-19, but the timing can fluctuate from two days to two weeks.
The novel coronavirus is not moving on the same time frame as the 1918 influenza, Greene told The Post. Everything is longer with the novel coronavirus — the symptoms, the sickness and even the long-term complications. Doctors are concerned covid-19 can lead to lasting cardiovascular complications.
Then there are asymptomatic carriers of the disease. That one detail makes it harder to mitigate the spread of the virus by simply taking temperatures. Symptoms are not a be-all-end-all solution to tracking the disease. With that in mind, the novel coronavirus is acting more like polio, where those with mild cases don’t know they’re sick, Greene said.
“It immediately raises a different set of problems for managing a disease,” Greene said. “One needs to relearn the way to think about who is dangerous, and that becomes, basically, everybody.”
Recognizing both the similarities and differences to past pandemics can provide a “meaningful mirror” for the present, Greene added. The million-dollar question is: What can the 1918 influenza outbreak tell us about how our current pandemic may end?
“The sad answer is not very much,” Markel said. “The operative word in this particular pandemic is ‘novel’ coronavirus. We’re learning as we go along, but we don’t really know that much.”
Has Covid-19 gone from pandemic to endemic?
The delta variant is prompting a spike in coronavirus cases across the US. But the pandemic may soon take yet another turn.
On CNBC’s Squawk Box last week, former Food and Drug Administration (FDA) commissioner and current Pfizer board member Scott Gottlieb said we’re “transitioning from this being a pandemic to being more of an endemic virus, at least here in the United States and other Western markets.” Gottlieb was responding to a question about the point at which the US might claim “something close to victory” over Covid, in light of upcoming approvals for booster shots and vaccines for children under age 12.
“This is going to become more of an endemic illness where you see sort of a persistent infection through the winter, but not at the levels that we’re experiencing certainly right now,” Gottlieb said (noting that this would be less true in countries with low vaccination rates). Booster shots will play a role in getting the US to that phase, he says, as will the delta variant.
So what does this transition actually mean? As Ed Yong explained in The Atlantic, “the pandemic ends when almost everyone has immunity, preferably because they were vaccinated or alternatively because they were infected and survived.” Because the delta variant is so transmissible, particularly among the unvaccinated, Gottlieb is suggesting that delta’s spread plus vaccinations will push wealthy Western countries into a new Covid era.
Endemic versus pandemic
To understand the import of Covid’s eventual shift from pandemic to endemic, it’s necessary to define both terms. This is a bit trickier than one might think.
In March 2020, the World Health Organization (WHO) declared Covid-19 to be a global pandemic. Although there is no universally agreed-upon definition of what constitutes a pandemic, the WHO had previously called a pandemic the “worldwide spread of a new disease.” The International Epidemiology Association’s Dictionary of Epidemiology says that a pandemic is “an epidemic occurring worldwide, or over a very wide area, crossing international boundaries and usually affecting a large number of people.” (The term epidemic, meanwhile, is typically used to describe a sudden, sharp increase in a disease throughout a particular community, population, or region.)
So it’s safe to say that a pandemic involves a disease that’s contracted by a lot of people in geographically diverse locations, though as a recent Nature article notes, such descriptions are “qualitative in nature.” A 2009 article in the Journal of Infectious Diseases adds that most diseases that get described as pandemics tend to be newer, and characterized by “high attack rates” (the proportion of people getting sick with the disease), “explosive spread” in a short period of time, lower levels of immunity, and higher levels of contagiousness. Covid-19 checks all those boxes.
Endemic diseases, like chicken pox or malaria, are not novel, and the rates of infection within a given population are fairly predictable. The Centers for Disease Control and Prevention (CDC) says that endemic “refers to the constant presence and/or usual prevalence of a disease or infectious agent in a population within a geographic area.” Speaking with the New York Times this spring, professor of infectious disease epidemiology David Heymann said that becoming endemic was “the natural progression of many infections we have in humans, whether it is tuberculosis or HIV.”
“We have learned to live with them and we learn how to do risk assessments and how to protect those we want to protect,” he explained.
The end of herd immunity hopes
It wasn’t always a foregone conclusion that Covid-19 would become endemic—for a while, the hope was that vaccines might allow populations to reach a level of herd immunity that would stomp out the virus almost entirely. But as Yong notes, because the delta variant spreads so quickly, most experts think herd immunity is no longer realistic—even if vaccination rates rose to the levels previously thought necessary. (At the low end of estimates, the CDC says that 90% of Americans would need to be vaccinated to reach herd immunity with delta; at the high end, Yong says, “herd immunity is mathematically impossible with the vaccines we have now.”)
And so endemic Covid is where we’re heading, sooner or later. “The optimistic view is that enough people will gain immune protection from vaccination and from natural infection such that there will be less transmission and much less Covid-19-related hospitalization and death, even as the virus continues to circulate,” immunologist Yonatan Grad tells the Harvard Gazette.
Will Covid last forever?
Not all countries have given up on the hope of “Covid zero.” China, for example, is pursuing a “zero tolerance” approach to the virus, with strict lockdowns, contact tracing, testings, and quarantines. Australia, too, has sought to shut out the virus with closed borders, lockdowns, and widespread testing. The highly contagious delta variant, however, is still managing to penetrate both countries, calling the long-term viability of a zero-Covid strategy into question.
We don’t know yet when Covid-19 will cross over into endemic territory, in the US or anywhere else. But when it does, it should present a much less significant threat to our health and our daily lives. Vaccines and immunity from previous infections will give most people protection against severe cases of the virus, and measures like regular testing and outbreak tracing can hopefully keep a lid on any resurgences.
It won’t be the ending to the pandemic we may have hoped for. But it will be better than where we’re at now.
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