A Bad Case of the Spanish Flu Introduction Influenza, commonly called the “flu,”

Question

A Bad Case of the Spanish Flu

Introduction

            Influenza, commonly called the “flu,” is a virus that infects birds and mammals, causing cyclical, seasonal outbreaks. The virus, which strikes mostly during the winter months, is primarily transmitted by aerosol droplets (as from a cough or a sneeze), but it can also be spread by blood, feces, and saliva. The respiratory symptoms of influenza result from infection of the epithelium lining the bronchial tree, which causes inflammation, increased mucus secretion, and destruction of epithelial cells. Annually, influenza kills several hundred thousand people, most of whom are very young children, elderly, and/or immunocompromised. Historically, influenza has caused several pandemics (worldwide outbreaks), none as severe as the so-called “Spanish flu” of 1918. At about the same time every year advertising for flu vaccines appears in a concentrated effort to minimize the impact of the upcoming flu season.

1. How does a virus such as influenza interact with our lymphatic and immune systems?

2. Why has a cure for influenza eluded modern medical science despite advances in virology?

3. The evolution of the human body has led to the development of mechanisms that combat pathogens such as the influenza virus as a means of survival. Lymphoid tissues and organs such as the spleen are examples of these defense mechanisms. Where you might find influenza virus in the spleen of an infected individual?

4. Mucous membranes are vulnerable to pathogens like influenza. Mucous membranes are exposed to the external environment, and they provide mechanisms that prevent pathogens from gaining entry into the body.

(a) Describe MALT; then describe how lymphoid follicles and lymphoid nodules differ, and indicate the region you would expect to find influenza virus.

(b) Assume that the influenza virus has eluded the defenses of MALT; describe the path through which influenza virus particles would circulate through the lymph nodes.

(c) Describe what is meant by “swollen glands” and explain why this term is a misnomer.

            Current medical evidence suggests that influenza virus is released in droplets created by infected individuals and can spread up to 6 feet away by sneezing, coughing, or even talking. Airborne droplets can find their way into mouths and noses or be inhaled into the lungs of nearby individuals. People may also be exposed to influenza by touching objects that have live influenza virus on them and then transferring the virus to their own mouth or nose.

5. One of the many immune system functions is to protect individuals from pathogens such as the influenza virus. Explain how innate immunity (non-specific defense) and adaptive immunity each respond differently to exposure to influenza virus?

6. A virus such as influenza is only one type of pathogen that can invade the human body and cause disease. Different pathogens interact with different components of the immune system in different ways.

(a) Describe the role of skin and mucosae as surface barriers and the mechanisms that enable these anatomical structures to prevent infections.

(b) Discuss three examples of how the lymphatic and immune systems work together both structurally and functionally to fight infections such as influenza.

Patients suspected of contracting the Spanish flu reported high fevers, with temperatures between 102 and 104 degrees Fahrenheit. Fever was one of the most consistent initial signs recorded by physicians in the pandemic of 1918. Patients also suffered from sore throat, fatigue, headaches, body aches, coughing, and often nosebleeds. In addition, some individuals also experienced vomiting and diarrhea. Many patients recovered, only to relapse with the return of elevated temperatures and severe respiratory distress. Postmortem examinations of patients who died of flu-related complications revealed that many suffered massive pulmonary hemorrhage, swollen lungs, and swollen spleens.

7. Which of the following statements correctly describes an event that could trigger a fever after exposure to the influenza virus?

Cells damaged by influenza virus release pyrogens, which trigger in the hypothalamus changes that increase body temperature.
Neutrophils and macrophages detect damaged cells and release pyrogens.
In response to the detection of damaged cells, the bone marrow increases production of leukocytes, triggering an increase in body temperature.
Cells damaged by influenza virus attract monocytes, which stimulate the hypothalamus to increase body temperature.

8. The inflammatory response is a non-specific reaction triggered by cellular injury. Discuss the cardinal signs of inflammation that you would expect to observe in a patient suffering from an infection (including an influenza infection), and describe what causes each of these signs.

            Influenza viruses target epithelial cells that line the respiratory tract, triggering an antiviral immune response once the host detects the virus. The innate immune system is the first line of defense against influenza infections. This non-specific response to viral exposure is composed of physical barriers that lack the ability to form any memory against the virus.

            The second line of defense is the adaptive immune response, which is triggered when the physical barriers of the innate immune system have failed. Adaptive immunity is a highly specific response that takes some time to develop upon the first encounter with the influenza virus. However, the memory that develops after that initial response produces a much quicker and stronger response if the same influenza virus is encountered again.

9. Adaptive immunity consists of both virus-specific antibodies generated by humoral immunity and cell-mediated immunity directed by virus-specific CD4 and CD8 T cells. Describes how a body cell infected with a virus interacts with the MHC molecule?

10. The expression of influenza antigens by infected body cells triggers the cell-mediated immune response.

(a) Describe the events that occur in influenza-infected cells that trigger T cell activation.

(b) Explain the process of clonal selection and the functions of the specific class of T cells that is activated by the process discussed in (a).

(c) Explain the functions of the specific T cell population that is activated.

            Even today influenza continues to challenge the medical community. Many people are more afraid of influenza vaccines than they are of the flu virus itself. Regardless, influenza outbreaks and the likelihood of a major pandemic still exist. An outbreak of so-called “killer flu” at Fort Dix, New Jersey in 1976 revealed fears of another Spanish flu pandemic. Experts later identified the virus as the less deadly swine flu. Nevertheless, the swine flu outbreak led to a nationwide vaccination effort to prevent a pandemic, and the outbreak was limited to Fort Dix.

            An influenza outbreak that occurred in the early spring of 2009 generated a significant scare. The Centers for Disease Control and Prevention (CDC), concerned that the viral outbreak would become a major pandemic, developed an emergency vaccine within weeks of the first reported case. The CDC estimated that the flu vaccine, given to over 80 million Americans, saved countless lives. Despite this vaccination effort, the deaths of between 8,000 and 18,300 individuals were attributed to the outbreak.

            Without mechanisms for a rapid response, including emergency vaccine development, an outbreak of a deadlier virus could claim many more lives. So how do flu vaccines prevent influenza infection, and more importantly, the spread of viral infection among individuals?

            Predicting which influenza viruses will predominate in a particular upcoming “flu season” is a daunting task for the healthcare community. An outbreak of a flu virus not protected against by that season’s vaccine undermines vaccination efforts, which puts more individuals at risk in following flu seasons.

11. Consider the consequences of administering a flu vaccine to a patient with an egg allergy. Which class of antibodies would trigger the inflammation associated with the allergic response to egg antigens in the flu vaccine?

12. A flu vaccine contains an antigenic portion of an influenza virus that when injected into a patient generates an immune response to that specific viral strain.

(a) Describe the primary response that occurs after an influenza vaccine has been administered.

(b) Describe the specific responses that occur when a fully vaccinated individual is exposed to the influenza virus.

(c) Briefly discuss the difference between memory B cells and plasma cells.

Wrapping Up the Case:

            The Spanish flu pandemic, which has been described as the “greatest medical holocaust in history,” lasted for 18 months from 1918 to 1920. Current research estimates that the virus killed between 50 and 100 million people worldwide, or about 2.5–5% of the world’s population at that time. Among its striking features were its 50% infection rate and the rapidity with which it spread. An estimated 25 million people were killed in its first 25 weeks; by contrast, HIV/AIDS killed 25 million people in its first 25 years. Other unusual features of the Spanish flu were that it began during the summer months and infected mostly young and previously healthy adults, populations that are atypical for most influenza strains.

            The disease was first detected in Kansas; it later acquired the name “Spanish flu” due to the amount of press coverage it received in Spain. The culprit in this pandemic was influenza A virus subtype H1N1. To investigate what made this strain so pathogenic, modern technology was used to analyze both virus recovered from the frozen corpse of a Native Alaskan woman buried nearly 80 years earlier and samples preserved during World War I. Several of the strain’s key proteins have been reconstructed and their DNA sequenced, but we still don’t know specifically what made this strain of influenza so pathogenic.

            The origin of the virus is a matter of some debate. It was previously believed that the virus first appeared in birds, then jumped to pigs and finally to humans. Now, however, good evidence suggests that this strain jumped from birds directly to humans. This idea has raised a great deal of concern over the H5N1 strain, a current strain of influenza otherwise known as “avian influenza” or the “bird flu.” Like the H1N1 strain from 1918, the H5N1 strain is highly pathogenic; current data estimate a 60% mortality rate from infection with the virus. The key difference between the two strains is that the H1N1 strain is transmitted from human to human extremely efficiently, whereas the H5N1 strain is not. However, there remains concern that the H5N1 strain will mutate such that it easily spreads from one infected person to another. In response to this concern, governments around the world are already looking into the best way to minimize the loss of lives should a pandemic arise. Understanding the pathogenicity of the Spanish flu is one key in the prevention of another “medical holocaust.”

Explanation / Answer

1. When a virus like those that cause chickenpox and the flu enters your body, specialized cells in your immune system recognize it as foreign, and start to attack. Some immune system cells make antibodies. These molecules float in the blood and attach to any viruses that are in the blood to destroy them. The immune system fights infection caused by the flu and other viruses. Cytokines are a kind of chemical distress call issued by T-cells, B-cells and natural killer cells of the immune systems in response to influenza infection. Cytokines cue the hypothalamus in the brain to raise body temperature, which slows down or inactivates enzymes involved in viral replication. Cytokines also activate receptors in the blood vessels of the brain causing headache and trip pain fibers in muscles, accounting for the sensation of non-specific muscle pain and soreness. Cytokine release is proportionate to immune system response. When the body is fighting infection, lymph nodes can become enlarged and feel sore. Spleen: The largest lymphatic organ in the body, which is on your left side, under your ribs and above your stomach, contains white blood cells that fight infection or disease.  When the lymph nodes in the body swell, it's actually because they're filling up with these cells which will attack the invader. The MHC class I/peptide complexes are recognized by the virus-specific CD8+ cytotoxic T cells (CTLs).

2. A cold is a viral infection of the upper respiratory tract and is characterised by fever, coughing and sneezing, sore throat and a runny nose. (Fever in colds is usually below 37.8°C.) There are many virus strains that can cause colds. More than 200 viruses can cause what a sick person would recognize as a cold, including "some strains of influenza virus, adenoviruses, coronaviruses, enteroviruses, and respiratory syncytial virus, the most common of which are rhinoviruses. Even the most common among those, rhinovirus, has more than a hundred different strains. A rhinovirus vaccine would do nothing to protect against those. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. Therefore, a cure for influenza has eluded modern medical science despite advances in virology.

3. In healthy individuals, influenza virus (IAV) infection generally remains localized to the epithelial cells of the respiratory tract.  IAV-specific effector CD8 T cells found systemically during the course of IAV infection were thought to have been primed in lung-draining lymph nodes with subsequent migration to other tissues.

The white pulp is lymphoid tissue that usually surrounds splenic blood vessels. The red pulp is a network of splenic cords (cords of Billroth) and sinusoids (wide vessels) filled with blood, and it is in the red pulp that most of the filtration occurs.

The white pulp of the spleen contains typical lymphoid elements, such as plasma cells, lymphocytes, and lymphatic nodules, called follicles in the spleen. Germinal centres in the white pulp serve as the sites of lymphocyte production. Similar to the lymph nodes, the spleen reacts to microorganisms and other antigens that reach the bloodstream by releasing special phagocytic cells known as macrophages. Splenic macrophages reside in both red and white pulp, and they serve to remove foreign material from the blood and to initiate an immune reaction that results in the production of antibodies. So, here I may find influenza virus in the spleen of an infected individual

4. a.

Mucosal Associated Lyphoid Tissue (MALT): Mucosal associated lymphoid tissues (MALT), sites of the immune response toward pathogens that enter via the mucosal surfaces. Examples of MALT include tonsils in the oropharynx, Peyer’s patches in the small intestine, and lymphoid aggregates in the large intestine. MALT also includes various sites of lymphocyte accumulation throughout the respiratory, gastrointestinal, and genitourinary tracts. Antigens at the mucosal surfaces are picked up by the lymphocytes in MALT.

Lymph nodule is a small, localized collection of lymphoid tissue, usually located in the loose connective tissue beneath wet epithelial (covering or lining) membranes, as in the digestive system, respiratory system, and urinary bladder. In the small intestine, collections of lymph nodules are called Peyer's patches.

lymphoid follicles are of two types:

Primary follicles: lymphoid follicles without a germinal centre.

Secondary follicles: lymphoid follicles with a germinal centre. These mostly contain B-cells.

Lymph nodules form in regions of frequent exposure to microorganisms or foreign materials and contribute to the defense against them.

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