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   VIROLOGY -  LECTURE THIRTEEN  
  INFLUENZA VIRUS  

Dr. Margaret Hunt

MEDICAL MICROBIOLOGY, MBIM 650/720    LECTURES: 69-70
READING: Murray et al., Microbiology, 3rd Ed., Chapter 56

 

TEACHING OBJECTIVES

Brief review of influenza virus structure and properties. 
Discussion of viral pathogenesis and disease, genetics, epidemiology, prevention and treatment

 

fluA.jpg (63006 bytes) Influenza A ©  Dr Linda M Stannard, 1995, University of Cape Town. Used with permission

fluC.jpg (39104 bytes) Influenza C  ©  Dr Linda M Stannard, 1995, University of Cape Town. Used with permission

INTRODUCTION

True influenza is an acute infectious disease caused by a member of the orthomyxovirus family: influenza virus A, B or, to a much lesser extent, influenza virus C. However, the term 'flu' is often used for any febrile respiratory illness with systemic symptoms which may be caused be a myriad of bacterial or viral agents as well as influenza.

Influenza outbreaks usually occur in the winter in temperate climates.

 

flu1.jpg (44099 bytes)  Properties of orthomyxoviruses

flu2.jpg (45163 bytes) Laboratory detection of of influenza in South Carolina 1996-97

 

  ORTHOMXYOVIRUSES  

flu3.jpg (57407 bytes) Orthomyxovirus structure

Disease potential

Major outbreaks of influenza are associated with influenza virus type A or B. Infection with type B influenza is usually milder than type A. Type C virus is associated with minor symptoms.

Proteins

The internal antigens (M and NP proteins) are used to determine whether a particular virus is A, B or C; these are the type-specific antigens. The M proteins of all members of each group show cross reactivity. The NP proteins of all members of each group also show cross reactivity.

The external antigens (HA and NA) show more variation and are the subtype and strain specific antigens. These are used to determine the particular strain of e.g. influenza A responsible for an outbreak.

 

PATHOGENESIS AND DISEASE

Spread

The virus is spread person to person via small particle aerosols (less than 10µm) which can get into respiratory tract. The incubation period is short: 18-72 hours.
Virus concentration in nasal and tracheal secretions remains high for 24-48 hrs after symptoms start and may last longer in children. Titers are usually high, so there are enough infectious particles in a small droplet to start a new infection.

Site of infection

Influenza virus infects the epithelial cells of the respiratory tract.
It interferes with the function of these cells and eventually kills them. Ciliary efficiency is reduced: "the mucus elevator functions less well' and clearance of infectious agents from the respiratory tract reduced.
Gaps in the protective epithelium provide other agents with access to other cells.
Viremia is rare.

Recovery

Interferon may play an important role in recovery, and in decreasing virus production. Many of the symptoms of uncomplicated influenza are due to induction of interferon (muscle aches, fatigue, fever). A cell-mediated immune response may play a role. Antibody response is usually not significant until after virus has been cleared. Repair of the respiratory epithelium begins rapidly, but may take some time to complete.

Protection

A humoral antibody response is the main source of protection. IgG and IgA are important in protection against reinfection. Antibody to the HA protein is most important since this can neutralize the virus and prevent infection. Antibody to the NA protein has some protective effect since it seems to slow the spread of the virus. IgG persists longer than IgA and so plays a more important role in long term immunity.

Clinical findings

The disease is usually most severe in very young children (who may have no antibodies. The small diameter of components of respiratory tract also means that inflammation and swelling can lead to blockage of parts of respiratory tract, sinus system or Eustachian tubes) and the elderly (who often have an underlying decreased effectiveness of the immune system and/or chronic obstructive pulmonary disease or chronic cardiac disease).

1. Uncomplicated influenza

Fever (38 - 40 degrees C)
Myalgias, headache
Ocular symptoms - photophobia, tears, ache
Dry cough, nasal discharge

2. Pulmonary complications, sequelae:

Croup (in young children)
Primary influenza virus pneumonia.
Secondary bacterial infection: Often involves Streptococcus pneumoniae, Staphylococcus aureus, Hemophilus influenzae
Build up of fluids and lack of mucociliary clearance provides good breeding grounds for bacteria.
Complications often occur in patients with underlying chronic obstructive pulmonary or heart disease. The underlying problems may not have been recognized prior to the influenza infection.

3. Non-pulmonary complications:

Myositis (rare, more likely to be seen in children after type B infection)
Cardiac complications

Guillain-Barré syndrome (CNS) - The cause of this syndrome is mysterious. Recent vaccines do not seem to increase the risk of developing this.

Reye's syndrome - The effects on the liver and brain are particularly serious. This is rare, but 40% of cases are fatal. The origin of Reye's syndrome is unclear but seems to follow certain viral infections such as influenza or chicken pox (varicella zoster/herpes zoster), especially if they are in the young and especially if they have been treated with aspirin. Aspirin is contraindicated for childhood or adolescent fevers because it is a risk factor in the development Reye's syndrome. Acetaminophen is apparently not associated with Reye's syndrome.

The major causes of influenza-associated death are bacterial pneumonia and cardiac failure.

 

DIAGNOSIS

Firm diagnosis is by means of virus isolation and serology. The virus can be isolated from the nose or a throat swab. This is used to infect cells in culture (or eggs). Hemadsorption may be used to detect infected cells.
Provisional diagnosis is often made clinically, based on knowledge of a current outbreak of influenza combined with appropriate clinical symptoms (fever, cough, runny nose, malaise).

 

EPIDEMIOLOGY

HA (hemagglutinin) protein

The HA protein is involved in attachment and membrane fusion in the endosome of the infected cell.
The receptor binding site on the virus is in a pocket that is not exposed to the immune system.
The antigenic domains are on the surface. These can be altered and the virus can thus  avoid a humoral response without affecting its ability to bind to the receptor.

NA (neuraminidase) protein

The NA protein is involved in penetration of mucus layer and in  facilitating release from infected cell.

Antigenic drift

Antibodies to HA are most important in protection, although those to NA also play a role. Both proteins undergo antigenic drift (i.e. accumulate mutations) and after a few years may have accumulated sufficient changes that an individual immune to the original strain is not immune to the drifted one. This results in sporadic outbreaks and limited epidemics.

Antigenic shift

In the case of influenza A,  antigenic shift periodically occurs. Apparently "new" HA and/or NA are found in the circulating viral strains. There is little immunity (particularly if both proteins change, or if new HA is present) and an epidemic/pandemic is seen.

PANDEMICS CAUSED BY INFLUENZA A

Major antigenic shifts associated with influenza A pandemics

Year

Sub type

Prototype strain

1947

H1N1

A/FM1/47

1957

H2N2

A/Singapore/57

1968

H3N2

A/Hong Kong/68

1977

H1N1

A/USSR/77

1987

H3N2

No pandemic
Various strains circulated worldwide

Adapted from Ryan et al. Sherris Medical Microbiology

Where does a "new" HA and/or NA come from? All (13)HA and (9)NA types circulate in ducks, some also circulate in other animals. It appears that some animal, somewhere, becomes infected with both a human and an animal virus, and that one of the reassortants contains genes for human internal components but a new HA and/or NA segment from the animal virus. If this virus can infect humans, it will have the same internal components as the current human virus, but new envelope components resulting in little immunity in the population. Influenza A strains/subtypes are therefore classified according to the nature of the HA and NA proteins. It is possible that we do not see such a shift in influenza B  because there is no animal reservoir for this virus.

SURVEILLANCE

A measure of the severity of influenza in any one year is the excess of deaths due to pneumonia or influenza compared to the seasonally adjusted norm

flu5.jpg (44992 bytes) Weekly pneumonia and influenza mortality as a percentage of all deaths in US 122 cities 1995-99  (CDC MMWR 48:374 1999)

The World Health Organization (WHO) maintains constant surveillance of influenza outbreaks world wide and has a series of 'sentinel' labs to look at what is happening in the circulating virus population. The CDC does the same in the United States and co-operates with WHO.

Usually the most  important influenza virus is influenza A, but in some recent years influenza B has played an important role. In recent years H1N1 and H3N2 have often co-circulated, the proportions of each can change dramatically from year to year.

 

PREVENTION

Vaccines

A new vaccine is formulated annually with the types and strains of influenza predicted to be the major problems for that year (predictions are based on worldwide monitoring of influenza). The vaccine is multivalent and the current one is to two strains of influenza A and one of influenza B.

The vaccine given to adults at present is an inactivated preparation of egg-grown virus. It is contraindicated for those with allergies to eggs. It has a short lived protective effect and so is usually given in the fall so that protection is high in December/January - the usual peak months for flu in the northern hemisphere. It needs to be given every year since besides the short lived nature of  the protection, the most effective strains for the vaccine will change due to drift or shift.

For children, a subunit vaccine is recommended.

The full text of the Advisory Committee on Immunization Practices (or ACIP) Recommendations for the Prevention and Control of Influenza is published in the Morbidity and Mortality Weekly Report (MMWR), Recommendations and Reports, April 30, 1999 / Vol. 48 / No. RR_4. http://www2.cdc.gov/mmwr/mmwr_rr.html

This is updated annually and includes extensive advice about who should or should not receive vaccine, when it should be administered, and antiviral drugs. 

 

A selection from 1999 information - http://www2.cdc.gov/mmwr/mmwr_rr.html

RECOMMENDATIONS FOR THE USE OF INFLUENZA VACCINE

Influenza vaccine is strongly recommended for any person aged >6 months who — because of age or underlying medical condition — is at increased risk for complications of influenza. In addition, health-care workers and others (including household members) in close contact with persons in high-risk groups should be vaccinated to decrease the risk of transmitting infection to persons at high risk. Influenza vaccine also can be administered to any person who wishes to reduce the chance of becoming infected with influenza (the vaccine can be administered to children as young as 6 months).

Persons at High Risk for Influenza-Related Complications

· persons aged >65 years

· residents of nursing homes and other chronic-care facilities that house persons of any age who have chronic medical conditions

· adults and children who have chronic disorders of the pulmonary or cardiovascular systems, including asthma

· adults and children who have required regular medical follow-up or hospitalization during the preceding year because of chronic metabolic diseases (including diabetes mellitus), renal dysfunction, hemoglobinopathies, or immunosuppression (including immunosuppression caused by medications)

· children and teenagers (aged 6 months to 18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing Reye syndrome after influenza

· women who will be in the second or third trimester of pregnancy during the influenza season.

Persons Who Can Transmit Influenza to Those at High Risk

Persons who are clinically or subclinically infected can transmit influenza virus to persons at high risk for complications from influenza. Efforts to protect members of high-risk groups against influenza might be improved by reducing the likelihood of influenza exposure from their care givers. Therefore, the following groups should be vaccinated:

· physicians, nurses, and other personnel in both hospital and outpatient-care settings

· employees of nursing homes and chronic-care facilities who have contact with patients or residents

· employees of assisted living and other residences for persons in high-risk groups

· persons who provide home care to persons in high-risk groups

· household members (including children) of persons in high-risk groups.

Other Groups To Consider include : persons infected with human immunodeficiency virus, travelers (see CDC site for more details).

General Population

Physicians should administer influenza vaccine to any person who wishes to reduce the likelihood of becoming ill with influenza (the vaccine can be administered to children as young as 6 months). Persons who provide essential community services should be considered for vaccination to minimize disruption of essential activities during influenza outbreaks. Students or other persons in institutional settings (e.g., those who reside in dormitories) should be encouraged to receive vaccine to minimize the disruption of routine activities during epidemics.

 

Chemotherapy

Rimantadine and amantadine block virus entry across the endosome and also interfere with virus release. They are good prophylactic agents for influenza A, but there are some problems in taking them on a long term basis. They may be given as protective agents during an outbreak, especially to those at severe risk and key personnel. They may also be given at the time of vaccination for a few weeks, until the humoral response has time to develop. (There is some evidence that these drugs can help prevent more serious complications if given early in infection.)

Some neuraminidase inhibitors  are currently in clinical trials, two (Relenza, Tamiflu) have  been approved by the FDA. They are active against both influenza A and inlluenza B.

Other treatment

The best treatments are rest, liquids, anti-febrile agents (not aspirin in the young or adolescent, since Reye's disease is a potential problem).

Be aware of and treat complications appropriately.

 

ONGOING VACCINE DEVELOPMENT

A new vaccine for influenza virus is currently in clinical trials.

1. The virus is a cold-adapted strain which can grow in the upper respiratory tract where it is cooler, but grows poorly in the lower respiratory tract. It is attenuated - much less pathogenic than wild-type virus - due to multiple changes in the various genome segments.

2. Reassortment is used to generate viruses which have six gene segments from the attenuated virus and the HA and NA coding segments from the virus which is likely to be a problem in the up-coming influenza season. A reassortant is generated for each strain expected to be a problem.

3. This is a live vaccine, given intranasally as a spray. It generates an IgA response and an IgM/G response.

 

COMPARISON OF INFLUENZA A, B AND C

 

TYPE A

 TYPE B

TYPE C

Severity of illness

++++

++

+

Animal reservoir

yes

no

no

Human pandemics

yes

no

no

Human epidemics

yes

yes

no (sporadic)

Antigenic changes

shift, drift

drift

drift

Segmented genome

yes

yes

yes

Amantadine, rimantidine

sensitive

no effect

no effect

Zanamivir (Relenza)

sensitive

sensitive

 

Surface glycoproteins

 2

2

(1)


 

 


 






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