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Influenza - Many features are common with those of the paramyxovirus infections of the respiratory tract

Many features are common with those of the paramyxovirus infections of the respiratory tract

Influenza is a disease caused by a member of the Orthomyxoviridae. Many features are common with those of the paramyxovirus infections of the respiratory tract

Clinical Features

Influenza is characterised by fever, myalgia, headache and pharyngitis. In addition there may be cough and in severe cases, prostration. There is usually not coryza (runny nose) which characterises common cold infections.

Infection may be very mild, even asymptomatic, moderate or very severe (see letter from 1918, - attached at end of page).

Source

The reservoir is acute infection in other human beings.

Spread

Is rapid via aerial droplets and fomites with inhalation into the pharynx or lower respiratory tract.

Incubation

Is short: 1-3 days. Rapid spread leads to epidemics

Complications

Tend to occur in the young, elderly, and persons with chronic cardio-pulmonary diseases

Consist of:

  1. pneumonia caused by influenza itself; and
  2. pneumonia caused by bacteria
    (Haemophilus influenzae - Staphylococcus aureus - Streptococcus pneuminiae )
  3. Other viral superinfection, eg. Adenovirus.
    (Overall death rates increase in times of influenza epidemics. )

Laboratory Diagnosis

A. Viral Isolation:

Respiratory secretions:

- direct aspirate - gargle - nasal washings

a) Rapid examination of cells by immunofluorescence.
b) Inoculation of cell cultures (or eggs).

B. Serology
serum antibodies by haemagglutination inhibition

Influenza Viruses

Diagramatic representation of the morphology of an influenza virion.

The virion is generally rounded but may be long and filamentous.
A single-stranded RNA genome is closely associated with a helical nucleoprotein (Np), and is present in eight separate segments of ribonucleoprotein (RNp), each of which has to be present for successful replication. The segmented genome is enclosed within an outer lipoprotein envelope. An antigenic protein called the matrix protein (Mp 1) lines the inside of the envelope and and is chemically bound to the RNp. The envelope carries two types of protruding spikes. One is a box-shaped protein, called the neuraminidase (NA), of which there are nine major antigenic types, and which has enzymic properties as the name implies.

The other type of envelope spike is
a trimeric protein called the haemagglutinin (HA)
(illustrated on the right)
of which there are 13 major antigenic types. The haemagglutinin functions during attachment of the virus particle to the cell membrane, and can combine with specific receptors on a variety of cells including red blood cells.
The lipoprotein envelope makes the virion rather labile - susceptible to heat, drying, detergents and solvents.

Replication

The Life Cycle of Influenza Virus

Receptor-bound viruses are taken into the cell by endocytosis. In the low pH environment of the endosome, RNp is released from Mp1, and the viral lipoprotein envelope fuses with the lipid-bilayer of the vesicle, releasing viral RNp into the cell cytoplasm, from where it is transported into the nucleus. New viral proteins are translated from transcribed messenger RNA (mRNA). New viral RNA is encased in the capsid protein, and together with new matrix protein is then transported to sites at the cell surface where envelope haemagglutinin and neuraminadase components have been incorporated into the cell membrane. progeny virions are formed and released by budding.
The cell does not die (at least not initially).

Flu is one of a rare few viruses that has its genome in separate segments (eight). - This increases the potential for recombinants to form (by interchange of gene segments if two different viruses infect the same cell), and may contribute to the rapid development of new flu strains in nature - can also be duplicated in the laboratory (used for making vaccine strains). Avian and human strains recombining in pigs in the Far East may permit virulent human strains to evolve.

Classification of Virus Strains

Is done on the basis of antigenicity of Np and Mp into three main groups:

Influenza A -HA undergoes minor and occasional major changes - very important.
- NA some variation.
Influenza B) Undergoes relatively slow change in HA with time. Known only in man.
Influenza C) Uncommon strain, known only in man. NOMENCLATURE

Influenza strains are named in the following way:

ASINGApORE686(H1N1)
TYpE
of influenza
TOWN
where first isolated
NUMBER
of isolates
YEAR
of isolation
MAJOR
TYpE of HA and NA

Epidemiology

Influenza A virus is essentially an avian virus that has "recently" crossed into mammals. Birds have the greatest number and range of influenza strains. Avian haemagglutinins sometimes appear in pig human and horse influenza strains.

Every now and then (10 - 15 years) a major new pandemic strain appears in man, with a totally new HA and sometimes a new NA as well (antigenic shift). This variant causes a major epidemic around the world (pandemic).

Over the subsequent years this strain undergoes minor changes (antigenic drift) every two to three years, probably driven by selective antibody pressure in the populations of humans infected.
See chart below indicating main pandemic strains in previous years.

Influenza A Evolution

1874 --- (H3N8) 1890 --- (H2N2) .........................pandemic
1902 --- (H3N2) 1918 --- (H1N1)..........................pandemic
1933 --- (H1N1)..........................First strains isolated
1947 --- (H1N1)..........................Variation detected
1957 --- (H2N2).........................."Asian" Flu pandemic
1968 --- (H3N2).........................."Hong Kong" Flu pandemic
1976 --- (H1N1).........................."Swine" Flu, non-epidemic
1977 --- (H1N1) + (H3N2)........."Russian" Flu epidemic

This constant antigenic change down the years means that new vaccines have to be made on a regular basis.

New influenza strains spread rapidly in children in schools and crches and in places where people crowd together. Influenza epidemics may cause economically significant absenteeism.

Treatment

Antibiotics are often prescribed - have no effect on virus but may prevent or cure bacterial superinfection. The drug Amantadine may prevent influenza if taken continuously by high-risk persons at the time of an epidemic, but is not used widely.

prevention

Vaccines at best give about 70% protection. They may sometimes not be effective against the most recently evolved strains because the rate of evolution outpaces the rate at which new vaccines can be manufactured.

Types of Vaccine

Killed Whole Virus
Rather pyrogenic, not used today.

Live Virus
Attenuated strains were widely used in Russia but not elsewhere.

Virus Subunit
HA extracted from recombinant virus forms the basis of today's vaccines.
For example, the WHO Recommendation for Influenza Vaccine, 1995-1996, contains two A strains and one B strain:-
A / Singapore / 6 / 86 (H1N1)
A / Johannesburg / 33 / 94 (H3N2)
B / Beijing / 84 / 93

Synthetic

Much research is being done to try and find a neutralising epitope that is more stable, and can therefore be used for a universal vaccine.

prospects

Because another devastating pandemic strain (cf 1918 pandemic) may appear at any time, the World Health Organisation (WHO) maintains worldwide surveillance of flu strains and makes predictions of suitable strains for vaccine production.

GA Keen
May 1995

UCT

pandemic influenza 1918

An illustration of what influenza can be like: a copy of a letter by professor N R Grist (Glasgow) published in the British Medical Journal of 22-29 December 1979:-

Epidemic influenza remains the biggest and unconquered acute threat to human health, inflicting damage and death far beyond familiar notification data. The impact of influenza A is particularly severe during periodic pandemics owing to novel antigenic variants which override immunity from experience of earlier subtypes. It is salutary to remember that we do not really understand why the devastating pandemic of 1918-19 was so severe, and that we cannot therefore be confident that our modern medical measures would succeed against a similar future challenge.

As a reminder of the grim reality of that pandemic, the following letter may be of interest. It was found in a trunk in Detroit among other medical papers handed to the department of epidemiology of the University of Michigan. A copy was given to me in 1959 by the late Dr T Francis, jun, and it is now published with the agreement of Dr V Hawthorne, his successor as head of department.
N R GRIST

Copy of original letter found in Detroit in 1959:

Camp Devens, Mass.
Surgical Ward No 16
29 September 1918
(Base Hospital)

My dear Burt-

It is more than likely that you would be interested in the news of this place, for there is a possibility that you will be assigned here for duty, so having a minute between rounds I will try to tell you a little about the situation here as I have seen it in the last week.

As you know I have not seen much pneumonia in the last few years in Detroit, so when I came here I was somewhat behind in the niceties of the Army way of intricate Diagnosis. Also to make it good, I have had for the last week an exacerbation of my old "Ear Rot" as Artie Ogle calls it, and could not use a Stethoscope at all, but had to get by on my ability to "spot" ' em thru my general knowledge of pneumonias. I did well enough, and finally found an old phonendoscope that I pieced together, and from then on was all right. You know the Army regulations require very close locations etc.

Camp Devens is near Boston, and has about 50,000 men, or did have before this epidemic broke loose. It also has the Base Hospital for the Div. of the N. East. This epidemic started about four weeks ago, and has developed so rapidly that the camp is demoralized and all ordinary work is held up till it has passed. All assembleges of soldiers taboo.

These men start with what appears to be an ordinary attack of LaGrippe or Influenza, and when brought to the Hosp. they very rapidly develop the most viscous type of pneumonia that has ever been seen. Two hours after admission they have the Mahogany spots over the cheek bones, and a few hours later you can begin to see the Cyanosis extending from their ears and spreading all over the face, until it is hard to distinguish the coloured men from the white. It is only a matter of a few hours then until death comes, and it is simply a struggle for air until they suffocate. It is horrible. One can stand it to see one, two or twenty men die, but to see these poor devils dropping like flies sort of gets on your nerves. We have been averaging about 100 deaths per day, and still keeping it up. There is no doubt in my mind that there is a new mixed infection here, but what I dont know. My total time is taken up hunting Rales, rales dry or moist, sibilant or crepitant or any other of the hundred things that one may find in the chest, they all mean but one thing here -pneumonia-and that means in about all cases death.

The normal number of resident Drs. here is about 25 and that has been increased to over 250, all of whom (of course excepting me) have temporary orders-"Return to your proper Station on completion of work". Mine says "permanent Duty", but I have been in the Army just long enough to learn that it doesnt always mean what it says. So I dont know what will happen to me at the end of this.

We have lost an outrageous number of Nurses and Drs., and the little town of Ayer is a sight. It takes Special trains to carry away the dead. For several days there were no coffins and the bodies piled up something fierce, we used to go down to the morgue (which is just back of my ward) and look at the boys laid out in long rows. It beats any sight they ever had in France after a battle. An extra long barracks has been vacated for the use of the Morgue, and it would make any man sit up and take notice to walk down the long lines of dead soldiers all dressed and laid out in double rows. We have no relief here, you get up in the morning at 5 .30 and work steady till about 9.30 p.M., sleep, then go at it again. Some of the men of course have been here all the time, and they are TIRED.

If this letter seems somewhat disconnected overlook it, for I have been called away from it a dozen times the last time just now by the Officer of the Day, who came in to tell me that they have not as yet found at any of the autopsies any case beyond the Red. Hepatitis. stage. It kills them before they get that far.

I dont wish you any hard luck Old Man but I do wish you were here for a while at least. Its more comfortable when one has a friend about. The men here are all good fellows, but I get so damned sick o pneumonia that when I go to eat I want to find some fellow who will not "Talk Shop" but there aint none nohow. We eat it live it, sleep it, and dream it, to say nothing of breathing it 16 hours a day. I would be very grateful indeed if you would drop me a line or two once in a while, and I will promise you that if you ever get into a fix like this, I will do the same for you.

Each man here gets a ward with about 150 beds, (Mine has 168) and has an Asst. Chief to boss him, and you can imagine what the paper work alone is - fierce,-- and the Govt. demands all paper work be kept up in good shape. I have only four day nurses and five night nurses (female) a ward-master, and four orderlies. So you can see that we are busy. I write this in piecemeal fashion. It may be a long time before I can get another letter to you, but will try.

This letter will give you an idea of the monthly report which has to be in Monday. I have mine most ready now. My Boss was in just now and gave me a lot more work to do so I will have to close this.

Good By old pal,
"God be with you till we meet again"
Keep the Bouells open.
(Sgd) Roy.

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