InfluenzaJ11.1

Influenza is an epidemic disease caused by the influenza virus that occurs during the cold season.

S.a. Influenzae virus

The influenza virus is an RNA virus of the orthomyxovirus family. Based on the two antigens nucleoprotein (NP) and matrix antigen (M) located inside the virus, the virus is divided into the 3 types A, B and C. The types A and B are morphologically similar.

The Influenza A virus is classified as influenza A virus because of the glycoproteins:

- haemagglutinin (H) and

- neuraminidase (N) into further subtypes.

Haemagglutinin (H) is rod-shaped and enables attachment to the host cells.

The neuraminidase (N) has the shape of a fungus and causes the release of the viruses from the infected cells and also their spread in the respiratory tract.

In the meantime, 18 H-subtypes and 9 N-subtypes are known. However, so far only 6 H-types (H1, H2, H3, H5, H7, H9) and 3 N-subtypes (N1, N2, N7) have been detected in human epidemics. However, other subtypes can occur at any time.

The designation of new subtypes depends on

- Type

- first site

- sequential number

- Year

- Antigen formula (H or N)

Example: Influenza A/ California/7/2009(H1N1)

Transmission

The transmission occurs by droplet infection and also by smear infection. However, a high virus titre must be present in the nasopharyngeal secretion and the haemagglutinin of the virus envelope must be enzymatically cleaved before the viruses can enter the cells of the host organism. This cleavage is made possible by certain bacteria (e.g. staphylococci, which are found in varying numbers in the anterior nasal cavity in healthy individuals, or streptococci). These bacteria produce proteases that cleave haemagglutinin and thus clear the way for influenza viruses. In this respect, a bacterial infection can pave the way for influenza pneumonia.

Incubation period

1-4 days

Influenza A and Influenza B are spread worldwide, while Influenza C occurs only sporadically.

Influenza epidemics occur with a time lag in the hemisphere:

- southern hemisphere May to October

- northern hemisphere November to April

In immunocompromised and elderly people, the mortality rate is significantly higher.

Since the immunity is subtype- or variant-specific, one can fall ill with influenza several times.

The influenza A virus causes most epidemics and also pandemics. In the A virus, antigenic changes occur repeatedly, in which individual amino acids in haemagglutinin are exchanged, the so-called point mutation. In addition or separately, an antigen drift can occur in which individual amino acids of the neuramidase are replaced by new variants. These new variants of the virus subtype can be observed in epidemics approximately every 2 -3 years.

Sometimes a new subtype (also called antigen shift ) is created by reassortment in epidemics, in which whole gene sections are exchanged between the viruses.

Since the genome of influenza A viruses consists of 8 individual RNA segments, reassortment is favoured as soon as a cell is infected with two different influenza A viruses.

Reassortment in pigs (see below "porcine influenza") between avian and human influenza A viruses leads to a severe pandemic with millions of deaths worldwide approximately every 10 - 40 years, as the population is unprotected against the new virus subtype.

Previous pandemics:

- 1918/19: Spanish A (H1N1) pandemic, so-called Spanish flu

- 1957/58: Asia A (H2N2) pandemic, so-called Asian flu

- 1968/69: Hong Kong A (H3N2) pandemic, so-called Hong Kong flu

- 2009/2010: A (H1N1/2009) pandemic, so-called swine flu

Avian influenza, also known as "bird flu" (A/H5N1) and (A/H7N9), comprises about 15 different avian influenza viruses and is a highly contagious disease exclusively for birds.

However, the avian viruses could combine with human viruses by reassortment and thus trigger a human pandemic. The transmission of H5N1 viruses from person to person has now been proven, but the risk of transmission is extremely low.

The situation is different with swine influenza, also called porcine influenza, A(H1N1) or A(H3N2). This can also infect humans. Patients without serious pre-existing conditions usually have a mild course, whereas people with pre-existing conditions often have a severe course with complications.

Influenza B mainly affects children and young people. The course is usually mild. An antigenic shift has not yet been detected in influenza B viruses, but changes in the antigens in the sense of antigen drift have been observed. Influenza B is exclusively human pathogenic, animals cannot become ill from it.

The Influenza C plays a subordinate role. Diseases occur only sporadically.

The clinical picture is very different depending on the type of virus. At about 1/3 d. F. a more or less severe febrile illness occurs, another third of the disease is mild and the last third is asymptomatic.

The course of the disease without complications lasts about 1 week.

Symptoms:

Typical is a sudden onset of the disease with

- severe illness

- fever >38.5° Celsius

- shivering

- Laryngo- tracheobronchitis with mostly unproductive cough

- rarely little, but tough sputum, occasionally then with low haemoptysis

- Rhinitis, possibly with nosebleeds

- Sore throat

- Conjunctivitis

- Photophobia

- Headaches

- joint and muscle pain

- the face looks bloated

- rarely gastrointestinal symptoms

The fever usually lasts for 2-3 days and shows a single peaked fever curve. If there is a second peak of fever, a secondary bacterial infection can be assumed.

In an uncomplicated course, BSG, leucocytes and CRP are usually within the normal range. The serum iron may be decreased.

In case of a bacterial superinfection BSG and CRP increase, leucocytosis is found. However, the serum iron shows normal values.

During a known influenza epidemic, clinical diagnosis is usually sufficient.

However, sporadic cases of influenza should always be clarified virologically. A clarification is also recommended for patients at risk and in cases of unclear diagnosis.

Nasal and throat swabs, pharyngeal irrigation fluid and sputum are suitable for pathogen detection.

The highest sensitivity is achieved with nasal swabs.

Caution: After the first two days of illness, the probability of a positive test result decreases continuously!

The following tests are available:

- Nucleic acid detection by PCR

- Antigen detection by ELISA

- Antigen detection by rapid test

- Virus Culture

- Antibody detection

The gold standard is the PCR test. However, the diagnosis is usually confirmed by rapid viral tests that detect either the viral nucleoprotein or the neuramidase. These tests have a specificity of 94-100 % and a sensitivity of 67-94 % (a negative result does not exclude the presence of disease).

Antibody detection is of retrospective importance only, as in this case an at least fourfold increase in titer must be observed within 1-2 weeks.

1. viral infections by rhinoviruses, parainfluenza viruses, adenoviruses, coronaviruses

Rule of thumb: an influenza starts suddenly out of well-being with fever >38,5 ° C and typical muscle and limb pain

2. pertussis

3. Pneumonia (s.d.) caused by other pathogens

Possible risk patients for complications are:

- Children

- older people > 60 years

- Pregnant women

- Patients with previous illnesses

- Patients with a weakened immune system

Complications can occur:

- Primary hemorrhagic or interstitial pneumonia (this often ends fatally)

- secondary bacterial pneumonia due to a superinfection (occurs most frequently); the following pathogens are usually involved: Staphylococcus aureus, pneumococcus, haemophilus influenzae, etc.

- Otitis media (mostly in children)

- Pseudocroup in infants

- Exacerbation of a pre-existing lung disease

- Purpura-Schönlein-Henoch (exclusively for infections with the influenza A virus)

- Myocarditis (sometimes with lethal course)

- peracutely fatal courses of disease rarely occur in young adults

If complications occur, the convalescence is significantly delayed. General weakness, fatigue and hypotension can last for weeks.

Patients should be isolated immediately for about 7 days in case of avian influenza and in case of a new pandemic. The medical staff must observe protective measures in the form of protective clothing, FFP2 masks or FFP3 masks, protective goggles, gloves, hand disinfection, etc.

It is recommended to contact the responsible health authority by telephone for further measures and also with regard to the obligation to report (for details see below Obligation to report).

For uncomplicated procedures, treatment with paracetamol or ASS is completely sufficient. ASA very effectively inhibits the reproduction of the virus, but relatively high doses are required.

Never give ASA to children or adolescents under 18 years of age due to the risk of Reye's syndrome!

As soon as there are signs of a bacterial superinfection (e.g. 2nd peak fever), antibiotics should be given after the pathogen has been detected, e.g.:

- Betalactam-betalactamase inhibitor plus macrolide:

e.g. amoxicillin/clavulanic acid 3 - 4 x 2.2 g/d

plus macrolide

e.g. Azithromycin 1 x 500 mg/d

- or pseudomonas active penicillin plus beta-lactamase inhibitor:

e.g. piperacillin/tazobactam 3 - 4 x 4.5g

plus fluoroquinolone

e.g. Levofloxacin 1 - 2 x 500mg/d

Antiviral therapy

If a serious course of the disease is suspected or the patient belongs to the above-mentioned risk groups (see above complication), antiviral therapy should be started, even if laboratory diagnostic confirmation is not yet available, provided that:

- an influenza epidimia has occurred in the region concerned and has been confirmed virologically

- a typical symptomatology with fever exists

- other infectious diseases have been excluded as causes of the symptoms

Virustatics block the activity of the neuramidase and the release of new viruses, which ultimately mitigates and shortens the course of the disease. The typical influenza symptoms are reduced by 40 % and 50 % fewer superinfections are allowed to occur.

Treatment should be started within the first 48 hours after the onset of symptoms. In severe cases, however, it is advisable to continue treatment beyond this period, but with higher doses and longer therapy duration, as it can still have a positive influence on the prognosis.

In the case of avian influenza, virustatics should also be used because of the presumably more severe course of the disease.

The following antivirals are available:

For influenza A and B:

- Zanamivir e.g. Relenza 5 mg powder for inhalation; dosage: 2 x 10 mg /d as powder inhalation for a total of 5 days. Relenza may cause bronchospasm, even in patients without known respiratory disease. No dose adjustment necessary in renal failure or elderly patients. Zanamivir is approved for children > 5 years. The medication should not be prescribed during pregnancy or lactation.

- Oseltamivir e.g. Tamiflu 75 mg hard capsules or Tamiflu 12 mg/ml powder; dosage: 2 x 75mg p.o. over 5 days. A dose adjustment is absolutely necessary in case of renal insufficiency. Tamiflu is approved for children over 1 year of age. Occasionally gastrointestinal symptoms may occur. Especially in children, confusion with a potential for self-harm can sometimes occur. In rare cases, Stevens-Johnson syndrome may also occur.

Only effective with influenza A:

- Amantadine

However, the drug is currently no longer recommended because circulating influenza A subtypes have now developed complete resistance.

Symptomatic therapy:

One should pay attention to a sufficient fluid intake.

For bedridden patients, a thromboembolism prophylaxis is advisable.

Patients should take it easy during the acute illness and only gradually increase the physical strain during convalescence.

Worldwide, influenza causes about 1 million deaths per year, and in the case of pandemics it can be considerably more. For example, the 1918/1919 pandemic caused > 20 million deaths due to influenza, i.e. more people than died in the First World War.

The average lethality rate of influenza is 0.4%, that of avian influenza (colloquially: bird flu) up to 50%.

We find a general excess mortality rate in immunocompromised and elderly people.

90 % of the deaths concern people > 60 years.

The active vaccination against Influenza contains a tri- or tetravalent inactivated vaccine (2 A strains plus 1-2 B strains. The vaccination must be repeated annually, as the vaccine is adapted to the recommendations of the WHO to ensure that the antigen composition corresponds to the current epidemic strains.

A problem is the reduced effectiveness of the vaccine in older people (see Frailty Syndrome) due to immunosenescence, which leads to a decrease in effectiveness to 50-60%, compared to 70-90% in persons < 65 years.

The mortality rate in people > 60 years can be demonstrably reduced by the vaccination. However, exact figures on this are very different in the literature.

There are also indications that the vaccination reduces cardiovascular mortality (apoplexy, myocardial infarction).

The nasal attenuated vaccine available for children or adolescents between the ages of 2 and 18 does not work reliably against A/H1N1 viruses.

Sufficient protection for the patient is available about 14 days after vaccination.

Up to now it was said that the active ingredient of the vaccination lasts only 3-4 months and therefore one should not be vaccinated too early. November was recommended as the optimum time, as the peak of the disease typically falls at around the beginning of February. In the meantime, there are manufacturer's statements according to which the vaccination effect lasts 6 - 12 months.

Side effects

Occasionally slight general reactions occur, such as

- pressure pain at the injection site

- egg protein allergy ( rare )

- Vasculitis (very rare)

- Thrombocytopenia (very rare)

- Guillain-Barré syndrome (1:1 million)

- Narcolepsy after vaccination against swine flu (very rare)

Indication

- generally all persons > 60 years

- Persons with a congenital or acquired immunodeficiency

- People with cardiopulmonary diseases

- Pregnant women

- Persons with increased exposure

- persons exposed to direct contact with birds, wild birds (there is no protection against avian infection, but there is protection against double infection)

- if epidemics occur, ALL patients should be vaccinated

Contraindication

- Patients who are acutely ill with a feverish infection

- Persons with protein allergy (here a chicken protein-free vaccine is available)

Important

After an influenza vaccination the HIV test can be false positive for up to 3 weeks!

Obligation to notify:

• According to § 7 of the Infection Protection Act (IfSG), there is a nationwide obligation to report influenza viruses to the laboratory by name in case of direct evidence.
• In Saxony, there is also an obligation for the doctor to report both the illness and the death from influenza according to the regulation on the extension of the obligation to report transmissible diseases and pathogens under the Infection Protection Act § 1.

1. Herold et al. (2017) Internal Medicine pp 875-877, pp 921-922.
2. Infection Protection Act (IfSG) of the Federal Ministry § 7 Notifiable evidence of pathogens.
3. Kasper DL (2015) Harrison's Internal Medicine pp 1144-1147
4. Köhler et al (2010) Pneumology 54: 90
5. Li YT et al (2019) Avian influenza viruses in humans: lessons from past outbreaks. Br Med Bull 132: 81-95.
6. Loscalzo J et al (2011) Harrison's pulmonary medicine and intensive care p 163-175.
7. LVWA Saxony Additional reporting obligation according to the ordinance on the extended reporting obligation for communicable diseases.
8. RKI Guide Influenza