Influenza J11.1

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 from the orthomyxovirus family. The virus is divided into 3 types, A, B and C, based on the two antigens located inside the virus, nucleoprotein (NP) and matrix antigen (M). Types A and B are morphologically similar.

The influenza A virus is recognized by the glycoproteins incorporated in the viral envelope:

• - haemagglutinin (H) and
• - neuraminidase (N) incorporated in the viral envelope.

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

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

There are now 18 known H-subtypes and 9 N-subtypes. However, only 6 H-types (H1, H2, H3, H5, H7, H9) and 3 N-subtypes (N1, N2, N7) have been detected in human epidemics to date. However, other subtypes can occur at any time. The designation of new subtypes is based on

• - type
• - first place of discovery
• - consecutive number
• - year
• - Antigen formula (H or N)

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

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

Influenza epidemics occur with a time lag in the hemispheres:

• - southern hemisphere May to October
• - northern hemisphere November to April

There is a significantly increased mortality rate (excess mortality) among people with weakened immune systems and older people.

Influenza was the infectious disease with the highest incidence and mortality rate in Europe until the COVID-19 epidemic emerged.

As immunity is subtype or variant-specific, it is possible to contract influenza more than once.

A study conducted in Israel examined age-specific mortality during the 1999-2006 influenza season. The overall mortality rates in this study ranged from 7.7 to 36.1 / 100,000 for all causes and from 4.4 to 24.4 / 100,000 for respiratory and circulatory diseases. Influenza-associated deaths from respiratory and circulatory diseases ranged from 280 to 1516 per year; importantly, about 90% of deaths occurred in persons over 65 years of age, while only about 1% occurred in persons under 50 years of age (Linhart Y et al. 2011).

The influenza A virus causes most epidemics and pandemics. In the case of the A virus, antigenic changes repeatedly occur in which individual amino acids in the 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 approximately every 2 - 3 years during epidemics.

Sometimes a new subtype (also known as an antigenic shift ) arises during epidemics through reassortment, in which entire gene segments are exchanged between the viruses.

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

Reassortment in pigs (see also "porcine influenza" below) 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, known as Asian flu
• - 1968/69: Hong Kong A (H3N2) pandemic, so-called Hong Kong flu
• - 2009/2010: A (H1N1/2009) pandemic, known as swine flu

Avian influenza, also known as "bird flu" (A/H5N1) and (A/H7N9), comprises around 15 different avian influenza viruses and is a highly contagious disease for birds only. However, the avian viruses could combine with human viruses through reassortment and thus trigger a human pandemic. The transmission of the H5N1 viruses from person to person has now been proven, but the risk of transmission is extremely low.

Swine flu: The situation is different with swine influenza, also known as porcine influenza, A(H1N1) or A(H3N2). This can also infect humans. However, patients without serious pre-existing illnesses usually have a mild course, whereas people with pre-existing illnesses often have a severe course with complications.

Influenza B mainly affects children and adolescents. The course is usually mild. An antigenic shift has not yet been detected in influenza B viruses, but changes in antigens in the sense of antigenic drift have been observed. Influenza B is exclusively pathogenic to humans; animals cannot contract the disease.

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

Transmission occurs by droplet infection and also by smear infection. Adhesion of the influenza virus via hemagglutinin to sialic acid on the surface of epithelial cells of the upper respiratory tract. However, a high virus titer must be present in the nasopharyngeal secretion and the haemagglutinin of the viral envelope must be enzymatically cleaved before the viruses can penetrate 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 of healthy people, or streptococci). These bacteria produce proteases that cleave the hemagglutinin and thus clear the way for the influenza viruses. In this respect, a bacterial infection can be a precursor to influenza pneumonia. Incubation period: 1-4 days

The clinical picture varies greatly depending on the type of virus. In approx. 1/3 d. F. develop a more or less severe febrile illness, a further third of F. show a mild course and the last third of F. are asymptomatic.

The course of the disease without complications lasts about 1 week. Typical is a sudden onset with:

- severe feeling of illness

- fever >38.5° Celsius

- chills

- Laryngo-tracheobronchitis with mostly unproductive coughing

- Rarely little but tough sputum, occasionally with slight hemoptysis

- Rhinitis, possibly with nosebleeds

- sore throat

- conjunctivitis

- photophobia

- Headache

- Pain in limbs and muscles as well as arthralgia

- the face appears puffy

- Rarely gastrointestinal symptoms

The fever usually lasts 2-3 days and shows a one-peak fever curve. If there is a second fever peak, 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, the 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 if the diagnosis is unclear.

Nasal and throat swabs, pharyngeal lavage fluid and sputum are suitable for detecting the pathogen.

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 neuramidase. These tests have a specificity of 94-100 % and a sensitivity of 67-94 % (a negative result therefore does not rule out disease).

Antibody detection is only of retrospective significance, as at least a four-fold increase in titre 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

Patients who may be at risk of complications are:

- children

- Elderly people > 60 years

- pregnant women

- Patients with pre-existing conditions

- Patients with a weakened immune system

Complications can occur:

- Primary hemorrhagic or interstitial pneumonia (often lethal)

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

- Otitis media (mostly in children)

- Pseudocroup in infants

- Exacerbation of a pre-existing lung disease

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

- Myocarditis (sometimes with a lethal course)

- peracute fatal courses rarely occur in still young adults

If complications occur, convalescence is significantly delayed. General weakness, fatigue and hypotension may persist 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 always adapted to the WHO recommendations so that the antigen composition corresponds to the current epidemic strains. The problem is the reduced effectiveness of the vaccine in older people (see frailty syndrome below) due to immunosenescence, which leads to a decrease in effectiveness to 50-60%, compared to 70-90% in people < 65 years.

The mortality rate in people > 60 years of age can be demonstrably reduced by vaccination. However, exact figures vary widely in the literature.

There is also evidence that vaccination reduces cardiovascular mortality (apoplexy, myocardial infarction).

The nasal attenuated vaccine available for children and adolescents from 2 to 18 years of age is not effective against A/H1N1 viruses.

Sufficient protection for the patient is provided approximately 14 days after vaccination. Previously, it was said that the active ingredient of the vaccine only lasts for 3-4 months and that people should therefore not be vaccinated too early. November was recommended as the optimal time, as the peak of the disease typically falls around the beginning of February. In the meantime, manufacturers have stated that the vaccine is effective for 6 - 12 months.

Side effects

Occasionally, mild general reactions occur, such as

- Pressure pain at the injection site

- Egg white 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 congenital or acquired immunodeficiency

- Persons with cardiopulmonary diseases

- pregnant women

- Persons with increased exposure

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

- in the event of epidemics, ALL patients should be vaccinated

Contraindication

- Patients who are acutely ill with a febrile infection

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

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 S 875-877, S 921-922
2. Infection Protection Act (IfSG) of the Federal Ministry § 7 Notifiable evidence of pathogens
3. Kasper DL (2015) Harrison's Internal Medicine S.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. Linhart Y et al. (2011) Excess mortality from seasonal influenza is negligible below the age of 50 in Israel: implications for vaccine policy. Infection 39:399-404.

7. Loscalzo J et al. (2011) Harrison's pulmonary medicine and intensive care p. 163-175
8. LVWA Saxony Additional reporting obligation according to the ordinance on the extended reporting obligation for communicable diseases
9. RKI guide Influenza