REPORT FOR FINAL ASSESSMENT

Subject:pathophsyology
Student’s name:‫احمد اياد عبدالرحمن‬
Stage:third

MINISTRY OF HIGHER EDUCATION

AND SCIENTIFIC RESEARCH
UNIVERSITY OF DUHOK
COLLEGE OF PHARMACY

SCORES
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Introduction:
Influenza virus:is an infectious diseases caused by members of the Orthomyxovirus famil,
which cause acute respiratory infection. Originally, influenza viruses were assigned to the now-
defunct myxovirus family of negative-sense RNA viruses, named from myxa, Greek for
“mucus,” due to the ability of the virions to bind to and degrade mucins. influenza viruses have
a segmented genome which replicates in the nucleus.(1) The membrane envelope forms a
barrier inside of which when the virus particle is in circulation are the viral components
protected from the environment. A layer of matrix produced by the matrix protein is
immediately underneath the membrane envelope. The matrix protein layer contains the viral
genome, which consists of eight nucleoprotein-enveloped segments single-stranded RNA in the
negative sense.(2)

The pathogen:
There are 4 types of seasonal influenza viruses, types A, B, C and D. Influenza A and B viruses
circulate and cause seasonal epidemics of disease.
 Influenza virus circulation Two subtypes of influenza A, H1N1 and H3N2 are currently
circulating alongside influenza B viruses in the human population. In documented history, there
have only been three subtypes of haemagglutinin (HA) (H1, H2, H3) (which is glycoprotein on
the surface of virus and is responsible for infectivity) and two subtypes of neuraminidase (NA)
(N1, N2)(which is a type of neuraminidase found on the surface of influenza viruses that allows
the host cell to release the virus. Neuraminidases are enzymes that cleave sialic acid groups
from glycoproteins and are necessary for replication of the influenza virus.) that caused
pandemics and established themselves as human seasonal influenza viruses. Interestingly,
viruses of the same HA group do generally not circulate at the same time in the human
population.(3)
Influenza C virus is less frequently detected and usually causes mild infections, therefore it is
not of public health importance.
Influenza D viruses mainly affect bovine animals and are not known to infect or cause disease
in humans.(4)

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Entry pathway:
Virus entry is the surface glycoprotein hemagglutininthat contains the binding site of the host
receptor to allow the virus particle to attach to specific host cells, the fusion peptide that is
inserted into the target cell membrane during membrane fusion, and other structural elements
that may refold during the membrane fusion procedure. Since hemagglutininthat is a surface
glycoprotein on the virus particle, host antibodies readily identify it when influenza virus infects
the host. Nonetheless, influenza virus with special mechanisms is very capable of escaping the
host defense mechanism.
The influenza virus, like other animal viruses, binds to the surface of the host cell by
recognizing a particular receptor. The commonly known influenza virus receptor molecule is a
sialic acid (also known as N-acetylneuraminic acid) covalently linked to oligosaccharide ending
on glycoproteins or glycolipids. Sialic acid is present on the surface of several types of cells and
also on products which are secreted by cells. Sialylation is an important mechanism for masking
cells or microorganisms, as well as the products they make, so that the host immune system
does not recognize them. At the same time, the sialyl moiety is often used as ligands for
attachment proteins which have important cellular functions, or as receptors (co-receptors) for
microorganisms including viruses , bacteria , fungi, and parasites. Influenza virus is one of the
best known example that uses sialic acid as the receptor for cell entry.
Within each subunit of trimeric hemagglutininthat is located the sialic acid binding site of
influenza virus (Fig. 1.00). As there are several copies of hemagglutininthat on each influenza
virus particle, the attachment of influenza virus to the host cell surface could be regarded as a
multivalent binding event. The viral attachment is therefore relatively tight, although the
affinity of each individual sialyl moiety to its binding site on hemagglutininthat may be weak.
The process of importing the incoming virus particle to a location inside the cell begins after the
virus is attached to the host cell surface by binding to sialic acid by hemagglutininthat. There
are a large number of hemagglutininthat molecules on influenza virus particles, which may be
important for proper binding to the cell surface to cause the process of internalization. The entry
process follows a particular course, involving a variety of cellular factors (Fig. 1.1). The
influenza virus is picked up by endocytosis at the cell plasma membrane. The virus particle
quickly enters the coated vesicles (endosomes) inside the cell. The internalized virus particles
are transported within endosomes to locations near the nucleus The fusion of the virus
membranes with endosomes is induced by the acidification of late endosomes. Fusion results in
the release of viral RNA-dependent polymerase-associated nucleocapsid (RNP) into the nucleus
where viral transcription begins.(2)

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Figure:1.00

Figure:1.1

Antigenic variation:
The viral-specific RNA polymerase makes errors in its synthesis of viral RNAs at a high
frequency during the replication cycle. The errors during replication can produce a large
number of variants of the hemagglutininthat glycoprotein. Some of these will allow the existing
host antibodies to become resistant to neutralization by the influenza virus. Through this
selection mechanism, a new influenza virus that can reduce the effectiveness of the antibodies
raised in response to an earlier exposure or vaccination, requiring frequent reformulation of
influenza vaccines, is generated to escape the host immune system and can easily replicate in
the infected host. The novel variant of the influenza virus can spread to other hosts if they have
not been previously exposed to this variant either through vaccination or through natural
infection. This is the key reason why influenza virus comes back year after year, because new
influenza virus strains are circulating variants in each season, to which the human population
has not developed enough immunity. The same variations also occur in the NA glycoprotein,
some other surface glycoprotein in influenza virus, which is the same mechanism. These
changes in Glycoproteins HA and NA are called "antigenic drift. Through antigenic drifts,
amino acid sequences are substituted in areas exposed to antibody detection, while at the same
time, amino acid substitutions are restricted from locations necessary for receptor binding,

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maintaining a fusion peptide feature, and proper structural changes to mediate membrane
fusion. When hemagglutininthat amino acid substitutions are produced in the influenza virus
strain repertoire, they are mainly on the glycoprotein's exposed surface except for the receptor
binding site, the fusion peptide, and the amino acids that fit the fusion peptide before
hemagglutininthat structural changes for membrane fusion. (2)

Signs and symptoms:

A sudden onset of fever , cough (usually dry), headache , muscle and joint pain, severe malaise
(feeling unwell), sore throat, and a runny nose characterize seasonal influenza. The cough can
be serious, and may last 2 weeks or more. Most people recover from fever and other symptoms
within a week without needing medical attention. But influenza can cause serious illness or
death particularly in high-risk people. Acute medial otitis, sinusitis, pneumonia, and bronchitis
are typical influenza complications. Among such complications is mainly responsible among
secondary bacterial invasion of destroyed respiratory epithelium with Streptococcus
pneumoniae or Staphylococcus. Illnesses vary from mild to severe, to death. Hospitalization and
death mainly occur among groups at high risk. Worldwide, these annual epidemics are
estimated to result in approximately 3 to 5 million severe disease cases and approximately 290
000 to 650 000 respiratory deaths. In industrialized countries, most influenza-related deaths
occur among people 65 years of age or older. Epidemics can lead to high rates of absenteeism
for the worker / school and losses in productivity. During periods of peak illness clinics and
hospitals may be overwhelmed. The consequences of seasonal influenza epidemics in
developed countries are not well understood, but research suggests that 99 per cent of deaths in
children under the age of 5 with lower respiratory tract infections due to influenza are reported
in developing countries . Children with underlying bronchopulmonary dysplasia, asthma, cystic
fibrosis, heart disease, and neuromuscular disease are at higher risk of serious illness and
complications.(5)

Epidemiology:

Three influenza virus strains currently circulate predominantly in humans, two of type A (H1N1
and H3N2), and one of type B. The challenge for infants each year is unique, as they lack their
own protective antibodies. Antibodies transferred from the mother only protect for the first few
months of their lives. Primary influenza infection attack rate in young children is highest, and
they shed virus longer than adults. While sporadic cases are recorded throughout the year,
winter and rainy season outbreaks occur in temperate areas, and tropics and subtropics.
Influenza Surveillance Network report in India shows an increase in cases of influenza between
June and September, coinciding with the Indian moonsoon. Overcrowding helps to transmit
infection quickly, affecting mostly urban and sub-urban areas. There is also a higher attack rate
in army barracks, schools , colleges, and public transportation systems. Transmission of the
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disease occurs by droplets from the infected person or by direct contact with the patient or the
fomites. The period of influenza incubation is short; 1–2 days only. Peak viral shedding occurs
on the first day of illness but the transmissible period in young children can last up to 7–10
days. Children who use immunosuppressive drugs or on state of immunodeficiency shed virus
for longer periods. Antibodies appear in the first week and in two weeks, they reach the
maximum level. There is no cross immunity between different strains, and the immunity drops
to the level of pre-infection by about 12 mounth periods.(5)

Diagnosis:

Influenza diagnosis is usually done on the basis of flu-like clinical features as symptoms
without localization, especially if epidemiologically linked to cases of influenza. In some cases,
routine investigations may reveal unspecific hematological and radiological changes, including
leucopenia or infiltration / atelectasis. For all cases, confirmation by laboratory is not needed. It
should however be done in all children with severe illnesses requiring hospitalization or in
children at higher risk of complications.(5)

Confirmation of influenza can be done by:

1. In about half of the cases, almost normal-to-low TLC with lymphopaenia, mainly due to
decline in CD4 + T cells.

2. Thrombocytopaine.

3. High enzymes in the liver: aminotransferases, creatine kinase, and LDH.

4. Virus isolation on respiratory sample, plasma, urine, or stool by reverse transcriptase-PCR.

5. tissue  culture.

6. Serum detection.(6)

In intubated patients, respiratory specimen for the culture of viruses and RT-PCR may be
obtained from nasopharyngeal / throat swab or tracheal aspirates, preferably within 4–5 days of
illness. Real-time polymerase chain reaction (RT-PCR) test remains the key and most accurate

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of diagnosis for all of these studies. The collection and transport of samples should be carried
out according to the guidelines.(5)

Treatment:

Uncomplicated Seasonal Influenza Patients:

Patients that are not from a high-risk population will be diagnosed with symptomatic care and
are recommended to remain at home, if symptomatic, to reduce the risk of infecting someone
throughout the community. Care is aimed at relieving influenza symptoms such as fever.
Patients should monitor themselves to detect if their condition deteriorates and seek medical
attention In addition to symptomatic treatment as soon as possible, patients known to be in a
group at high risk for developing severe or complicated disease (see above) should be treated
with antiviralsAntiviral drug should be treated as soon as possible for patients with severe or
progressive clinical illness associated with suspected or confirmed influenza virus infection
(i.e., clinical pneumonia syndromes, sepsis or exacerbation of chronic underlying diseases).
(Antiviral drugs used for the treatment of influenza include oseltamivir, zanamivir, amantadine
and rimantadine, although oseltamivir is readily available and simple to use for both diagnosis
and prophylaxis. While oseltamivir is usually well tolerated in children, nausea, vomiting ,
stomach pain, epistaxis and rash can be observed).(5)

1.To optimize therapeutic benefits, neuraminidase inhibitors (i.e. oseltamivir) should be

administered as soon as possible (ideally within 48 hours of the initiation of the symptom).
Drug administration should also be considered in patients who subsequently present in the
course of illness.

2.Treatment is recommended for a minimum of 5 days, but may be extended until the clinical
improvement is satisfactory.

3.Corticosteroids should not be used routinely, except for other reasons ( e.g., asthma and other
specific conditions); since they have been associated with prolonged viral clearance,
immunosuppression leading to bacterial or fungal superinfection.

4.All influenza viruses currently circulating are immune to antiviral adamantane drugs (such as
amantadine and rimantadine), and are thus not approved for monotherapy.

Chemoprophylaxis is approved for oral oseltamivir and inhaled zanamivir; however oseltamivir
is a first choice. Prophylaxis should be performed for a cumulative duration of 6 weeks before
10 d after last exposure. For infants <3 mounth age, prophylaxis is not indicated. They should
be referred to the critical evaluation specialist in this respect.(5)

The WHO global influenza surveillance and response system (GISRS) monitors antiviral
resistance among circulating influenza viruses to provide timely guidance for antiviral use in
clinical management and potential chemoprophylaxis.(4)

Prevention:

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Vaccine and chemoprophylaxis are two commonly used methods of influenza prevention.
Current influenza virus vaccines are effective and are the best countermeasure available against
influenza virus infections. There are two types of influenza vaccine available: inactivated
influenza vaccines (IIV) and live attenuated influenza vaccines (LAIV: is for intranasal
administration while IIV is administered intramuscularly). Influenza vaccines (both IIV and
LAIV) have generally been developed to protect against 3 different seasonal influenza viruses
(also called trivalent vaccines). This is still the case in most countries and the current trivalent
vaccines contain influenza A(H3N2), pandemic A(H1N1), and lineage viruses of 1 of 2
influenza B. Recently, however, vaccines that protect against 4 different viruses, including both
influenza B lineage viruses (quadrivalent vaccines), have become available in some countries
(world healthy organization). Conserved virus domains / proteins need to be targeted to design
these types of vaccines. The protection mechanism of these vaccines depends largely on the
choice of conserved target / protein and the method and strategy of vaccination. Several targets
for universal influenza virus vaccines, including hemagglutinin 's retained stalk domain, and
nucleoprotein (NP) and matrix protein (M1) internal proteins. However, the main antigen of the
influenza virus, haemagglutinin (HA), has a very high plasticity and constantly changes due to
the high rate of viral polymerase error and immune pressure selection of circulating antibodies.
(3)

Influenza vaccine provides protection among healthy adults, even when circulating viruses do
not exactly match the viruses in the vaccine. However, influenza vaccination among the elderly
may be less effective in preventing disease but decreases disease severity and incidence of
complications and death. Vaccination is particularly important for people at high risk for
complications of influenza, and for people who live with or care for people at high risk.
WHO recommends vaccinations annually for:

• Women pregnant at any stage of pregnancy

• children aged 6 months to 5 years

• elderly people (over 65 years of age)

• Those with chronic health conditions

• Sanitary workers.

Influenza vaccine is most effective when circulating viruses match well with viruses in
vaccines. The best way to prevent seasonal flu is to get vaccinated yearly.(4)

Infection control measures:

At Community / Individual level.

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1.Hand hygiene is the most effective measure to reduce the risk of transmission of infection
from one person to another. Upon contact with respiratory secretions or polluted surfaces, hands
should be washed with non-medicated soap and water / alcohol based hand rub.

2.Cough etiquette must be practiced by all people with flu like symptoms. This includes
covering the nose and mouth with clean cloth / tissue paper while coughing. Use tissue paper to
clear the respiratory secretions and dispose of them in the nearest waste disposal bin. Clean
hands after contact with respiratory secretions or contaminated surfaces.

3.Mask use is not routinely recommended unless there is an emergency situation. Family
contacts may be advised to use surgical three-layer mask, as a matter of extreme precaution.

4. Patients and contacts will all wear three layered surgical masks when transferring the patient
to a health-care facility.

5. Waste produced from cases of influenza should be treated as clinical infectious waste.(5)

Questions:
1- What are the causes of Influenza pandemics?
2- What are the causes of increased rate & severity of Pneumonia in the recent years?

The answere:

1. Animal causes of the influenza pandemic — including birds and pigs — are hosts of
influenza A viruses that usually do not infect people. Influenza A viruses are constantly
changing, making it possible for non-human influenza viruses to change on very rare occasions
in such a way that they can easily infect people and spread effectively from person to person .
(7)In the 1918–1919 influenza pandemic was caused by an H1N1 subtype influenza A virus.
Analysis of the sequence indicates the ultimate ancestral source of this virus is almost definitely
avian. Waterfowl enteric tracts such as ducks and geese serve as reservoirs for any known
influenza A virus. Usually, waterfowl experiences asymptomatic infection, and exerts little
selection pressure on viral growth. In order to switch to new hosts such as chickens or mammals
and infect very different types of cells, such as human lung cells, rather than enteric duck cells,
an influenza virus may need to adapt by acquiring one or more point mutations or by reassorting
with a gene segment from another influenza virus. A third potential genetic mechanism,
homologous recombination of specific viral gene segments. Which host served as the source of
the 1918 virus – and how the virus adapted to humans – is unknown. Examination of the
genome of the influenza virus H1N1 from 1918 has not given full answers; indeed, new
questions have been posed with difficulty. While all 8 gene segments of the 1918 virus are
obviously avian-like, they are genetically distinct from all of the hundreds of avian or
mammalian influenza viruses collected and analyzed between 1917 and 2006, primarily due to
larger than expected changes in the silent nucleotide.(8)

2. increases the rate and severity of pneumonia due to increases environment

pollution due to increase human activity so will affect oldery people and
children and in recen year a lot of people are addicated with use of
tobacco(cigarette and shisha…etc) thus in recent year Pneumonia incidence

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increas from ≈72,060 in 1997–98 to 101,381 in 2004–05 . over the study period,
the age-standardized incidence rate increased by 34 percent from 1.48 per
1,000 population to 1.98 per 1,000 population (Table). The rise was observed
in all age groups but in older adults was more noticeable. Over the study
period, the age-specific rate of hospitalization with pneumonia as a primary
diagnosis for male patients was 7 per cent higher overall than for female
patients. Throughout the study period the proportion of overall admissions
due to pneumonia increased.(9)

Reference:

1. Kawaoka Y. influenza virus: methods and protocols   2012.

2. Luo M. Influenza virus entry. Adv Exp Med Biol. 2012;726:201-21.
3. Nachbagauer R, Krammer F. Universal influenza virus vaccines and therapeutic antibodies.
Clinical Microbiology and Infection. 2017;23(4):222-8.
4. orgnization wh. influenza (seasonal) 6 November 2018 [Available from:
https://www.who.int/en/news-room/fact-sheets/detail/influenza-(seasonal).
5. Kumar V. Influenza in Children. The Indian Journal of Pediatrics. 2017;84(2):139-43.
6. mohan m. textbook of pathology2005.
7. prevention cfdca. June 19, 2020 [
8. Morens DM, Fauci AS. The 1918 influenza pandemic: insights for the 21st century. The Journal
of infectious diseases. 2007;195(7):1018-28.
9. Trotter CL, Stuart JM, George R, Miller E. Increasing hospital admissions for pneumonia,
England. Emerging infectious diseases. 2008;14(5):727.

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