Applied Therapeutic

Dr.Mohammed
Lec:20
Date:9/12/2023

Viral infections

INFLUENZA
Influenza, also known as flu is a highly contagious acute respiratory infection
caused by the virus of the Orthomyxoviridae family. Epidemics of influenza are
usually caused by the type A virus; type B virus is generally associated with more
sporadic infection. Influenza A and B responsible for seasonal flu from
September to April with peaks around December to February. Influenza C may
lead to mild illness but not to epidemics or sporadic.
Influenza virus invades the respiratory tracts of individuals and uses it to spread
the infection. Infection is transmitted by the inhalation of virus-containing
droplets ejected from the respiratory tract of a person with influenza. Influenza
can be spread by direct contact, large droplets, or items recently expelled from
the nasopharyngeal secretions of infected patients. These droplets can be
propelled for a few feet into the air when talking, coughing or sneezing and then
lands on the eyes, nose or mouth of people nearby. Or touching contaminated
surfaces prior touching their nose eyes or mouth.
The incubation period is typically 2 days (range, 1–4 days). In which individuals
starts to spread the virus one day before the onset of the symptoms until 5 to 7
days after being sick (symptomatic). So people are increased risk of contracting
the virus if they have close contact with infected individuals or in small spaces
with large groups of people during flu season. Common places for influenza
spread are schools, workplaces, nursing home or public transport.
After getting the virus, they began to multiply and spread throughout the cells
lining the upper respiratory tract. In response the immune system launches an
inflammatory response that leads to reddening of the tracheobronchial tracts and
swelling with mucus discharge formation that can help in trapping the pathogen
and expel out the pathogen.
In certain cases, the infection can be more severe and spread to nearby areas
leading to sinusitis or ear infections, or invades the lower respiratory tract to cause
pneumonia (that is characterized by fluid and pus build up in the lungs).
Furthermore, the disease weakens the immune system, making the patient more
susceptible for bacterial infections. Patients at high risk of developing
complications are children less than 5 years, elderly over 65 years, pregnant
women or patients with chronic pulmonary or cardiac diseases.
Symptoms
Flu typically manifests as symptoms that are present about 4 days after exposure
and lasts about a week. Common symptoms include headache, fever, chills,
fatigue, weakness, and muscle aches. Patients may also experience runny nose,
with watery nasal discharge, sore throat and cough. Upon auscultation the lung
breaths are normal. In addition to the mentioned symptoms, influenza B can cause
also GI symptoms like nausea, vomiting and diarrhoea. Most symptoms get better
in a week, but the cough persists for up to two weeks and patients with
comorbidities or over 65 years may have continued lethargy or weakness for
weeks after flu.

Diagnosis
Influenza typically diagnosed based on the patient’s history, physical assessment
and knowing that there is an influenza outbreak in the community around the time
of symptoms onset.
There are three diagnostic tests to detect the presence of flu in patient’s secretion:
real time polymerase chain reaction (rt-PCR), rapid molecular assay and rapid
influenza diagnostic test (RIDTs).

Treatment
There is no cure for influenza. Usually, treatment involves supportive care to
reduce the symptoms, rest and rehydration as well as medications that include
analgesics, antipyretics and antihistamines. Patients may be treated with antiviral
medications (neuraminidase inhibitors) oseltamivir, zanamivir and peramivir.
These medications can help to prevent the release of viruses from infected cells
minimizing its spread and reducing the duration of the disease. Antivirals should
be started as soon as possible for patients at high risk of developing complications
as well as those with sever or complicated diseases and hospitalized patient.
The neuraminidase inhibitors, zanamivir (Relenza) and oseltamivir (Tamiflu) are
active against influenza A and B. These agents work by selectively inhibiting the
enzyme neuraminidase, an enzyme necessary for viral replication and spread.
Zanamivir is available as an oral powder for inhalation. For the treatment of
influenza infection in adults, 10 mg (two inhalations) BID for 5 days should be
used. Oral Oseltamivir is currently indicated for the prevention and treatment of
influenza in patients 1 year of age and older; oral zanamivir is indicated for the
prevention of influenza in patients 7 years of age and older. When administered
within 48 hours of onset of illness, zanamivir and oseltamivir reduce influenza
symptoms by approximately 1 day.

Oseltamivir is pharmacologically related to zanamivir but has significantly better

oral bioavailability, allowing oral dosing. It is approved for children over 1 year
of age and for adults. The dosage of oseltamivir for the treatment of influenza in
adults is 75 mg BID for 5 days. Oseltamivir is available as a suspension with
pediatric dosing recommendations. Common side effects include nausea,
vomiting, dyspepsia, diarrhoea and headache. Regarding zanamivir,
bronchospasm after use can occur, and if bronchodilators are also prescribed, the
bronchodilator should be used before zanamivir. Proper use of the delivery
system (Rotadisk/Diskhaler) is important, and thus patients should be instructed
by the pharmacist on proper delivery technique, with a demonstration device.
Resistance to amantadine and rimantadine has increased dramatically in recent
years; consequently, these agents are no longer recommended for the routine
prevention or treatment of influenza infections.

Prophylaxis
The most effective way to prevent influenza is through vaccination, which can be
done as injection or nasal spray. Flu vaccines are either trivalent that consist of
two strains of influenza A and one influenza B; and quadrivalent which contains
2 type A and 2 type B weakened and inactivated influenza strains that are
predicted to dominate the next season. Since the virus mutate rapidly, these
vaccines are updated twice yearly. Since the vaccine is based on prediction,
therefore some years it would be better than others.
Flu vaccine are indicated for high-risk individuals like pregnant woman, those
with chronic health conditions, over 6 months, over 65 years.
Flu vaccine can reduce the risk of illness by half from about 10% to 5% in term
of likelihood of getting sick over the entire flu season. That mean the average
person to get a flu once in every 10 seasons without vaccination, but could get a
one very 20 seasons. The vaccine should be taken at the end of October in the
upper hemisphere.
Taking into account the low protection percentage of reduction that may not
worth taking the vaccine. However, take in consideration that flu can be severe
and life threatening with the need of hospitalization in some cases. In addition to
the fact that between 2016 and 2017, flu vaccine prevented 5.3 million cases,
decreased 2.6 million medical visits and 85000 hospitalizations compared with
the previous season. Furthermore, it is important that getting vaccine would
decrease the chance of passing the virus to someone else. The more people in the
community been vaccinated the fewer people with contract and spread the
disease, this would protect those who can not been vaccinated like infants of less
than 6 months. This is called herd immunity, because the herd is protecting the
weakest members.
Flu vaccine is contraindicated in infants less than 6 months, individuals with egg
allergy and those in Gillian-Barre syndrome.

Varicella Zoster Virus (VZV)

VZV is a herpes virus that is responsible for two diseases; varicella (chicken pox)
and herpes zoster (shingles). Zoster means a belt due to the appearance of the
shingles.
When an infected person coughs or sneezes, the virus leaves the lungs and get
released into the air. The virus can be transmitted through contact with oral or
skin lesions of the person. When the virus comes in contact with the respiratory
mucosa or the skin lesion of an infected person, it starts replicating in the
epithelial cells, it soon gets picked up by the immune cells and get transported to
the nearby lymph nodes. The virus now can cause primary infection called
varicella or chicken pox. Once the virus reaches the skin, they start infecting
keratinocytes. Then the infection spread into the skin cells. Infected keratinocytes
start to diffuse together to create a giant multinucleated cell called Tzanck cells.
Uninfected skin cells start to release interferon alpha and beta which inhibit
further viral protein synthesis and protecting the remaining uninfected cells from
the virus. As a result, the patient gets tiny lesions on the skin, separated by normal
area of the skin.
In addition to infecting keratinocytes, the virus also infects sensory neurons in the
skin, then the virus travels retrogradely through the neurons to the dorsal root
ganglion or to the trigeminal ganglions if it in the face.
Over time when adaptive immune response kicks in, most viruses in the body
eliminated but once the virus reaches the ganglions it is spared and remain
dormant there.
When the immune system weakens due to ageing, stress or immunosuppressants
use, the virus reactivated and can travels back through the sensory nerve anti-
retrogradely to the skin and causing an infection in the inverted dermatome to
cause herpes zoster (shingles).
With both chicken pox and shingles, the most common complications are
secondary bacterial infection of the skin lesions, so if the liver become infected
hepatitis can occur, if in the lungs, pneumonia can occur, and if in the brain or
meninges, encephalomeningitis can occur.

Symptoms
Symptoms of chicken pox begins about two weeks after the virus entry. The
infection usually causes fever, headache, and overall weakness. After a couple of
days, skin lesions start to appear on scalp, face and trunck. Flat, red, and itchy
spots called macules. Over time, they become elevated and develop to papules
and then to small fluid vesicles. Within 1-2 days these vesicles begin to crust over
and form scabs.
After about 5 days, the scabs fall off, usually without leaving a scare. Then new
crops of lesions are continuously forming in different places in the body every 3-
5 days. So, it is possible to see lesions of different stages at the same time. In
addition, to the itchy lesions, painful sores can occur on mucosal surfaces like
inside the mouth.

Shingles
In shingles there is typically pain, itching or tingling in the affected area where
the rash will develop. It may be accompanied by excessive sensitivity to touch.
So, a single strip of vesicles around either the left or right side of the body or on
one side of the face. It usually takes 4 weeks for the rash to disappear. Pain at the
infected dermatome which last for more than 90 days called postherpetic
neuralgia (PHN).
Diagnosis
Chicken pox and shingles are diagnosed based on the way the skin lesions appear.
The diagnosis can be confirmed by finding Tzanck test. More commonly, blood
test for varicella zoster antibody or PCR test to look for viral DNA.

Treatment
Chicken pox treatment involves cool baths and application of calamine or other
topical antipruritic agents (topical diphenhydramine, dimethindene, crotamiton)
to decrease itching. Fingernails should be trimmed to avoid scratching and
secondary bacterial infections. In severe cases, a systemic antipruritic and
antihistamine preparation may be useful because some degree of sedation may be
desired.

Analgesics and antipyretic can help in reducing the fever. However, aspirin
should be avoided in patient with chicken pox as it may triggers Reye syndrome
(in which the liver become affected by the virus and asprin) that leads to build up
of ammonia in the body. For immunocompromised individuals, antiviral like
acyclovir, famciclovir and valacyclovir can be used.

Shingles
The goal of pharmacotherapy in acute herpes zoster is to inhibit viral replication,
to reduce pain and duration of rash. Ultimately, by inhibiting the virus, nerve
damage can be prevented and the incidence and severity of PHN can be
decreased.
Acyclovir is the standard antiviral agent against which new VZV therapies are
compared. In immunocompetent patients, oral acyclovir 800 mg 5 times daily for
10 days is moderately beneficial in reducing acute pain during the first 28 days.
Acyclovir therapy should be initiated within 72 hours of the onset of the rash. The
benefit of acyclovir in reducing PHN and chronic pain is modest at best.
Famciclovir (Famvir) is approved for the treatment of acute herpes zoster
infection. Famciclovir is a prodrug and is rapidly absorbed and converted to the
active drug penciclovir in the intestine. The bioavailability of famciclovir is
greater than acyclovir, resulting in higher concentrations of active drug in the
infected cells. Famciclovir 500 mg TID is as effective as acyclovir 800 mg 5 times
a day in reducing the duration of acute pain and healing of the rash. Although
famciclovir does not decrease the incidence of PHN, it may reduce the duration
of PHN.
To overcome the poor oral bioavailability of acyclovir, valacyclovir (Valtrex), a
prodrug of acyclovir, was developed. Valacyclovir is rapidly and extensively
absorbed and converted to acyclovir after oral administration. Valacyclovir 1 g
TID is as effective as acyclovir 800 mg 5 times a day in terms of reducing rash
progression and time to rash healing, and valacyclovir is more effective than
acyclovir in relieving zoster-associated pain. Valacyclovir is comparable to
famciclovir with respect to decreasing the duration of acute zoster-associated pain
and PHN.
The only FDA-approved treatments for PHN are topical capsaicin cream or gel,
capsaicin patch 8% (Qutenza), topical lidocaine 5% patches (Lidoderm), and oral
gabapentin (Neurontin) and pregabalin (Lyrica). Other agents that have been used
in the treatment of PHN include tricyclic antidepressants (e.g., amitriptyline,
desipramine) and opioids.