Herpes simplex

Herpes simplex

.



Herpes simplex



1. is a viral infection

2. caused by the Herpes Simplex Virus (HSV),

3. one of the herpesviridae.



There are two types of Herpes Simplex Virus:



1. HSV Type 1 and

2. HSV Type 2.



Most cases of genital herpes are caused by



1. HSV-2.

2. It is a pandemic,

3. effecting 1 in 4 females and

4. 1 in 5 males in the United States.

5. There is no cure.



HSV disease









Infectious fluid-filled blister on lower lip (herpes labialis)



Herpes is also formed on the tongue as bumps or white dots



Orofacial infection (generally HSV-1); Prodromal symptoms





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1. Skin appears irritated

2. Sore or cluster of fluid-filled blisters

3. Lesion heal without scarring



Genital infection (generally HSV-2); Prodromal symptoms



1. Itching in affected area

2. Sore appears

3. Lesion heal, without scarring



The appearance of herpes lesions and outbreaks in these areas

varies tremendously among individuals.



Herpes lesions on/near the genitals may look like



cold sores.



An outbreak may look like



a paper cut, or



appear a yeast infection.



Symptoms of a genital outbreak may include



1. aches and pains in the area,

2. discharge from the penis or vagina, and

3. discomfort when urinating.

4. Initial outbreaks are usually more severe than subsequent

ones,



o flu-like symptoms and swollen glands for a week or so.



Subsequent outbreaks tend to be



1. periodic or episodic,

2. typically occur four to five times a year,

3. and can be triggered by stress, illness, fatigue,

menstruation, and other changes.



The virus sequesters in the





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nerve ganglia that serve the infected dermatome during non-

eruptive periods,



where it cannot be conventionally eliminated by the body's

immune system.



Outbreak Triggers Oral herpes



1. Local injury to the face, lips, eyes or mouth, as through

traumasurgery, or

2. actinic (ultraviolet) radiation (e.g., sunburn) are well established

triggers of recurrent orolabial herpes due to herpes simplex

virus type 1 (HSV-1).



Similarly, intercurrent infections, such as



upper respiratory viral infections or other febrile diseases, can cause

outbreaks, hence the historic terms "cold sore" and "fever blister".



Genital herpes



Is due to HSV-2.







Incidence is increased in conditions



1. stress,

2. menstruation,

3. diet (such as foods high in arginine, like chocolate, peanuts and

walnuts, or

4. sexual activity may increase the chance and severity of

outbreaks.



Symptoms; Herpes infections, whether initial or recurring, are

usually first felt as



1. a tingling or itching sensation in the affected location.

2. followed, by the emergence of a raised or swollen area on the

skin.

3. This swollen area then becomes painful in general,





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4. but acutely sore when touched, stretched or moved.

5. Eventually the sore area will abscess, and emit a virus laden

clear fluid for several days before scabbing over.

6. Once scabbed over the lesion will usually heal completely

within a period of a week to ten days.

7. In immuno-compromised individuals this cycle can be

significantly protracted.



From the onset of infection/outbreak, many patients experience



1. headaches,

2. fatigue (sometimes extreme),

3. and peculiar twitching sensations in the nerves that lead to the

area of the outbreak.







Transmission



1. Herpes is contracted through direct skin contact

2. (not necessarily in the genital area) with an infected person,

and less frequently by indirect contact (for instance, by sharing

lip balm or a virus infested shared towel).

3. The virus travels through tiny breaks in the skin (or mucous

membranes in the mouth and genital areas), so, healthy skin

and mucous membranes are normally an effective barrier to

infection.

4. However, in the case of mucous membranes, even microscopic

abrasions are sufficient to expose the nerve endings into which

the virus splices itself.

5. This is why most herpes transmission happens in mucous

membranes, or in areas of the body where mucous membranes

and normal skin merge (e.g., the corners of the mouth).

6. Symptoms may not appear for up to a month or more after

infection.



Transmission most common during



1. an active outbreak;

2. however the virus can be shed from the skin in the absence of

symptoms.



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3. It is estimated that between 50% and 80% of new HSV-2 cases

are from asymptomatic viral shedding.[



Recurrence



1. Herpes recurs only at a site of previous infection.

2. The periodicity (frequency) and amplitude (severity) of



recurrence varies greatly depending on



1. the individual and various environmental factors

2. including stress (both physical and mental).

3. the infection will recur only two or three times,

4. With severity attenuating (decreasing) each time.



Herpetic whitlow,



Is Self Reinfection



1. Self reinfection, known medically as autoinoculation,

2. is primarily limited to the initial infection with either HSV-1 or

HSV-2.

3. The most common manifestations are herpetic whitlow,

4. a pustular lesion typically of a finger,

5. persons with recurrent oral or genital herpes should avoid direct

contact with active lesions and

6. should wash their hands immediately after using the toilet or

touching the area of an oral lesion,

7. to further limit the low risk of autoinoculation.

8. However not very common.



Asymptomatic Shedding



 Shedding is known to be more frequent within the first 12

months of acquiring HSV-2,

 and concurrent infection with HIV also increases the frequency

and duration of asymptomatic shedding

 There are some indications that some individuals may have

much lower patterns of shedding,

 Sex should always be avoided in the presence of symptomic

lesions.





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 Oral sex performed by someone with oral lesions or other

symptoms should be avoided, to avoid transmission of HSV-1

to the partner's genitals.

 Even without symptoms it is possible for transmission to occur.

Many people still believe Herpes cannot be transmitted through

oral sex. This is a dangerous myth.









Other measures that have been suggested include:



1. Management of stress

2. Adequate sleep and nutrition

3. Avoidance of cross-infecting different sites on the body if HSV

blisters are present

4. Use of a lip protectant or lip gloss

5. Treatment using ascorbate-Cu(II) [10]



Herpes zoster









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Herpes zoster,



1. known as shingles,

2. is the reactivation of varicella zoster virus (one of the

Herpesviridae group),

3. leading to a crop of painful blisters over the area of a

dermatome.



in the U.S., incidence of shingles increased with



advancing age.



The incidence rate in children aged less than 10 years was

approximately



70 cases/100,000 person-years,



Among adults aged 50 to 59 years



550 cases/100,000 person-years.



incidence of shingles is linked to



1. the reduced frequency of periodic exogenous (outside)

exposures to children with varicella (chickenpox)

2. due to the increasing vaccination of that population.

3. These exposures produced an immunologic boost that helped

suppress the reactivation of shingles.



Shingles incidence is high in



1. the elderly (over 60),

2. as well as in any age group of immunocompromised patients.



It affects some



1. 1 million people per year in the United States and

2. can involve excruciating pain.



Many patients develop a painful condition called



1. postherpetic neuralgia



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2. which is often difficult to manage.



Treatment is generally with



1. antiviral drugs such as aciclovir (Zovirax),

2. famciclovir (Famvir) or

3. valaciclovir (Valtrex).



For the antiviral drugs to be effective,



patients typically need to begin taking them within 2-3 days of the

appearance of the rash.



In some patients, herpes zoster can reactivate ,



1. subclinically

2. with pain in a dermatomal distribution

3. without rash.

4. This condition is known as zoster sine herpete and may be

more complicated,

5. affecting multiple levels of the nervous system and

6. causing multiple cranial neuropathies, polyneuritis, myelitis, or

aseptic meningitis.



Signs and symptoms; The earliest symptoms of shingles include



1. headache,

2. sensitivity to light,

3. flu-like symptoms without fever

4. itching,

5. tingling, and

6. extreme pain where the rash is developing.

7. Often, pain is the first symptom.



This pain can be characterized as



1. stinging,

2. tingling,

3. numbing, or

4. throbbing, and

5. can be pronounced with quick stabs of intensity.





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Then 1-3 crops of red lesions develop,



1. small blisters

2. filled with serous fluid.

3. A general feeling of unwellness

4. urticaria



As long as the blisters have not dried out,



1. HZ patients may transmit the virus to others.

2. This could lead to chickenpox

3. in mainly young children who are not yet immune to this virus.

4. Chickenpox virus can remain dormant for decades,

5. inside the ganglion near the spinal cord.

6. As the virus is reactivated it spreads down peripheral nerve

fibers and produces intense pain.

7. The blisters therefore only affect one area of the body and do

not cross the midline.

8. They are most common on the torso, but can also appear on

the face (where they are potentially hazardous to vision) or

other parts of the body.



Outbreaks occur for many different reasons,



1. decrease the immune system such as aging,

2. severe emotional stress,

3. severe illness or long-term use of corticosteroids.

4. stress or other stresses to the skin such as pinching in more

sensitive areas of the skin (nipples, ears, and underarms),

scratching, or biting.



Diagnosis



1. The diagnosis is visual —

2. very few other diseases mimic herpes zoster,

3. especially in the localization of the rash, which is otherwise

quite similar in appearance and initial effect to that of poison

oak or poison ivy.



In case of doubt,







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1. herpes tests can be performed

2. where fluid from a blister may be taken

3. so the cells can be analyzed in a medical laboratory

4. a viral culture of the skin, which involves a microscopic

examination of the skin using a Tzanck preparation.

5. While looking at the cell obtained from the blister,



the cells infected with the herpes virus will appear



1. very large and

2. contain many dark nuclei.



Blood picture by taking a complete blood count



1. there may be an elevated number of white blood cells,

2. which is an indirect sign of infection.



On Serology



1. rise in the antibody to the virus

2. is an indication of the virus’ reactivation



Lab tests are necessary because,



depending on the affected sensory nerve, the pain that is

experienced before the onset of the rash may be misdiagnosed as

pleurisy, myocardial infarction, appendicitis, or a migraine headache.



Pathophysiology









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A course of Shingles



The causative agent for herpes zoster is ,



1. varicella zoster virus (VZV).

2. Most people are infected with this virus as a child,

3. as it causes chickenpox.

4. The body eliminates the virus from the system,

5. but it remains dormant in the ganglia adjacent to the spinal cord

(called the dorsal root ganglion) or the ganglion semilunare

(ganglion Gasseri) in the cranial base.



Reactivation of the virus is due to ,



1. In the elderly, whose immune response generally tends to

deteriorate,

2. patients whose immune system is being suppressed,

3. sunburn and other,

4. unrelated stresses that can affect the immune system may also

lead to viral reactivation.)

5. The virus starts replicating in the nerve cells,

6. and newly formed viruses are carried down the axons to the

area of skin served by that ganglion (a dermatome).

7. Here, the virus causes local inflammation in the skin, with the

formation of blisters.



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The pain characteristic of herpes zoster is thought to be due to



irritation of the sensory nerve fibers in which the virus reproduces.







Therapy



1. antiviral drug Acyclovir inhibits replication of the viral DNA, and

is used both as prophylaxis (e.g., in patients with AIDS) and as

therapy for herpes zoster.

2. Other antivirals are valacyclovir and famciclovir.

3. Steroids are often given in severe cases.



During the acute phase



oral acyclovir should be given five times daily for 7 to 10 days.



Immunocompromised patients



may respond best to intravenous acyclovir.



In patients who are at high risk for recurrences,



an oral dose of acyclovir, taken twice daily, is usually effective. Use

of acylovir is most effective



1. in moderating the progress of the symptoms if taken as early as

possible,

2. so medical care should be obtained as soon as the condition is

recognized.

3. It is also reported that the amino acid lysine inhibits the

replication of herpes zoster.



The long term complication



postherpetic neuralgia may cause persistent pain that lasts for

years.



Pain management is difficult



as conventional analgesics may be ineffective.



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Alternative agents are often used,



1. including tricyclic antidepressants (particularly amitriptyline),

2. anticonvulsants (e.g. gabapentin), and/or

3. topical capsaicin.



Is there any vaccine for herpes zoster ?



Zostavax is a vaccine developed by Merck & Co.



which has proven successful in preventing half the cases of herpes

zoster in a study of 38,000 people who received the vaccine.



The vaccine also reduced by two-thirds the number of cases of

postherpetic neuralgia.



Autoimmunity



1. adults received natural immune boosting from contact with

children infected with varicella.

2. This helped to suppress the reactivation of herpes zoster



Prognosis



The rash and pain usually subside within 3 to 5 weeks.



The most common chronic complication of herpes zoster



is postherpetic neuralgia.



Pain that persists for longer than one to three months after

resolution of the rash



is generally accepted as the sign of postherpetic neuralgia.



Sometimes serious effects include



1. partial facial paralysis (usually temporary),

2. ear damage, or

3. encephalitis may occur.









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Shingles on the upper half of the face (the first branch of the

trigeminal nerve)



1. may result in eye damage and require urgent ophthalmological

assessment.

2. Ocular complications occur in approximately one half of

patients with involvement of the ophthalmic division of the

trigeminal nerve.

3. These complications include mucopurulent conjunctivitis,

episcleritis, keratitis and anterior uveitis.









What other nerves can be involved?



1. Cranial nerve palsies of the third,

2. fourth and sixth cranial nerves may occur,

3. affecting extraocular motility.



Can it be induced by exposure to another person with shingles

or chickenpox ?



1. Since shingles is a reactivation of a virus contracted

previously—often decades earlier—it cannot be induced by

exposure to another person with shingles or chickenpox.

2. Those with active blisters, however, can spread chickenpox to

others who have never had that condition and who have not

been vaccinated against it.



Stages



1. Back or underarm pain and small rash spots appear

2. Rash (itchy for some) spreads around the body

3. More pain develops

4. Bubbles filled with fluid pop up

5. After 4-5 weeks pain is gone and bubbles turn dark purple and

peel off









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Herpes zoster blisters day 1.









Herpes zoster blisters day 2.









Herpes zoster blisters day 5, pain disappearing.









Herpes zoster blisters day 6, characteristic purple colour.





Herpes zoster oticus



 Herpes zoster oticus is essentially a herpes zoster infection

 that affects cranial nerves VII (facial nerve) and VIII

(vestibulocochlear nerve).

 Patients present with facial paralysis, ear pain, vesicles,

sensorineural hearing loss, and vertigo.

 Management includes antivirals and oral steroids.



Aciclovir



 is a antiviral drug

 used for the treatment of herpes simplex virus infection.

 It is one of the most commonly-used antiviral drugs,

 trade names such as Zovirax and Zovir

 low in cytotoxicity.



Pharmacology & mechanism of action



 Aciclovir is a nucleoside analogues



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 Its incorporates into the viral DNA, resulting in chain

termination.

 Therefore, aciclovir can be considered a prodrug – it is

administered in an inactive (or less active form) and is

metabolised into a more active species after administration.



Microbiology



Aciclovir is active against most species in the herpesvirus family. In

descending order of activity:[1]



 Herpes simplex virus type I (HSV-1)

 Herpes simplex virus type II (HSV-2)

 Varicella zoster virus (VZV)

 Epstein-Barr virus (EBV)

 Cytomegalovirus (CMV)

 Activity is predominately active against HSV,

 and to a lesser extent VZV.

 It is only of limited efficacy against EBV and CMV.

 It is inactive against latent viruses in nerve ganglia.



Pharmacokinetics



Aciclovir is poorly water soluble and



hence intravenous administration is necessary if high concentrations

are required.



When orally administered, peak plasma concentration occurs after

1–2 hours.



Indications



Aciclovir is indicated for the treatment of HSV and VZV infections,

including:[3]



 Genital herpes simplex (treatment and prophylaxis)

 Herpes simplex liabilis (cold sores)

 Herpes zoster (shingles)

 Acute chickenpox in immunocompromised patients

 Herpes simplex encephalitis





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 Acute mucocutaneous HSV infections in immunocompromised

patients

 Herpes simplex keratitis (ocular herpes)



Dosage forms



 Aciclovir is commonly marketed as tablets (200 mg and 400

mg),

 topical cream (5%),

 intravenous injection (25 mg/mL) and

 ophthalmic ointment (3%).

 Cream preparations are used primarily for labial herpes

simplex.

 The intravenous injection is used when high concentrations of

aciclovir are required.

 The ophthalmic ointment preparation is only used for herpes

simplex keratitis.



Adverse effects systemic therapy



Common adverse drug reactions (≥1% of patients) associated

with systemic aciclovir therapy (oral or IV) include:



 nausea,

 vomiting,

 diarrhoea and/or

 headache.

 In high doses, hallucinations have been reported.

 Infrequent adverse effects (0.1–1% of patients) include:

agitation, vertigo, confusion, dizziness, oedema, arthralgia, sore

throat, constipation, abdominal pain, rash and/or weakness.

 Rare adverse effects (<0.1% of patients) include: coma,

seizures,



Topical therapy



Aciclovir topical cream is commonly associated (≥1% of

patients) with:



 dry or flaking skin and/or

 transient stinging/burning sensations.



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 Infrequent adverse effects include erythema and/or itch.[3]



Toxicity



 Since aciclovir can be incorporated also into the cellular DNA, it

is a chromosome mutagen,

 therefore, its use should be avoided during pregnancy.

 However it has not been shown to cause any teratogenic nor

carcinogenic effects.

 The acute toxicity (LD50) of aciclovir when given orally is greater

than 1 mg/kg, due to the low oral bioavailability.



Footnotes



 The herpes simplex virus (HSV) is a virus that manifests itself

in two common viral infections,

 each marked by painful, watery blisters in the skin or mucous

membranes (such as the mouth or lips) or on the genitals.

 The disease is contagious,

 particularly during an outbreak,

 and is incurable with present technology.

 An infection on the lips is commonly known as a "cold sore" or

"fever blister".

 HSV is present in the cell bodies of nerves at all times,

 growing down the axon to the skin when active and lying

dormant in the bodies of the nerve cells when not.



When the outbreak has passed, the virus 'dies back' along the

nerve until it is only present in the nerve body.

 The dormancy of the virus within the nerve bodies contributes

to the difficulty of treatment.



Transmission



 HSV is generally transmitted by direct contact of lips or genitals

when the sores are present, or

 just before they appear (known as shedding).

 In addition, herpes may be transmitted during childbirth,

 which can be fatal to the infant.

 The first outbreak after exposure to HSV is commonly more

severe than future outbreaks,

 as the body has not had a chance to produce antibodies;



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 this first outbreak also carries the risk of developing meningitis.



Treatment



 There is currently no known cure or vaccine for HSV.

 Nucleoside Analogs reduce the duration of symptoms and

accelerate healing.

 Nucleoside analogs are molecules which possess a similarity to

natural nucleosides -- the building-blocks of DNA and RNA.

 Because the replicating virus incorporates these analogs into

viral DNA, the genetic material produced contains defects and

mutations.

 As a result, the subsequent generation of virus produced is

damaged and reduced in number.



Analog of Nucleoside

Oral Prodrug Drug

Nucleoside Family

Famciclovir[2] Penciclovir

(bioavailability: 75% (1.5% oral, IV,

oral) locally topical)

(trade names: (Denavir,

Famvir) Fenistil)

Valaciclovir Aciclovir

(55% oral) (10-20% oral)

purine

(Valtrex) (Zoviraz, Zovir) guanosine

Ganciclovir

(5% oral, IV,

Valganciclovir

locally

(60% oral)

intraocular)

(Valcyte)

(Cytovene,

Cymevene)

Brivudine[3](BVDU) thymidine pyrimidine



 Treatment should begin at the first symptoms of an outbreak for

best results as far as duration and healing;

 should treatment begin before the lesions appear, it is possible

that the outbreak can be averted.

 Another option is the use of daily suppressive therapy,





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 in which antivirals are taken every day over the course of years.

Suppressive therapy reduces frequency of symptoms and

recurrence of outbreaks.

 In addition, suppressive therapy reduces subclinical shedding,

lowering the risk of transmission through sexual contact or

kissing.









herpes simplex virus







The herpes simplex virus (HSV) is a virus that manifests itself in

two common viral infections,



each marked by painful, watery blisters in the skin or mucous

membranes (such as the mouth or lips) or on the genitals.



The disease is contagious, particularly during an outbreak, and is

incurable with present technology.



An infection on the lips is commonly known as a "cold sore" or "fever

blister".



These are sometimes confused with canker sores or aphthous ulcers,

which have a similar appearance; these appear inside the mouth and

are not caused by the herpes simplex virus.









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When asymptomatic, HSV lies dormant in the bodies of the nerve

cells, replicating within the axons towards the skin during an

outbreak.



When the outbreak has passed, the virus 'dies back' along the nerve

until it is only present in the nerve body. The dormancy of the virus

within the nerve bodies contributes to the difficulty of treatment.











Transmission



HSV is generally transmitted by direct contact of lips or genitals when

the sores are present, or just before they appear (known as

shedding).



In addition, herpes may be transmitted during childbirth, which can

be fatal to the infant.



The immature immune system of the child is unable to defend against

the virus and even if treated, infection can result in brain damage.



The first outbreak after exposure to HSV is commonly more severe

than future outbreaks, as the body has not had a chance to produce

antibodies; this first outbreak also carries the risk of developing

meningitis.



Outbreaks are generally preceded by



1. sensations of burning,

2. itching or tingling before visible blistering occurs.

3. Subclinical shedding can also occur at any time, resulting in

transmission without symptoms.



Treatment



There is currently no known cure or vaccine for HSV.



Nucleoside Analogs







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Treatment is available in the form of antiviral medications such as

nucleoside analog, which reduce the duration of symptoms and

accelerate healing.



Nucleoside analogs are molecules which possess a similarity to

natural nucleosides -- the building-blocks of DNA and RNA.



Mode of action of nucleoside



Because the replicating virus incorporates these analogs into viral

DNA, the genetic material produced contains defects and mutations.

As a result, the subsequent generation of virus produced is damaged

and reduced in number.



 Aciclovir (trade name Zovirax)

 Penciclovir (trade name Fenistil)

 Valaciclovir (trade name Valtrex)

 Famciclovir (trade name Famvir) [3]

 Ganciclovir

 BDVU



Treatment should begin at the first symptoms of an outbreak for best

results as far as duration and healing;



should treatment begin before the lesions appear, it is possible that

the outbreak can be averted.



Another option is the use of daily suppressive therapy, in which

antivirals are taken every day over the course of years.



Suppressive therapy reduces frequency of symptoms and recurrence

of outbreaks. In addition, suppressive therapy reduces subclinical

shedding, lowering the risk of transmission through sexual contact or

kissing.



Of these, Ganciclovir and Famciclovir are known to have cytotoxic

effects on infected cells[while Aciclovir is not known to have this

effect.



Fusion Inhibitors







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Fusion inhibitors prevent "fusion" of the viral envelope with the cell

membrane. This prevents viral entry to the cell.



 Docosanol



Helicase-Primase Inhibitors



One of three key protein structures involved in HSV DNA replication

is the Helicase-Primase structure. New research compounds which

bind to this megamolecule show remarkable effectiveness against

HSV. In particular, BAY 57-1293 has been used to treat infant HSV-2

encephalitis, and has also shown positive results in animals models

of HSV infection.[4]









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