micro sheet # 16

بسم الله الرحمن الرحيم

[Note: This is the last lecture included in the mid exam.]

In this lecture we will discuss Herpes virus type 2 and type 3 .
The last lecture we talked about Oral Herpes manifestations, which is associated with Herpes virus type 1 ( HSV-1) , now we will talk about Genital Herpes.

 Genital Herpes:
Mostly caused by Herpes virus type 2 (HSV-2).
NOTE:
The difference between HSV-1 and HSV-2 is not much, because DNA homology is ~ 70% , which means that they might cause the same features of disease whether in relation to Respiratory Tract (RT) or Genital Tract, due to the presence of common genes, which express the production of certain glycoprotein, for attachment, and later for replication of the virus..etc

- In the past (30 years ago), genital herpes was 99% caused by HSV-2 .
- Recently ( in the last 10 years), they discovered that HSV-1 became more spread in relation to genital tract, and approximately up to 50% of genital herpes infection in young women is caused by HSV-1 . so, we can see the change through the years.

- Genital herpes viruses are widely distributed in developed countries more than in developing countries.
E.g. in Jordan, there was a study that found that less than 1% of women might be infected with HSV-1 or HSV-2, very rare.
But, with the sexuality freedom in Western countries (USA, European countries) , they have more HSV-2 than many other types of Sexually Transmitted Disease (STD).
- Concerning HSV-2 , they found that once the patient develops this disease, then he’s more susceptible to aquire other STDs, in particular, infection with HIV which causes AIDS.
Explanation:
Due to the developing of ulcerations in the mucosa of the genital tract, especially in women, because the infection will cause ulceration in the mucosa of the vagina and the cervix,in addition to the external genitalia, but the more important is the ones related to the cervix.
This allows other STDs (e.g. Neisseria gonorrhea, Treponema pallidum, syphilis , Chlamydia, mycoplasma genitalium,as well as AIDS) to easily develop infection.

- Generally,in women , infection in 50% is considered asymptomatic ; there’s no signs or symptoms of the infection. Only by clinical examination, the physician might recognize the presence of ulcerations.
NOTE:
This is dangerous because it means that it can’t be detected, especially in men more than women, in contrast to other STDs.
- The other 50% can be associated with certain signs and symptoms, mostly developing:
1- dysuria.
(dysuria: pain during urination, and it might also happen due to bacterial UTI infection).
2- With or without fever.
3- Non-specific urethritis (without discharge),or can be associated with vaginal or urethral discharge, but usually less than in other STDs (like Neisseria gonorrhea, where there’s more extensive discharge which can be easily detected in infected host).
4- Regional lymphadenopathy.

- Infections in women is 50% asymptomatic and 50% symptomatic.
- Infection in men is more asymptomatic, and this might contribute to dissemination of infection.
- Infection in men is recognized in association with the external genitalia ( usually glans penis), as well as the surrounding the skin, and there may also be lesions in rectum.
- The same features observed in women is also seen in men, ( urithritis, fever, anorexia, regional lymphadenopathy..)
- The problem in genital herpes is the same as in oral herpes, which is Recurrence of the disease.
- Recurrence in genital herpes is mostly milder and not recognized.
=> this contribute to dissemination of infection via sexual contact, or via direct, close contact and contamination of hands .
-recurrency might reach up to 3-6 times/ year.

 Neonatal Herpes Virus Infection:

 Pregnant ladies might transmit the infection to their infant, or directly to the fetus.
 Most type of infection recognized is the one following the delivery.

Explanation:

When there are ulcerations on the genitalia, they contain a large number of virus particles. During the delivery of the baby, these virus particles will be transmitted to the baby causing infection, especially via conjunctiva, or respiratory tract (RT), resulting in what is called “ Neonatal Sepsis”.

 Neonatal Herpes happens be due to 2 major causes:

1) Directly, from mother to infant during delivery, most cases. The causative virus in this case is HSV-2.

2) Acquired in the hospital during hospital care. E.g. from contact with a nurse who has oral herpes HSV-1, or during close contact with other infected newborn babies, or from the oral cavity of the mother (if she has the virus in her oral cavity during delivery).
The causative virus in this case is HSV-1.
 Manifestation of Neonatal Herpes:

1- Localized skin infection, oral lesions (exactly like oral herpes in children or normal host), or conjunctivitis.
2- Meningitis/encephalitis.
These are complications in case that we have a baby who suffers from immunodeficiency or has extensive viremia. The virus might reach meninges and brain causing meningitis/encephalitis, and here there is high fatality.

3- General sepsis.
Virus reaches blood stream and carried to many internal locale, spreading to, for example, lungs (causing infection, pneumonia),or the liver (producing jaundice), or the skin ( thrombocytopenia, bleeding and skin lesions).
It’s also associated with mortality.

 The high mortality is usually in relation with meningitis and encephalitis.

SO => in any case of genital infection in pregnant woman, if physician recognize the presence of ulceration and the ulceration is mostly associated with HSP-2, then cesarean section for delivery is recommended, NOT vaginal delivery; in order to prevent contamination and transmission to the newborn baby.

 In addition, if the physician is suspicious, he should start the treatment for the infant, if necessary.


 Diagnosis and Treatment:
Diagnosis and treatment of both HSP-1 and HSP-2 can be done by one of the followings:
1) Culture:
Done in special research centers usually, and requires at least 1 week to recognize and identify the type.
Or directly by using PCR, to detect specific DNA sequences related to HSP-1 or HSP-2. We have this method in Jordan .

2) Serology:
More related to detect the presence of infection (acute or chronic infection) related to HSP-1 or HSP-2. It detects specific antibodies (total antibodies).
 Here we can distinguish between acute, subacute, or old infection. Then they use Enzyme immuno-assay to detect these specific antibodies. This is also available in Jordan.

 Treatment:

Concerning treatment, there’s 2 important and available anti-viral drugs; 1) Aciclovir.
2) Valaciclovir.
Both are available and can be used for treatment of all suspected clinical cases.

MoA:
These 2 drugs inhibit the replication of DNA of the virus, directly affecting the DNA segments.
But, they have observed that during treatment, there might be developing in resistance to these anti-viral drugs. In up to 20% of patients treated with these drugs, the types of HSPs develop resistance.
 So, we must be careful in using these drugs, because the wide use of them might result in more increase in resistance.

 Forms of the drugs:
1- Oral : used in oral and genital infection.
2- Topical : in oral cavity.
3- Intravenous (IV): in case of meningitis, encephalitis, systemic infection.

 Treatment for usually lasts for 1 week.
 There’s no vaccine available for HSP-1 and HSP-2.








 Varicella-Zoster virus (HSP-3)

Note:
HSP-1,HSP-2,HSP-3 are all parts of the alpha Herpes group. Because these 3 viruses have large similarity in the genome and in the presence of different glycoprotein in the envelope.


 Varicella-Zoster virus is related to 2 types of diseases:

1- Chicken pox/ varicella:

- Recognized to spread among children and usually young children. it is easily acquired via Respiratory tract(RT), or conjunctiva.

- Once children up to age of 10 years acquire the infection, they either develop Asymptomatic infection, they show no signs or symptoms, OR develop symptomatic infection.

• The symptomatic infection: it is manifested by the presence of skin rashes, starting on the face, head and trunk , by developing of small vesicles , red in color then it becomes colorless.
- Sometimes they may be infected with bacteria, especially if children manipulate these vesicles with their fingers, so that they injure their skin and inflammation and secondary bacterial infection occur and there maybe even sepsis.
=> So as a solution, there’s a topical ointment. It is applied to relieve the sensation in skin in the place of the vesicles so that they can accept it and don’t scratch it.
- Usually, these vesicles are diminished in about 1 week (rarely,their presence extend more than 1 week).

- Chicken pox infection of adults is more severe. Usually it is associated with more clinical features related to fever, malaise, and even dissemination of the virus to internal organs.
SO => small children mostly accept the infection and rarely develop any complication. Whereas in the adults, the infection mostly result in complications, but generally not so severe.

 Immunity:
Following the infection with chickenpox, the body develops 2 types of immunity:
1) Cellular immunity.
2) Humeral immunity: it becomes sufficient to prevent reinjection with the same clinical features(e.g. skin rashes).
But, at the same time, a few number of viruses might manage to travel up the nerve axon of sensory nerves, and they reside there as dormant virus with the infected nerve.
 This is exactly like HSP-1 and HSP-2.

Note:
In certain cases, especially in neonates, if the mother is infected during pregnancy with chickenpox in the first or second trimester, there will be no problem.

 Because the mother begins to produce antibodies, especially IgGs, which in turn, can cross the placenta to the fetus, so the infant will be immunized, and there’s no problem.

But, the problem happens if the mother is infected few days before delivery ( usually less than 1 week). She might acquire the infection specially if she has other children infected with chickenpox. The problem arise from the fact that she cannot produce sufficient amount of IgGs in these few days, and the IgM antibodies, as u know, cannot cross the placenta, So the infant might acquire the infection.

- Following the delivery, in order to prevent the complications especially in relation to CNS in the form of encephalitis, the newborn should be protected by using passive immunization, by administration of specific immunoglobulins against chickenpox virus.
- The mother might also be developing complications, especially a severe form of pneumonia, and should be treated with anti-viral drugs, to prevent further complications.

- Generally, in our country,
 up to 95% of children become infected with chickenpox virus during the first few years of their lives.
 5% acquire the infection later up to the age 12 years. It’s rare to recognize an adult under natural conditions that hasn’t been infected with chickenpox. This is in Jordan and in developing countries.

- In western countries, they have less natural infection than us, so they have more complications related to chickenpox if they are not immunized. But in most of the times, there’s a vaccine which can be used to reduce the incidence of chickenpox, and so reduce the related complications.



2- Zoster/Shingle:
The second clinical entity associated with the same virus (Varicella/Zoster virus), is Herpes Zoster.
- Herpes/Zoster often develop from reactivation from primary infection with the varicella virus
Note: the same virus which is Herpes/Zoster virus, causes the 2 diseases.
The primary  infection with this virus is known as chickenpox/varicella,
The reactivation later  is considered as Zoster infection.

- Developing of Zoster infection is usually observed later in age, usually people with age >= 50 years, may develop Zoster infection in their life, because the virus is already present but dormant, in their sensory ganglia.
So => anytime under certain condition, the virus may be reactivated.
Note :
-It’s not known why some people develop later infection. 1-2% of the population who had primary infection with chickenpox, might later in life develop Zoster infection.
-It may be due to diminishing in the immunoresponse of the body, caused by some immunosuppressant conditions, by the use of certain drugs (cytotoxic drugs), or other reasons.
NOW on the picture,
Zoster clinical manifestation means the following:
 The Virus, following the primary infection, reaches the sensory ganglion from periphery of the infected nerves by traveling up nerve axons, where it resides as dormant virus.
 It’s unnecessary that the whole viral genome be included in the chromosomes of the infected nerve cells, maybe part of it.
But, this part in enough to later to reactivate and produce a complete virus, and later in age, reactivation of the virus allows it to travel again from the dormant stage in the body, returning back from the sensory ganglia to the periphery nerves, via the nerve axon, and reside in usually only one dermatome, whether Thoracic or Upper lumbar dermatome, and begin to produce inflammatory reaction in the localized nerve segments.

 This results in the developing of the clinical features of the disease.

 Along the dermatome, there will be eruption in the skin, exactly like what is observed in chickenpox.[There will be vesicles, which will increase along the site of the infection (as you can see in the picture), associated with erythema, and burning sensation, very painful.
 It depends on the number of dermatomes affected by the virus.

 This may last 3-4 weeks.

- In 50% of people infected with Zoster, there may not be eruption of vesicles. They might only recognize painful sensation within the dermatome, in the skin.

- Shingles is the same as الحزام الناري


 Major Complications:

1- Ocular Zoster:
More dangerous case that is if the virus reach the nerve of the ophthalmic branch of the trigeminal nerve. If the virus resides there and begins to attack the ophthalmic nerve, which support the eye, a more severe form of ocular Zoster is recognized.
 It affects the cornea, damaging the cornea and producing ulcerations, stromal keratitis which results in scarring and even loss of vision.
2- Acute neurotitis.

 Mild or severe form of neurotitis, which is also called “post herpetic neuralgia”.
 Uncomfortable, painful sensation at the site of infection. It might be associated with raising in body temperature, malaise ..
 More dangerous is Acute neuritis, which might affect CNS.
It is more dangerous and damaging In immunocompromised patients; it produces more complications related to other organs, and may even affect the brain.
 Very rare condition, but has been observed in some patients with immunocompromised conditions.

But generally, in healthy condition, it is in the form of mild acute neuritis, or in the form of ocular Zoster.


- The only way to reduce the severity of the infection,is by treating the patients with:
1) Specific antibodies.
2) Supportive therapy. (reduce the severity of sensation and fever..etc).

 Diagnosis:
Mostly by clinical means, no need to do any lab tests.
- we might demonstrate specific antibodies against the virus during infection.
But, despite the presence of the specific antibodies, this cannot control the infection, UNLIKE some other viral infections.
These specific antibodies result only in later prevention of reoccurrence of the infection, but they can’t delay or reduce the severity of the infection, especially in Zosters.



Done by: Hala Al-Ansari.
Lecture date: Tuesday, 15-3-2011