Herpes viruses

Herpes simplex type 1 (HSV 1): HHV 1: Labial herpes
Herpes simplex type 2 (HSV 2): HHV 2 : Genital herpes
Varicella-zoster virus (VZV): HHV 3 : Varicella, herpes zoster
Epstein-Barr virus (EBV): HHV 4: Infectious mononucleosis
Cytomegalovirus (CMV): HHV 5 : Multiple diseases
Human herpesvirus 6: HHV 6: Infectious erythema up to 2 years
Human herpesvirus 7: HHV 7: Infectious erythema over 3 years of age
Human herpesvirus 8: HHV 8: Kaposi sarcoma

DNA viruses
Most of EBV, CMV, HHV 6, 7 i 8 originates in asymptomatic sources of infection  (exception: varicella)
Reactivation upon immunosuppression
Elimination of Herpes viruses from human body is impossible

Location during latency

Sensory neurons: HSV 1, HSV 2, VZV
Lymphocytes B: EBV
Monocytes, Neutrofiles: CMV
CD4 Lymphocytes: Human herpesvirus 6, Human herpesvirus 7

Route of spread

Perinatal, direct contact: HSV 1, HSV 2
Perinatal, direct contact, droplet: VZV
Perinatal, transfusions, direct contact: EBV, CMV
Direct contact, other: Human herpesvirus 6, Human herpesvirus 7
Direct contact, transfusions, other: Human herpesvirus 8

Varicella

Acute viral illness
Varicella zoster virus (VZV) is one of eight herpes viruses
Humans are the only known reservoir for VZV

Primary infection results in varicella (chickenpox)
chickenpox is a disease of childhood, because 90% of cases occur in children younger than 13 years
Recurrent infection results in herpes zoster (shingles) in adults and rarely in children

Pathogenesis

Respiratory transmission of virus
Replication in nasopharynx and regional lymph nodes
Repeated episodes of viremia
Multiple tissues, including sensory ganglia, infected during viremia
Transmission - airborne droplet, direct contact with lesions
Communicability - 1-2 days before to 4-5 days after onset of rash

symptoms

Incubation period 14-16 days (range 10-21 days)
Mild prodrome for 1-2 days
The early symptoms in adolescents and adults are nausea, loss of appetite, aching muscles, and headache
The rash - generalized, pruritic, and rapidly progresses from macules to papules to vesicular lesions before crusting; rash is polymorphic with lesions present in several stages of maturity
The rash begins on the scalp, moves to the trunk, and then the extremities.
In children the illness is not usually preceded by prodromal symptoms, and the first sign is the rash or the spots in the oral cavity

rash

Lesions are usually 1 to 4 mm in diameter (the so – called „dewdrop on the rose petal” )
Lesions also can occur on mucous membranes of the oropharynx, respiratory tract, vagina, conjunctiva and the cornea.

Groups with increased risk of varicella complications

Healthy adults
Immunocompromised persons
Newborns of mothers with rash onset within 5 days before to 48 hours after delivery

Complications

Bacterial infection of lesions
CNS manifestations (meningitis, cerebellar ataxia, encephalitis, paralysis of cranial nerves) - cerebrospinal fluid often demonstrates lymphocytosis and elevated levels of protein
Pneumonia
Congenital Varicella Syndrome

Congenital Varicella Syndrome

Results from maternal infection during the first two trimesters of pregnancy, the incidence is estimated to be about 2%
Period of risk may extend through first 20 weeks of pregnancy
Low birth weight, skin lesions in dermatomal distribution (76%), neurologic defects (60%), eye diseases (51%), skeletal anomalies (49%)

Laboratory Diagnosis

Isolation of varicella virus from clinical specimen
Rapid varicella virus identification using PCR
Significant rise in varicella IgG by any standard serologic assay

Vaccine

Composition: Live virus
Efficacy: 95% (Range, 65%-100%) 
Duration of  Immunity : >7 years
May be administered with measles, mumps, and rubella (MMR) vaccine

Varicella Zoster Immune Globulin (VZIG)

May modify or prevent disease if given within 96 hours after exposure
Indications:
immunocompromised persons
newborn of mothers presented varicella symptoms with onset 5 days before to 48 hours after delivery
premature infants with postnatal exposure
pregnant women

Therapy

Acyclovir therapy in normal children, adolescents, and adults shortens the duration of lesion formation, reduces the total number of new lesions
Highly recommended for persons with chronic cutaneous or pulmonary disorders
In immunocompromised children and adults with complications – i.v.
Not recommended for postexposure prophylaxis
Symptomatic treatment (antipyretic, antypruritic drugs)

Herpes simplex - HSV

Herpes Zoster

VZV becomes latent after primary infection within the dorsal root ganglia.
Herpes zoster - reactivation of varicella zoster virus
Associated with: aging, immunosuppression, intrauterine exposure, varicella at <18 months of age

prodromal symptoms 2018

Malaise
hyperaesthesia (burning or tingling pain, or sometimes numbness or itch in one particular location on only one side of the body)
subfebrile body temperature
pain within the dermatome precedes the rush by 48 to 72 hours.

rash

Herpes zoster is characterized by a unilateral vesicular eruption with a dermatomal distribution
maculopapular lesions appear that rapidly evolve into a vesicular rash.
Thoracic and lumbar dermatomes are most commonly involved.
If herpes zoster occurs in children, the course is generally benign and not associated with progressive pain

complications

Zoster generalisatus – 2% of cases, particularly in people with immunosupression
Zoster ophtalmicus – possible ulceration of cornea, iritis, paralysis of cranial nerves – III, IV, VI; always necessary – ophtalmological consultation
Zoster oticus (when the geniculate ganglion is involved - the Ramsay Hunt syndrome) - pain and vesicles in the external auditory meatus, loss of taste on the anterior two thirds of the tongue, deafness, vertigo, ipsilateral facial palsy.
Meningitis, encephalitis, pneumonia, myelitis

treatment

Acyclovir (p.o., i.v), Vitamins B
Treatment of neuralgia:
tramadol, carbamazepine, gabapentin, NSAIDs

Two types of HSV:
HSV-1 - lesions on the skin of the face, trunk, on the mucous membranes of the mouth, cornea
HSV-2 - lesions on the skin and mucous membranes of the genitals
They are transmitted by direct contact with body fluids (saliva, semen, vaginal fluid) or the fluid from herpetic blisters
Portal of entry: mucous membranes and damaged skin

Primary contact with HSV-1 usually occurs in the first year of life
Incubation period: 1-26 days
Primary infection with asymptomatic course in 30% in HSV-1 infection, 60% in HSV-2

patogenesis

After infection the viruses are transported along sensory nerves to the nerve cell bodies, where they reside lifelong
Causes of recurrence may include: decreased immune function, stress and sunlight exposure
Herpesviral encephalitis is thought to be caused by the transmission of virus along a nerve axon to the brain

clinical forms

Herpetic gingivostomatitis - is often the initial presentation during the first herpes infection (children – at the age 1-5 years)
Herpes eczema (infants and young children) - changes on the skin of the cheeks and upper chest with fever
Genital herpes - inflammation of the vulva, vagina, cervix, glans, foreskin, urethra, anus
Herpes gladiatorum - skin ulceration on the face, ears, neck and trunk. Individuals who participate in contact sports such as wrestling, rugby

Neonatal herpes - usually caused by vertical transmission of virus from mother to newborn - in three forms:
localized disease - skin, eyes, and mouth herpes (SEM)
disseminated herpes (DIS) - affects internal organs (particularly the liver)
central nervous system herpes (CNS)
Herpetic conjunctivitis and keratitis
Generalized HSV infection associated with AIDS

Roseola

(sixth disease, three-day fever)
It is caused by human herpesvirus 6 (HHV-6) or human herpesvirus 7 (HHV-7)
Spread is usually through the saliva, it may also spread from the mother to baby during pregnancy
Roseola typically affects children between six months and two years of age - high fever 3-4 days, then pale pink, spotty rash (the rash is not itchy) mainly on face and trunk persist for 2 days
In children over 3 years of age and adults, infection may occur as a mononucleosis-like syndrome, hepatitis

Diagnosis is typically based on symptoms
During the fever, neutrophilic leucocytosis then leucopenia with lymphocytosis
Treatment – symptomatic, prognosis is generally good

Infectious mononucleosis

Acute, viral infectious disease
Occurrence in the period of childhood and adolescence
Infectious material: saliva of a patient, a convalescent or asymptomatic carrier
Period of being infective - up to 6 months
Infection contracted through:
Direct contacts (a kiss), Infected objects, Blood transfusion

clinical course

Period of incubation: 30-50 days
Prodromal symptoms (precedes occurrence of the typical disease symptoms for a few days): feeling of discomfort, weakness, lack of appetite, musculo-articular pains
Main symptoms: acute pharyngitis, fever, enlargement of lymph glands,
Sickening smell from the mouth, nasal speech

Sore throat
Tiny haemorrhagic rash (exanthema) on the palate
Glanzman’s symptom – oedema of eyelids, nasal base and brow arches, occurs mainly in children
Enlargement of lymph glands - their size can be considerable, shiftable, tender at examination (generalised in children, regional lymphadenopathy in adolescents and adults)

Enlargement of the liver
Enlargement of the spleen
Measles-like, rubella-like, scarlatina-like exanthema (rash) sometimes with haemorrhagic component (associated with the deposition of immune complexes – Gianotti-Crosti syndrome)
Administration of ampicillin causes incidence of allergic rash in almost 90-100% of patients (half-synthetic penicillin, cephalosporins)

diagnosis

Increased WBC count due to lymphocytosis
Abnormal/activated lymphocytes – mononuclears (mostly stimulated lymphocytes T)
Increase of aminotransferase activity
Mild thrombocytopenia, Serologic reaction – anty-EBV IgM

complications

Haematological

Autoimmunologic haemolytic anaemia, Thrombocytopenia,
Neutropenia (antibodies – in 80% of patients – reacting with native granulocytes)

CNS symptoms

Paralysis of cranial nerves (mainly VII)
Encephalitis with cerebellum syndrome
Guillaine-Barre syndrome, Epilepsy attacks
Transverse myelitis, Psychosis

Rupture of the spleen

Occurres extremely rare
Most frequently in 2-3rd week of the disease It is an indication to surgical intervention
Symptoms: most frequently sudden or gradually increasing stomachache, peritonitis

Extremely rare:
Io atrioventricular block
Pericarditis
Myocarditis

differentiation

Acute pharyngitis with swelling of palatal tonsils in the course of streptococcal infection (B-haemolysing Streptococcus from the group A) or caused by Herpes virus
Mononucleosis-like syndrome in the course of CMV infection or in acute symptomatic HIV infection
Abnormal/activated lymphocytosis (rubella, mumps, measles, viral hepatitis, adenoviral disease, whooping cough, toxoplasmosis)
Acute leukaemia – sporadicaly (bone marrow biopsy)

treatment

exclusively symptomatic:
Light diet, vitamins
Topical throat disinfecting agents,
Febrifuge medicines, Steroids
Antibiotic therapy (only in the case of bacterial coinfections!)

PROGNOSIS

The disease usually ends with the full recovery,
People with inborn or acquired immunity disorders the prognosis is uncertain,
In case of lack of diagnosis or ignoring of complications (e.g. rupture of the spleen) may result with death

Cytomegaloviral disease

Cytomagalovirus – Herpesviridae – HHV5
Viral genome - double stranded DNA
Typical inclusions containing genetic material of virus within nucleus and cytoplasm
Cellular immunity plays crucial role in a controle of CMV replication

Usually self-limited acute infection in immunocompetent persons
The most frequent pathogen in organ transplant recipients
CMV infects endothelial and epithelial cells, monocytes, macrophages, granulocytes and smooth muscles

Primary infection – antigen presenting cells stimulate T-lymphocytes and increase production of cytokines and chemokines activating NK cells
Latency – CMV present intracellularly without gene expression
Secondary infection –  reactivation of latent infection or superinfection with another viral strain

routes of spread

In early childchood, teenagers and young adults: droplet way, sexual transmission
Blood and blood products/transfusions,  organ transplantations
During pregnancy and delivery: through placenta, amniotic membranes and fluid, vaginal and cervical excretions
After delivery: breastfeeding

Primary infection

Incubation period: 20-60 days
The disease lasts for 2-6 weeks
Symptoms: fever, fatigue, headache, muscle pain, cough, generalized lymphadenopathy, hepatosplenomegaly
90% of infections are asymptomatic!!!

Congenital CMV infection

Most frequently – result of primary CMV infection in pregnant woman (risk of vertical transmission about 40%), less frequently as a result of reactivation of CMV infection (risk of vertical transmission <0,5%) or reinfection with another CMV strain.

10-15% develops severe sequeles – psychomotoric retardation, deafness, retinitis, uveitis, optical nerve atrophy, brain calcifications
1% inclusive disease – low birth weight, hyperbilirubinemia, hepatosplenomegaly, microcephaly, petechiae
5-15% of asymptomatic neonates will develop progressive vision and hearing deficits, speech problems

Perinatal CMV infection

40-60 % of neonates
Very mild or asymptomatic clinical course, sporadic cases of pneumonia or hepatitis.

CMV and HIV

Most frequently - result of reactivation  of latent CMV infection
CMV retinitis
Inflammation of gastrointestinal mucosa
Central nervous system CMV disease
Pneumonia, Immune reconstitution syndrome (IRIS)

CMV retinitis 

Symptoms depend on the location of the necrotizing lesions of the retina
The symptoms of cytomegalovirus retinitis have it usually starting in one eye - blurred vision, blind spots
Blindness caused by retinal necrosis, inflammation of the optic nerve or retinal detachment
Diagnosis – ophthalmoscopy - hemorrhagic necrosis on white/yellow cloudy retinal lesions, „frosted branch”

CMV infection after organ transplantation

CMV infection via organ transplantation, transfusion of blood products containing latently CMV-infected leucocytes – primary infection (symptomatic in 60-90% of cases) or superinfection with another CMV strain
Reactivation of latent CMV infection in organ recipient (symptomatic in 20-30% of cases)
Symptoms occur most frequently 1-4 months after transplantation
Cytomegaloviral disease - enteritis, hepatitis, pancreatitis, interstitial pneumonia, myocarditis, urocystitis, encephalitis, retinitis

Risk factors for CMV infection in organ recipient

Discordant serological status between donor and recipient
CMV viral load and virulence in donor
Severity of immunosuppression
Discordant HLA genotype between donor and recipient
Concomitant infections, Type of organ transplantation
Age of recipient

Indirect effects of CMV infection

Chronic inflammation leading to damage to cells and tissues
Acute transplant rejection or chronic graft dysfunction
Hemolytic - uremic syndrome
Increased cardiovascular risk, post-transplantation lymphoproliferative disease, posttransplant diabetes
Exacerbation immunosuppression → higher risk of opportunistic infections

diagnosis

Diagnostic material

saliva, urine, cervical excretion, amniotic fluid
blood (including umbilical cord blood), cerebro-spinal fluid

Serological testing
ELISA (IgM, IgG), Indirect hemaglutination – IgM, Immunofluoresce - IgM
Detection of genetic material: CMV DNA – hybrydization in leucocytes, PCR in whole blood or serum, CSF or tissue samples
Detection of viral antigens: antigen pp65 in peripheral blood leucocytes, sensitivity for symptomatic CMV disease - 100%

Fast CMV replication in cell cultures – high specificity, low sensitivity
Isolation of CMV – standard cell cultures (2-4 weeks), high specificity, low sensitivity
Microscopic findings – intranuclear and intraplasmatic inclusions – „owl eyes”
Electron microscopy – virions visible

Antiviral medications as a treatment and prophylaxis of CMV disease

Gancyclovir (Cymevene) – nucleoside analogue, viral DNA polymerase inhibitor, interferes with replication of all Herpes viruses, given i.v. or as an intraocular implant (Vitrasert).
Valgancyclovir (Valcyte) – gancyclovir precursor, given orally.
Foscarnet (Foscavir) – pirophosforan analogue, high nephrotoxicity and neurotoxicity.
Anti-CMV immunoglobulin – questionable therapeutic activity, high costs.

Unspecific prophylaxis

General precautions/ID prophylaxis.
Fundoscopy every 3 months  in patients with CD4 count < 100 cells/µl.
ART therapy of HIV disease.
Transfusion of CMV–negative blood products or with a use of filters for leucocytes.
Seronegative recipient should receive transplant organ from seronegative donor.