Case 17- Herpes

Question 1

Herpesviridae virus family

Answer 1

• Herpes simplex virus (HSV) 1 and 2
• Varicella Zoster virus (VZV)
• Cytomegalovirus (CMV)
• Human herpes virus 6 (HHV6)
• Human herpes virus 7 (HHV7)
• Epstein Barr Virus (EBV)
• Human Herpes Virus 8 (HHV8)- Kaposi’s sarcoma associated herpes virus

Question 2

CMV life cycle

Answer 2

Primary infection –> Latency –> Reactivation

Question 3

CMV pathogenesis

Answer 3

Lytic replication and host immune response. Latency in a number of blood cells i.e. Lymphocytes. T cell based immunity is important.

Question 4

CMV

Answer 4

Seroprevalence- 40% for young adults

Transmission is via direct contact with infected secretions (saliva, sexual, blood). Can be congenital

Question 5

CMV- Infection in immunocompetent patients

Answer 5

• Primary infection- usually asymptomatic. Can get Lymphadenopathy, Hepatitis, General malaise and headache
• Reactivates intermittently throughout life- asymptomatic, virus excreted in urine and saliva
• Long term association (maybe from chronic inflammation)- atherosclerosis, immune senescence

Question 6

Congenital CMV

Answer 6

• CMV can cross the placenta
• The virus is transmitted from mother to baby during pregnancy
• Normally asymptomatic but can get IUGR, jaundice, hepatosplenomegaly, encephalitis, SNHL
• 20% mortality
• You get serious neurological problems in the survivors
• Some who are asymptomatic at birth get later problems like hearing loss and developmental delays
• Leading cause of non genetic SNHL (Sensorineural hearing loss)

Question 7

What causes CMV infection in immunocompromised patients

Answer 7

• Solid Organ transplant recipients especially lungs- greatest risk is when the donor is positive and the recipient negative, results in primary infection
• Stem Cell (Bone marrow) transplant recipients- greatest risk is when the donor is negative and the recipient is positive. The recipient has CMV but the bone marrow contains no CMV specific T cells to control it.
• AIDS (especially GI tract and retinitis)
• Biological agents

Question 8

Types of CMV infections in the immunocompromised

Answer 8

• CMV syndrome- fever, neutropenia, unspecific

* Organ invasive disease- Retinitis, Pneumonitis. Hepatitis, Encephalitis. Myocarditis, GI disease

Question 9

Diagnosing CMV

Answer 9

• Serology- CMV IgM and IgG
• Molecular- detection of viral DNA by PCR in bodily fluids. It can be found in the blood in immunocompromised people, in the urine/amniotic fluid for congenital infections and sometimes in the tissues
• Histology- Owl’s eye (Cowdry bodies) inclusion bodies

Question 10

Treatment of CMV

Answer 10

• Ganciclovir (only IV)- inhibits viral DNA polymerase. Requires activation by a viral enzyme. Valganciclovir (oral) is a prodrug with better bioavailability
• Ganciclovir is more toxic then acyclovir- myelosuppressive, nephrotoxic and teratogenic
• Second line- Foscarnet and cidofovir

Question 11

CMV- when do you treat

Answer 11

• Immunocompetent- treatment not required unless in very specific circumstances
• Congenital infection- Ganciclovir is given to symptomatic babies, it can reduce hearing loss later in life. Use acyclovir in pregnancy
• Immunosuppressed- reduce immunosuppression if possible, give IV ganciclovir or oral valganciclovir

Question 12

Prevention of CMV

Answer 12

• Prophylaxis- give oral valganciclovir for several months post transplant, Letermovir
• Pre-emptive monitoring- monitor CMV in the blood, if detected give treatment

Question 13

Epstein Barr virus

Answer 13

Primary infection -> Latency -> Reactivation
Can replicate in a wide range of cell type including B lymphocytes and epithelial cells. 95% seropositive by 40. Transmission is via direct contact with infected secretions (saliva). The means peaks of incidence are in childhood and adolescence.

Question 14

Epstein Barr virus age

Answer 14

• Young children- usually asymptomatic, can present with sore throat
• Adolescence- infectious Mononucleosis, may be asymptomatic

Question 15

Infectious mononucleosis

Answer 15

Mono/glandular fever

Question 16

Mono symptoms

Answer 16

• Low grade fever
• Lymphadenopathy
• Sore throat (viral tropism for epithelial cells)
Abnormal liver function- mild transaminitis. Splenomegaly which can lead to Splenic rupture. Malaise, anorexia, tiredness. The incubation period is 1-2 months.

Question 17

Diagnosis of primary EBV

Answer 17

Monospot test, EBV serology (IgM and IgG). Atypical lymphocytes as seen on histology/blood film (T lymphocytes reacting to EBV infected B lymphocytes)

Question 18

Monospot test- EBV

Answer 18

Detects heterophile antibodies, causes clumping of red blood cells Low sensitivity in young children and in the first week (false negatives), low specificity in adults (false positives).

Question 19

EBV treatment

Answer 19

Usually self-limited, no effective antivirals or vaccines

Question 20

Reactivation of EBV

Answer 20

Reactivates intermittently through life, normally asymptomatic unless immunocompromised. Virus is excreted in the saliva. EBV is associated with some cancers.

Question 21

EBV and cancer

Answer 21

• Burkitt’s lymphoma
• Nasopharyngeal carcinoma
• Post-transplant lymphoproliferative disorder (PTLD)
• Other associations- Hodgkins lymphoma, HIV associated lymphoma

Question 22

Burkitt’s lymphoma

Answer 22

Highly malignant cancer associated with B cells, rapidly growing. Endemic form- seen mostly in young children from Africa, arises most often in the jaw. Sporadic/immunodeficiency forms- less associated with EBV, occurs in the abdomen, bone marrow and CNS. No benefit from antivirals.

Question 23

Nasopharynngeal carcinoma

Answer 23

Rare, EBV associated tumour of the head and neck. Antivirals dont help

Question 24

Post-transplant lymphoproliferative disorder

Answer 24

Reduced T cell immunity -> uncontrolled EBV replication -> B cell proliferation -> PTLD. Occurs with reduced T cell immunity, seen in the first year after transplantation. Normally after primary EBV. Treatment- Rituxamab.

Question 25

HHV6 virus

Answer 25

Two different types of HHV6 virus- A and B. More then 90% of people are infected by HHV6 by 2. Transmission is via direct contact with infected secretions (saliva) i.e. at nursery. Peak infections 9-21 months

Question 26

HHV7

Answer 26

Similar clinical features to HHV6

Question 27

What does HHV6 infect

Answer 27

It infects mononuclear cells in the blood, salivary glands and CNS. Can integrate itself into the host DNA in gremlin cells- chromosomal integration.

Question 28

Roseola infantum

Answer 28

Rash illness in infants. HHV6/7 is the most common cause, Enterovirus, Adenovirus and Parainfluenzavirus can also be a cause. The rash appears as fever settles, very mild or asymptomatic. Complications- febrile convulsions (primary infection), Encephalitis (primary infection)

Question 29

At risk groups for Roseola infantum

Answer 29

Immunocompromised (primary or reactivation). This can cause a generalised infection, Organ-specific disease namely encephalitis, Bone marrow engraftment failure and risk of CMV reactivation.

Question 30

HHV8 i.e. Karposi's Sarcoma Associates virus

Answer 30

30% general population serotypes. Disease may not develop. Antiviral therapy has no benefit. You get Kaposi’s sarcoma in HIV infected individuals. Kaposi’s sarcoma is endemic in areas of Africa (not associated with HIV). Progresses from flat patches to plaques, nodules and tumours.

Question 31

Rare diseases caused by HHV-8

Answer 31

Primary effusion lymphoma, Multicentric Castleman’s disease