EBV/CMV infections - Stillwell

Question 1

alpha herpes viruses

Answer 1

• HHV-1 (Herpes simplex virus-1/HSV-1) (oral>genital herpes)
  - HHV-2 (Herpes simplex virus-2/HSV-2) (genital>oral herpes)
  - HHV-3 (Varicella zoster virus- VZV) (chickenpox/shingles)
  - HHV-B (Herpes simiae virus- Herpes B virus) (rash/meningoencephalitis/lymphadenitis)

Question 2

gamma herpes viruses

Answer 2

• HHV-4 (Epstein-Barr virus- EBV) (infectious mononucleosis)

- HHV-8 (Kaposi’s sarcoma herpesvirus- KSHV) (Kaposi’s sarcoma)

Question 3

beta herpes viruses

Answer 3

• HHV-5 (Cytomegalovirus- CMV) (infectious mononucleosis)
  - HHV-6 (Roseolovirus) (roseola)
  - HHV-7 (Roseolovirus) (roseola)

Question 4

EBV (HHV-4)

Answer 4

• infectious mononucleosis/”kissing disease”**
• many infected in childhood and adulthood
• only infects primates**

Question 5

EBV transmission

Answer 5

• spread through bodily fluids –> saliva, blood, semen (sexual contact; STI), organ transplants**
• spread on fomites**
• once one is primarily infected, can spread to others even after symptoms resolve**
• virus can reactive asymptomatically to be spread to others**
• most people are seropositive for EBV**
• long incubation time 30-50 days (same for CMV)**

Question 6

EBV viral acquisition

Answer 6

1. tropism- tropism for endothelial cells –> multiple rounds of lytic replication
2. B cells - EBV tropic to B cells –> antigen infects B cells –> B cells present to T cells
3. T cells - EBV causes CD8 T cell response –> atypical lymphocytes (downey cells)***
   - cellular immunity better than humoral immunity

Question 7

EBV latency

Answer 7

1. B cells - serve as reservoir for lifelong infection**
   - shedding of EBV into body fluids upon reactivation is always asymptomatic in healthy people**
2. EBV-infected B cells transformed into immortalized lymphocytes* –> transform to oncogenic state in immunocompromised
3. EBV lives in episome in nucleus of B cell
4. EBV can be malignant with latent infection/gene expression, not acute infection

Question 8

EBV humoral response

Answer 8

• EBNA (ebstein-barr nuclear antigen) on B cells
• VCA (viral capsid antigen) with infectious mono
• Can form cross reactive IgM antibodies (heterophile antibodies) against antigens of certain animals –> used to test for EBV mono* called monospot test

Question 9

monospot test (heterophile antibody)

Answer 9

• not the best way to test for EBV mono (not always +)

- never + for CMV mono (tests neg)

Question 10

EBV pathology

Answer 10

• reactive follicular hyperplasia of lymph nodes with lymphadenopathy**
• splenomegaly –> immunoblasts can resemble Reed-Sternburg cells (in Hodgkin’s) or have hemophagocytosis (RBCs in phagocytic cells as histiocytes)
• blood abnormalities, but bone marrow biopsy is normal**
• hepatitis (common) and cholestasis (rare)

Question 11

follicular hyperplasia vs. follicular lymphoma

Answer 11

• hyperplasia –> mix of lymphocytes, Macs, and plasma cells –> “starry night”*** with immunoblasts
• lymphoma –> unicellular type appearance**

Question 12

EBV clinical illness

Answer 12

1. age has influence on expression
2. children asymptomatic (50% + for heterophile antibody)**
3. infectious mono syndrome (glandular fever)** occurs in adolescent/adult –> symptomatic (90% + for heterophile antibody)**
4. infectious mono syndrome –> high prolonged fever* (also in CMV), retro-orbital headache** (seen in HIV or EBV), severe pharyngitis**
5. rash (uncommon)
6. rash with EBV infection + amoxicillin/ampicillin*** - hypersensitivity rxn that can involve palms/soles (EBV-induced drug sensitization), more severe
7. posterior cervical lymphadenopathy*** (also in CMV)
8. hepatitis - high liver enzymes (ALT, AST)
9. splenomegaly** - spleen can rupture (refrain from contact sports)
10. tonsillo-pharyngitis** - “kissing” tonsil obstruction, exudate, petechia on palate
11. autoimmune hemolytic IgM cold agglutinins (rare)* - more typical is elevated WBC count and atypical lymphocytes** on diff.
12. neurologic - septic meningitis
13. cardiac - myocarditis (rare)
14. pulmonary - pneumonia (rare)

Question 13

EBV - other associated illnesses

Answer 13

1. X-linked lymphoproliferative syndrome/Duncan’s syndrome** - boys/adolescents, proliferative response of B/T cells to EBV –> life-threatening rxn (hemophagocytic lymphohistiocytosis); pancytopenia from destroying bone marrow, multi organ failure, die at young age, no treatment
2. chronic, active EBV infection (rare) - multiorgan failure
3. oral hairy leukoplakia** - in immunosuppressed (ex. AIDS), white lesions on side of tongue (can’t scrape off like candida/thrush infections leading to misdiagnosis)**

Question 14

EBV - associated malignancies

Answer 14

1. Post-transplant Lymphoproliferative Disorder (PTLD)** - B cells undergo mutations –> malignant lymphoma; immunosuppressive drugs and rituximab kill B cells
2. Primary central nervous system lymphoma (B-cell)** - seen in AIDS patients –> lymphoma with HIV due to EBV reactivation
3. Burkitt’s lymphoma** - type of non-Hodgkin lymphoma, in Africa (associated with falciparum malaria), rapidly growing tumor around mandible associated with EBV** (responds well to chemo)**
4. Hodgkin’s lymphoma - replication of malignant B cells; Reed-sternburg cells*
5. Nasopharyngeal carcinoma
6. gastric carcinoma

Question 15

EBV - diagnosis

Answer 15

1. atypical lymphocytes (downey cells)** - antigen stimulated CD8 cytotoxic T cells, cytoplasm indented by RBCs, also seen in CMV, HIV**
2. lymphocytosis
3. leukocytosis - sometime neutropenia/thrombocytopenia
4. serology - viral capsid antigen (VCA) IgM antibody** in 100% of patients –> gold standard to detect primary EBV; VCA IgG develops shortly after
5. heterophile antibody/monospot/test - usually pos with EBV and neg with CMV mono** (can have false NEG with EBV) –> false POS seen with autoimmune, lymphoma, viral, or malaria**
6. EBV DNA PCR - less sensitive with acute infectious mono

Question 16

EBV treatment

Answer 16

• Acyclovir, ganciclovir and foscarnet - no good antiviral treatment for infectious mono
• steroids can help with obstructive tonsillo-pharyngitis
• lymphoproliferative disease treated with reduction in immunosuppressive drugs –> tumor regression** (but can increase risk of graft rejection)
• oral hairy cell leukoplakia –> EBV usually in lytic phase and responds to acyclovir

Question 17

B symptoms**

Answer 17

• fever for more than 3 days, drenching night sweats, unintentional weight loss over 6 months** –> associated with Hodgkin’s and non-hodgkin’s lymphoma
• Pel-ebstein fever**
• other signs with HL, NHL: itching, fatigue, hepatosplenomegaly, anorexia, lymphadenopathy and lymph node pain (if they occur after drinking EtOH, they aren’t B symptoms)***

Question 18

infectious mononucleosis syndrome

Answer 18

• mostly due to EBV, CMV**
• EBV most common
• others can cause it (rare) - ex. primary HIV syndrome in 2% cases

Question 19

CMV - epidemiology

Answer 19

• aka HHV-5, cytomegalic inclusion virus or salivary gland virus
• largest virus to infect humans - large cells
• passed same way as EBV - also perinatal (birth, breast feeding)
• usually get in adulthood (rare in newborns) - risk increases with age***
• long incubation time (20-60 days)**
• multiple strains –> recurrent infections
• can be STI –> saliva, urine, semen, vaginal secretions, blood, etc.

Question 20

CMV - viral stages

Answer 20

• tropism for more cell types than EBV –> latent infections after recovering from primary infection
• usually acquired from person who is asymptomatic and shedding the virus**
• does not develop into malignancy like EBV**
• can live latently in non-replicating form in many types of cells –> spontaneous reactivation with body stresses
• once acquired, you carry it forever (herpes forever!!)**

Question 21

CMV - immune system

Answer 21

• cell mediated immunity (Macs, monocytes, T lymphocytes)** –> most problems with AIDS and transplant patients**
• humoral immunity for EBV
• have drugs for treatment

Question 22

atypical lymphocytes

Answer 22

• activated CD8 T lymphocytes

- seen in both CMV, EBV***

Question 23

CMV - pathology

Answer 23

• Owl’s eye inclusion bodies** (nuclear and cytoplasmic inclusions) –> confused with Reed-sternburg cells in HL
• “starry sky with reed-sternburg cells**

Question 24

CMV - clinical illness

Answer 24

1. most acute infections never diagnosed (asymptomatic)
2. infectious mono syndrome: even though always heterophile antibody/EBV IgM negative, CMV should be considered a cause if mononucleosis scenario* (CMV IgM to test for mono)
   - less risk of lymphadenopathy, splenomegaly, unlike EBV*
   - high liver enzymes, jaundice rare, typhoidal syndrome (long fever, malaise, headache, myalgias)
   - rash brought on with amoxicillin/ampicillin*
3. hepatits - after transfusion
4. myocarditis - most common cause of FATAL myocarditis in immunosuppressed**
5. thrombocytopenia/hemolytic anemia
6. CNS infections - can get Guillain-Barre syndrome

Question 25

CMV - other scenarios

Answer 25

1. congenital CMV** - mom is not immune and comes down with acute primary CMV infection while pregnant –> can lead to many morbidities (lethargy, respiratory distress, seizures), even mortality in babies
   - CT with Brain calcifications***
2. perinatal CMV - passage through birth canal or breast feeding
3. CMV with AIDS** - worry if CD4 count becomes too low; CMV severe alongside HIV
   - cause retinitis/blindness (starts peripherally –> centrally)
   - CNS involvement (polyradiculopathy, ascending weakness in lower limbs, lose deep tendon reflexes and bowel/bladder control, low back pain)
   - GI involvement (ulcerative esophagitis, colitis)**
   - pancytopenia in certain populations**
4. CMV reactivation in critically ill - ex. ICU patients, prolonged hospital admissions –> hepatitis and cytopenia after transfusions due to CMV in blood
5. CMV in renal transplant patients** - usually secondary reactivation; morbidity lower than other transplants
   - “CMV syndrome” in renal transplants with primary infection from transplantation –> fever, leukopenia, atypical lymphocytosis, hepatosplenomegaly
   - secondary infection only associated with fever, hepatitis, interstitial pneumonia
   - CMV increases risk of transplant rejection
6. CMV in liver transplants** - CMV most common pathogen –> lead to high liver enzymes (AST/ALT) and cholestasis
7. CMV in HSC transplant patient - most common, life threatening, CMV pneumonitis** (high mortality), increased risk of graft-vs-host disease, respiratory failure

Question 26

HAART therapy

Answer 26

-treatment for HIV, helps keep CD4 levels high

Question 27

CMV - diagnosis

Answer 27

• elevated WBCs (not as high as EBV) and atypical lymphocytosis**
• elevated liver enzymes, anemia, thrombocytopenia
• CMV IgM antibody for acute CMV - IgG develops weeks after and stays for life**
• CMV DNA PCR - useful in transplant and HIV+ patients
• tissue culture - extensive

Question 28

CMV - treatment (drugs)

Answer 28

1. Ganciclovir (IV) and valganciclovir (orally) - myelosuppression
2. foscarnet - reversible nephrotoxicity**, low Ca2+, Mg2+, phosphate
3. cidofovir - irreversible acute renal failure**
4. letermovir
5. maribavir
6. Brincidofovir

Acyclovir, Famciclovir, Valacyclovir are inactive against CMV***

Question 29

looks like mono, but is negative for heterophile antibody mono spot test??

Answer 29

need to send off VCA and CMV monospot test for mono***