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Herpes Viruses

     Infectious Diseases/Microbiology Sequence Course




                David J. Miller, M.D., Ph.D.




Spring 2010
Objectives
•  Know the common and unique features of herpes viruses

•  Appreciate the roles of both lytic and latent replication cycles of
   herpes viruses

•  Understand the interactions between herpes viruses and the
   immune system

•  Know the transmission routes of the herpes viruses

•  Know the laboratory methods used to diagnose particular
   herpes virus infections



      Reading assignment: Schaechter s 4th edition, chapters 41 and 42
Herpes viruses
                                     Clinical                                      Antiviral
        Subfamily   Transmission    Syndromes        Latency site   Diagnosis        Rx         Vaccine


           Alpha     Cutaneous      Cutaneous          Neurons        Clinical     Acyclovir      No
HSV
                                     - localized                        PCR
                                   (oral, genital)                  Culture/DFA
                                         CNS


           Alpha     Respiratory     Cutaneous         Neurons        Clinical     Acyclovir     Yes
VZV
                                   - disseminated                       PCR
                                    and localized                   Culture/DFA



            Beta     Secretions       Systemic        Monocytes,     Serology     Ganciclovir     No
CMV
                        (oral,       Ocular, GI,     macrophages        PCR
                     urogenital)   hematopoietic,                   Culture/DFA
                                     respiratory


          Gamma      Secretions      Systemic          B cells       Serology,      None          No
EBV                    (oral)                                           PCR
                                    Lymphoma
                                                                    Culture/DFA



      D. Miller
Herpes viruses
•  Family: Herpesviridae
•  Large, enveloped virus
•  Double-stranded DNA genome (100-150 proteins)


                                                          Envelope with
                                                          glycoproteins


                                                             Tegument



                                                            Nucleocapsid



         Source Undetermined        Source Undetermined
Herpesvirus life cycle (lytic)
                                      Immediate
                                        early      Early

                                                                 Late


•    Nuclear dependence

•    Temporal gene
     expression

•    Importance of viral
     thymidine kinase (TK)

•    Direct cell lysis
                                         Acyclovir/ganciclovir          Viral TK
                             Source Undetermined
Herpesvirus life cycle (latent)




                                                       -Episomal
                                                    (no integration)
                                                     -Minimal gene
                           Reactivation stimuli:      expression
                           UV light, infections,   -Prevent immune
                      stress, immunosuppression       recognition




Source Undetermined
19 year old sexually active male college student presented
to student health services with a two day history of painful
ulcers on his penis. He had unprotected sexual intercourse
with a female roommate several days prior to developing
symptoms. The lesions initially progressed over one week
and coalesced into larger shallow ulcers, but eventually
resolved completely after another two weeks. Over the
next two semesters he had recurrence of similar symptoms
that weren t related to sexual activity.
Source Undetermined
19 year old sexually active male college student presented
to student health services with a two day history of painful
ulcers on his penis. He had unprotected sexual intercourse
with a female roommate several days prior to developing
symptoms. The lesions initially progressed over one week
and coalesced into larger shallow ulcers, but eventually
resolved completely after another two weeks. Over the
next two semesters he had recurrence of similar symptoms
that weren t related to sexual activity.


                      Diagnosis?
Herpes simplex
•  Alphaherpesvirus

•  Two serotypes (HSV-1, 2)

•  Direct contact transmission
   –  HSV-1: primarily oral
   –  HSV-2: primarily genital
   –  Asymptomatic transmission possible


•  Epidemiology
   –  HSV-1: 2/3 of adults seropositive
   –  HSV-2: 1/5 of adults seropositive
       •  Varies with sexual promiscuity
HSV clinical disease
•  Cutaneous lesion (NOT absolute)
   –  HSV-1: oral, perioral
   –  HSV-2: genital
   –  Can be asymptomatic (especially
         with reactivation)

•  Pathogenesis                                        Source Undetermined


   –  Direct epithelial cell lysis and spread to adjacent cells

•  Complications
   –  Ocular disease
   –  CNS involvement (encephalitis)
   –  Dissemination
HSV latency
•  Establishment                    •  Reactivation
   –  Retrograde transmission          –  Anterograde transmission
   –  Sensory ganglia nerve cells      –  UV light, stress, infection,
                                          menstruation
                                       –  Systemic spread rare




  Source Undetermined
HSV and immunity
•  NO viral clearance

•  Immune system maturation crucial
   –  Neonatal HSV infections can be devastating


•  Control of reactivation
   –  Cell mediated immunity essential
   –  Limited role of humoral immunity


•  Prevent systemic spread
   –  Immunosuppression greatly increases risk
HSV diagnosis

•  Clinical syndrome

•  Virus detection
   –    Tzanck smear
   –    Direct fluorescent antibody (DFA) test
   –    PCR
   –    Culture
                                                          Source Undetermined

•  Serologies not helpful                        Multinucleated giant
                                                 cell with intranuclear
                                                       inclusions
HSV treatment and prevention
•  Available drugs
   –  Acyclovir, valacylovir, famciclovir

•  Target groups
   –    Neonatal HSV infections
   –    Immunosuppressed patients (localized or systemic)
   –    CNS disease
   –    Genital HSV lesions

•  Prophylaxis
   –  Immunosuppressed patients
   –  Genital recurrences


•  No vaccine available
55 year old male presented to his primary care physician
with a two day history of painful blisters on his left chest
wall. The area initially felt tingly several days before the
blisters appeared, and he had a mild headache but no
fevers or other systemic symptoms. The area increased in
size with a coalescence of the small blisters, but the
lesions never crossed the midline. The blisters eventually
crusted over and resolved after about three weeks, but the
area remained extremely tender, even to the slightest
touch.
Source Undetermined
55 year old male presented to his primary care physician
with a two day history of painful blisters on his left chest
wall. The area initially felt tingly several days before the
blisters appeared, and he had a mild headache but no
fevers or other systemic symptoms. The area increased in
size with a coalescence of the small blisters, but the
lesions never crossed the midline. The blisters eventually
crusted over and resolved after about three weeks, but the
area remained extremely tender, even to the slightest
touch.

                      Diagnosis?
Varicella zoster virus (VZV)

•  Alphaherpesvirus

•  Aerosol/respiratory transmission
   –  Highly contagious
   –  Direct inoculation unusual


•  Epidemiology
   –  >90% of adults seropositive
   –  Vaccination program may change epidemiology
VSV clinical disease
•  Primary exposure
   –    MOST exposures produce symptomatic disease
   –    Local respiratory lymph node replication
   –    Primary viremia – secondary viremia (lymphocyte infection)
   –    Cutaneous lesion development

•  Pathogenesis
   –  Direct epithelial cell lysis and spread to adjacent cells

•  Complications
   –  Pneumonia and CNS involvement
   –  Immunosuppressed at highest risk
   –  Ramsay-Hunt syndrome (CN VII palsy, loss of taste, auricle
      vesicles)
VZV latency
•  Establishment
   –  Dorsal root sensory ganglia nerve cells infected during
      viremia
   –  Contrast to HSV (direct retrograde spread)

•  Reactivation (shingles)
   –  Anterograde transmission
   –  Dermatomal distribution
       •  Opthalmic division of trigeminal nerve - DANGER
   –  Advancing age, immunosuppression
   –  Systemic spread rare
   –  Post-herpetic neuralgia most troublesome complication
VZV diagnosis

•  Clinical syndrome
                                                                      Fluorescent dye
   –  Simultaneous lesions at all
      stages
                                    VZV antigens
                                                                        Antibody to
                                                                        VZV antigen
•  Virus detection
   –  Direct fluorescent antibody
      test (DFA)                               VZV infected
                                                  cell
   –  PCR
   –  Culture
                                         Sanchez, wikimedia commons

•  Serologies helpful to
   determine exposure risk
VZV treatment

•  HSV drugs (acyclovir) less active but still useful

•  Target groups
   –    Immunosuppressed patients
   –    CNS/ocular disease
   –    Reactivation (reduce post-herpetic neuralgia)
   –    Most effective if given <72 h from symptom onset
   –    Prednisone efficacy for shingles questionable
VZV prevention
•  Effective vaccine available
   –  Live, attenuated virus

•  Target populations
   –  Routine childhood vaccination (VARIVAX®, ProQuad®)
   –  Persons > 60 yo regardless of previous shingles history
   –  Healthy adolescents and adults without evidence of immunity
       •  High risk for VZV transmission (healthcare workers, teachers, childcare
          employees, chronic care facilities)
       •  Non-pregnant women of childbearing age
   –  Household contacts of immunocompromised persons

•  Contraindications
   –  Immunosuppression
   –  Pregnancy

     http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm
46 year old female had kidney transplant secondary to
diabetic nephropathy three months ago. Her postoperative
course was uneventful, and she was tolerating her
immunosuppressive medications. She rarely left the
house out of concern for picking up an infection, but over
the past three weeks she developed fever, fatigue, and
decreased appetite but no significant localizing symptoms.
Blood tests showed a severely decreased white blood cell
count.
46 year old female had kidney transplant secondary to
diabetic nephropathy three months ago. Her postoperative
course was uneventful, and she was tolerating her
immunosuppressive medications. She rarely left the
house out of concern for picking up an infection, but over
the past three weeks she developed fever, fatigue, and
decreased appetite but no significant localizing symptoms.
Blood tests showed a severely decreased white blood cell
count.


                     Diagnosis?
Cytomegalovirus (CMV)

•  Betaherpesvirus

•  Direct contact transmission
   –  Saliva, breast milk, urogenital
   –  Blood products, organ transplantation
   –  Transplacental ( TORCH infections)


•  Epidemiology
   –  Approximately 50% of adults in U.S. seropositive
   –  >90% in underdeveloped countries
CMV clinical disease
•  Primary exposure
  –  Usually asymptomatic
  –  Can produce mono-like syndrome (non-specific
     symptoms)

•  Complications
  –  Congenital CMV
     •  CNS involvement (encephalomalacia, hydrocephalus, retinitis)
  –  End-organ damage in immunosuppressed
     •    Ocular (retinitis)
     •    CNS (encephalitis)
     •    Respiratory
     •    Gastrointestinal
     •    Bone marrow


                                           University of Michigan Kellogg Eye Center
CMV latency
•  Establishment
   –  Monocytes and macrophages
   –  Mechanisms poorly understood

•  Reactivation
   –  DIRECTLY linked with immune status
   –  Replication in wide variety of cell types
       •  Transplanted organs
   –  Can augment immunosuppression
CMV diagnosis

•  Clinical syndrome non-specific
                                                  Large nuclear inclusion
                                                 With peripheral clear zone
•  Virus detection
   –    PCR (quantitative)
   –    Histopathology ( owl eye )
   –    Direct fluorescent antibody (DFA) test
   –    Culture


•  Serologies helpful                                    Source Undetermined

   –  Assess risk for reactivation if immunosuppression
      anticipated
CMV treatment and prevention
•  Antiviral drugs available
   –  HSV drugs (acyclovir) less active
   –  Ganciclovir (valganciclovir), foscarnet, cidofovir
   –  Resistance problematic


•  Target groups
   –  NOT for primary infection in immunocompetent patient
   –  Immunosuppressed patients
   –  Pre-emptive therapy often used
       •  CMV disease versus infection


•  Prevention
   –  No vaccine available
   –  Prophylactic ganciclovir frequently used
18 year old student presented to his primary physician with
one week history of fever, fatigue, sore throat, swollen
glands. He recently started a new relationship with a
classmate who had no symptoms. On physical exam, his
oropharynx was erythematous without tonsillar exudate and
he had prominent cervical lymphadenopathy. Rapid strep
test was negative. Blood test showed an increased white
blood cell count with atypical appearing lymphocytes. His
symptoms eventually resolved over 2 weeks, but his fatigue
persisted for 6 months.
Source Undetermined
18 year old student presented to his primary physician with
one week history of fever, fatigue, sore throat, swollen
glands. He recently started a new relationship with a
classmate who had no symptoms. On physical exam, his
oropharynx was erythematous without tonsillar exudate and
he had prominent cervical lymphadenopathy. Rapid strep
test was negative. Blood test showed an increased white
blood cell count with atypical appearing lymphocytes. His
symptoms eventually resolved over 2 weeks, but his fatigue
persisted for 6 months.

                      Diagnosis?
Epstein-Barr virus (EBV)

•  Gammaherpesvirus

•  Direct contact transmission
   –  Saliva, respiratory secretions
   –  Transfusion, transplantation


•  Epidemiology
   –  Approximately 50-70% of adults in U.S. seropositive
   –  >90% in underdeveloped countries
EBV clinical disease
•  Primary exposure
   –  Often asymptomatic
   –  Typically produce mononucleosis syndrome
       •  Fever, sore throat, fatigue (prolonged)
       •  Hematologic abnormalities, hepatitis


•  Complications (malignancies)
   –  Linked to immune status and latency in B cells
   –  Post-transplant lymphoproliferative disorder (PTLD)
   –  Lymphoma
       •    Nasopharyngeal carcinoma
       •    Burkitt s lymphoma (Africa)
       •    Primary CNS lymphoma (HIV/AIDS)
       •    Hodgkin s disease
EBV diagnosis
•  Clinical syndrome non-specific

•  Virus detection
   –  PCR
   –  Direct fluorescent antibody (DFA) test
   –  Culture


•  Serologies helpful
   –  Assess risk for reactivation
   –  Monospot test
       •  Heterophil antibodies directed against RBC from other
          species (NOT EBV-specific)
EBV treatment and prevention

•  Antiviral drugs (acyclovir, ganciclovir)
   –  In vitro activity but no evidence for effectiveness in
      patients


  Correct underlying immunosuppressed status


•  Prevention
   –  No vaccine available
Other herpesviruses

•  Human herpes virus 6 (HHV6)
  –  Betaherpesvirus (similar to CMV)
  –  Etiology of roseola infanatum



•  HHV8
  –  Gammaherpesvirus (similar to EBV)
  –  Also called Kaposi s sarcoma herpes virus
     (KSHV)
Additional Source Information
                         for more information see: http://open.umich.edu/wiki/CitationPolicy

Slide 5: David Miller
Slide 6: Sources Undetermined
Slide 7: Source Undetermined
Slide 8: Source Undetermined
Slide 10: Source Undetermined
Slide 13: Source Undetermined
Slide 14: Source Undetermined
Slide 16: Source Undetermined
Slide 19: Source Undetermined
Slide 24: Adapted from Reven Sanchez,Wikimedia Commons, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/
Slide 30: University of Michigan Kellogg Eye Center
Slide 32: Source Undetermined
Slide 35: Source Undetermined

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05.04.09(a): Herpes Viruses

  • 1. Author(s): David Miller, M.D., Ph.D., 2009 License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Noncommercial–Share Alike 3.0 License: http://creativecommons.org/licenses/by-nc-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  • 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicy Use + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (17 USC § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation License Make Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  • 3. Herpes Viruses Infectious Diseases/Microbiology Sequence Course David J. Miller, M.D., Ph.D. Spring 2010
  • 4. Objectives •  Know the common and unique features of herpes viruses •  Appreciate the roles of both lytic and latent replication cycles of herpes viruses •  Understand the interactions between herpes viruses and the immune system •  Know the transmission routes of the herpes viruses •  Know the laboratory methods used to diagnose particular herpes virus infections Reading assignment: Schaechter s 4th edition, chapters 41 and 42
  • 5. Herpes viruses Clinical Antiviral Subfamily Transmission Syndromes Latency site Diagnosis Rx Vaccine Alpha Cutaneous Cutaneous Neurons Clinical Acyclovir No HSV - localized PCR (oral, genital) Culture/DFA CNS Alpha Respiratory Cutaneous Neurons Clinical Acyclovir Yes VZV - disseminated PCR and localized Culture/DFA Beta Secretions Systemic Monocytes, Serology Ganciclovir No CMV (oral, Ocular, GI, macrophages PCR urogenital) hematopoietic, Culture/DFA respiratory Gamma Secretions Systemic B cells Serology, None No EBV (oral) PCR Lymphoma Culture/DFA D. Miller
  • 6. Herpes viruses •  Family: Herpesviridae •  Large, enveloped virus •  Double-stranded DNA genome (100-150 proteins) Envelope with glycoproteins Tegument Nucleocapsid Source Undetermined Source Undetermined
  • 7. Herpesvirus life cycle (lytic) Immediate early Early Late •  Nuclear dependence •  Temporal gene expression •  Importance of viral thymidine kinase (TK) •  Direct cell lysis Acyclovir/ganciclovir Viral TK Source Undetermined
  • 8. Herpesvirus life cycle (latent) -Episomal (no integration) -Minimal gene Reactivation stimuli: expression UV light, infections, -Prevent immune stress, immunosuppression recognition Source Undetermined
  • 9. 19 year old sexually active male college student presented to student health services with a two day history of painful ulcers on his penis. He had unprotected sexual intercourse with a female roommate several days prior to developing symptoms. The lesions initially progressed over one week and coalesced into larger shallow ulcers, but eventually resolved completely after another two weeks. Over the next two semesters he had recurrence of similar symptoms that weren t related to sexual activity.
  • 11. 19 year old sexually active male college student presented to student health services with a two day history of painful ulcers on his penis. He had unprotected sexual intercourse with a female roommate several days prior to developing symptoms. The lesions initially progressed over one week and coalesced into larger shallow ulcers, but eventually resolved completely after another two weeks. Over the next two semesters he had recurrence of similar symptoms that weren t related to sexual activity. Diagnosis?
  • 12. Herpes simplex •  Alphaherpesvirus •  Two serotypes (HSV-1, 2) •  Direct contact transmission –  HSV-1: primarily oral –  HSV-2: primarily genital –  Asymptomatic transmission possible •  Epidemiology –  HSV-1: 2/3 of adults seropositive –  HSV-2: 1/5 of adults seropositive •  Varies with sexual promiscuity
  • 13. HSV clinical disease •  Cutaneous lesion (NOT absolute) –  HSV-1: oral, perioral –  HSV-2: genital –  Can be asymptomatic (especially with reactivation) •  Pathogenesis Source Undetermined –  Direct epithelial cell lysis and spread to adjacent cells •  Complications –  Ocular disease –  CNS involvement (encephalitis) –  Dissemination
  • 14. HSV latency •  Establishment •  Reactivation –  Retrograde transmission –  Anterograde transmission –  Sensory ganglia nerve cells –  UV light, stress, infection, menstruation –  Systemic spread rare Source Undetermined
  • 15. HSV and immunity •  NO viral clearance •  Immune system maturation crucial –  Neonatal HSV infections can be devastating •  Control of reactivation –  Cell mediated immunity essential –  Limited role of humoral immunity •  Prevent systemic spread –  Immunosuppression greatly increases risk
  • 16. HSV diagnosis •  Clinical syndrome •  Virus detection –  Tzanck smear –  Direct fluorescent antibody (DFA) test –  PCR –  Culture Source Undetermined •  Serologies not helpful Multinucleated giant cell with intranuclear inclusions
  • 17. HSV treatment and prevention •  Available drugs –  Acyclovir, valacylovir, famciclovir •  Target groups –  Neonatal HSV infections –  Immunosuppressed patients (localized or systemic) –  CNS disease –  Genital HSV lesions •  Prophylaxis –  Immunosuppressed patients –  Genital recurrences •  No vaccine available
  • 18. 55 year old male presented to his primary care physician with a two day history of painful blisters on his left chest wall. The area initially felt tingly several days before the blisters appeared, and he had a mild headache but no fevers or other systemic symptoms. The area increased in size with a coalescence of the small blisters, but the lesions never crossed the midline. The blisters eventually crusted over and resolved after about three weeks, but the area remained extremely tender, even to the slightest touch.
  • 20. 55 year old male presented to his primary care physician with a two day history of painful blisters on his left chest wall. The area initially felt tingly several days before the blisters appeared, and he had a mild headache but no fevers or other systemic symptoms. The area increased in size with a coalescence of the small blisters, but the lesions never crossed the midline. The blisters eventually crusted over and resolved after about three weeks, but the area remained extremely tender, even to the slightest touch. Diagnosis?
  • 21. Varicella zoster virus (VZV) •  Alphaherpesvirus •  Aerosol/respiratory transmission –  Highly contagious –  Direct inoculation unusual •  Epidemiology –  >90% of adults seropositive –  Vaccination program may change epidemiology
  • 22. VSV clinical disease •  Primary exposure –  MOST exposures produce symptomatic disease –  Local respiratory lymph node replication –  Primary viremia – secondary viremia (lymphocyte infection) –  Cutaneous lesion development •  Pathogenesis –  Direct epithelial cell lysis and spread to adjacent cells •  Complications –  Pneumonia and CNS involvement –  Immunosuppressed at highest risk –  Ramsay-Hunt syndrome (CN VII palsy, loss of taste, auricle vesicles)
  • 23. VZV latency •  Establishment –  Dorsal root sensory ganglia nerve cells infected during viremia –  Contrast to HSV (direct retrograde spread) •  Reactivation (shingles) –  Anterograde transmission –  Dermatomal distribution •  Opthalmic division of trigeminal nerve - DANGER –  Advancing age, immunosuppression –  Systemic spread rare –  Post-herpetic neuralgia most troublesome complication
  • 24. VZV diagnosis •  Clinical syndrome Fluorescent dye –  Simultaneous lesions at all stages VZV antigens Antibody to VZV antigen •  Virus detection –  Direct fluorescent antibody test (DFA) VZV infected cell –  PCR –  Culture Sanchez, wikimedia commons •  Serologies helpful to determine exposure risk
  • 25. VZV treatment •  HSV drugs (acyclovir) less active but still useful •  Target groups –  Immunosuppressed patients –  CNS/ocular disease –  Reactivation (reduce post-herpetic neuralgia) –  Most effective if given <72 h from symptom onset –  Prednisone efficacy for shingles questionable
  • 26. VZV prevention •  Effective vaccine available –  Live, attenuated virus •  Target populations –  Routine childhood vaccination (VARIVAX®, ProQuad®) –  Persons > 60 yo regardless of previous shingles history –  Healthy adolescents and adults without evidence of immunity •  High risk for VZV transmission (healthcare workers, teachers, childcare employees, chronic care facilities) •  Non-pregnant women of childbearing age –  Household contacts of immunocompromised persons •  Contraindications –  Immunosuppression –  Pregnancy http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5604a1.htm
  • 27. 46 year old female had kidney transplant secondary to diabetic nephropathy three months ago. Her postoperative course was uneventful, and she was tolerating her immunosuppressive medications. She rarely left the house out of concern for picking up an infection, but over the past three weeks she developed fever, fatigue, and decreased appetite but no significant localizing symptoms. Blood tests showed a severely decreased white blood cell count.
  • 28. 46 year old female had kidney transplant secondary to diabetic nephropathy three months ago. Her postoperative course was uneventful, and she was tolerating her immunosuppressive medications. She rarely left the house out of concern for picking up an infection, but over the past three weeks she developed fever, fatigue, and decreased appetite but no significant localizing symptoms. Blood tests showed a severely decreased white blood cell count. Diagnosis?
  • 29. Cytomegalovirus (CMV) •  Betaherpesvirus •  Direct contact transmission –  Saliva, breast milk, urogenital –  Blood products, organ transplantation –  Transplacental ( TORCH infections) •  Epidemiology –  Approximately 50% of adults in U.S. seropositive –  >90% in underdeveloped countries
  • 30. CMV clinical disease •  Primary exposure –  Usually asymptomatic –  Can produce mono-like syndrome (non-specific symptoms) •  Complications –  Congenital CMV •  CNS involvement (encephalomalacia, hydrocephalus, retinitis) –  End-organ damage in immunosuppressed •  Ocular (retinitis) •  CNS (encephalitis) •  Respiratory •  Gastrointestinal •  Bone marrow University of Michigan Kellogg Eye Center
  • 31. CMV latency •  Establishment –  Monocytes and macrophages –  Mechanisms poorly understood •  Reactivation –  DIRECTLY linked with immune status –  Replication in wide variety of cell types •  Transplanted organs –  Can augment immunosuppression
  • 32. CMV diagnosis •  Clinical syndrome non-specific Large nuclear inclusion With peripheral clear zone •  Virus detection –  PCR (quantitative) –  Histopathology ( owl eye ) –  Direct fluorescent antibody (DFA) test –  Culture •  Serologies helpful Source Undetermined –  Assess risk for reactivation if immunosuppression anticipated
  • 33. CMV treatment and prevention •  Antiviral drugs available –  HSV drugs (acyclovir) less active –  Ganciclovir (valganciclovir), foscarnet, cidofovir –  Resistance problematic •  Target groups –  NOT for primary infection in immunocompetent patient –  Immunosuppressed patients –  Pre-emptive therapy often used •  CMV disease versus infection •  Prevention –  No vaccine available –  Prophylactic ganciclovir frequently used
  • 34. 18 year old student presented to his primary physician with one week history of fever, fatigue, sore throat, swollen glands. He recently started a new relationship with a classmate who had no symptoms. On physical exam, his oropharynx was erythematous without tonsillar exudate and he had prominent cervical lymphadenopathy. Rapid strep test was negative. Blood test showed an increased white blood cell count with atypical appearing lymphocytes. His symptoms eventually resolved over 2 weeks, but his fatigue persisted for 6 months.
  • 36. 18 year old student presented to his primary physician with one week history of fever, fatigue, sore throat, swollen glands. He recently started a new relationship with a classmate who had no symptoms. On physical exam, his oropharynx was erythematous without tonsillar exudate and he had prominent cervical lymphadenopathy. Rapid strep test was negative. Blood test showed an increased white blood cell count with atypical appearing lymphocytes. His symptoms eventually resolved over 2 weeks, but his fatigue persisted for 6 months. Diagnosis?
  • 37. Epstein-Barr virus (EBV) •  Gammaherpesvirus •  Direct contact transmission –  Saliva, respiratory secretions –  Transfusion, transplantation •  Epidemiology –  Approximately 50-70% of adults in U.S. seropositive –  >90% in underdeveloped countries
  • 38. EBV clinical disease •  Primary exposure –  Often asymptomatic –  Typically produce mononucleosis syndrome •  Fever, sore throat, fatigue (prolonged) •  Hematologic abnormalities, hepatitis •  Complications (malignancies) –  Linked to immune status and latency in B cells –  Post-transplant lymphoproliferative disorder (PTLD) –  Lymphoma •  Nasopharyngeal carcinoma •  Burkitt s lymphoma (Africa) •  Primary CNS lymphoma (HIV/AIDS) •  Hodgkin s disease
  • 39. EBV diagnosis •  Clinical syndrome non-specific •  Virus detection –  PCR –  Direct fluorescent antibody (DFA) test –  Culture •  Serologies helpful –  Assess risk for reactivation –  Monospot test •  Heterophil antibodies directed against RBC from other species (NOT EBV-specific)
  • 40. EBV treatment and prevention •  Antiviral drugs (acyclovir, ganciclovir) –  In vitro activity but no evidence for effectiveness in patients Correct underlying immunosuppressed status •  Prevention –  No vaccine available
  • 41. Other herpesviruses •  Human herpes virus 6 (HHV6) –  Betaherpesvirus (similar to CMV) –  Etiology of roseola infanatum •  HHV8 –  Gammaherpesvirus (similar to EBV) –  Also called Kaposi s sarcoma herpes virus (KSHV)
  • 42. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy Slide 5: David Miller Slide 6: Sources Undetermined Slide 7: Source Undetermined Slide 8: Source Undetermined Slide 10: Source Undetermined Slide 13: Source Undetermined Slide 14: Source Undetermined Slide 16: Source Undetermined Slide 19: Source Undetermined Slide 24: Adapted from Reven Sanchez,Wikimedia Commons, CC:BY-SA, http://creativecommons.org/licenses/by-sa/3.0/ Slide 30: University of Michigan Kellogg Eye Center Slide 32: Source Undetermined Slide 35: Source Undetermined