Cytomegalovirus: Difference between revisions

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−
== Background ==
 +
==Background==
   
−
=== Microbiology ===
 +
===Microbiology===
−
* A dsDNA virus and the largest member of the [[Human herpesviruses|human herpesvirus]] family
  
−
* DNA in the nucleoprotein core is embedded in matrix proteins and pp65 antigen, which is surrounded by lipid envelope
  
−
* UL54 encodes DNA polymerase and is highly conserved
  
−
* UL97 encodes a tyrosine kinase required to phosphorylate (and therefore activate) ganciclovir
  
−
* May have four genotypes
  
   
  +
*A dsDNA virus and the largest member of the [[Herpesviridae]] family
−
=== Antiviral resistance ===
  
  +
*DNA in the nucleoprotein core is embedded in matrix proteins and pp65 antigen, which is surrounded by lipid envelope
−
* Inherent acyclovir resistance
  
  +
*UL54 encodes DNA polymerase and is highly conserved
−
* Tyrosine kinase mutation UL97 confers resistance to (val)ganciclovir
  
  +
*UL97 encodes a tyrosine kinase required to phosphorylate (and therefore activate) ganciclovir
−
* Polymerase mutation UL54 confers resistance to (val)ganciclovir and to foscarnet
  
  +
*May have four genotypes
   
−
=== Epidemiology ===
 +
===Antiviral Resistance===
−
* Transferred by droplets and blood transfusions
  
−
* 80% of people are CMV-IgG positive
  
   
  +
*See [[antiviral resistance in CMV]]
−
=== Risk Factors ===
  
  +
*Inherent acyclovir resistance
−
* Crowding
  
  +
*Tyrosine kinase mutation UL97 confers resistance to (val)ganciclovir
  +
*Polymerase mutation UL54 confers resistance to (val)ganciclovir and to foscarnet
   
  +
===Epidemiology===
−
== Clinical Presentation ==
  
−
* Often asymptomatic when young
  
   
  +
*Transferred by droplets and blood transfusions (though less now that we leukoreduce donor blood)
−
=== Infectious mononucleosis syndrome ===
  
  +
*50 to 80% of people are CMV-IgG seropositive
−
* CMV causes 21% of IM
  
  +
**Increases with age
−
* Fever, lymphadenopathy, and lymphocytosis
  
  +
**Higher in poor countries[[CiteRef::cannon2010re]] and First Nations[[CiteRef::preiksaitis1988co]]
−
* Often mild liver abnormalities
  
−
* Occasionally cold agglutinin disease, RF positivity, cryoglobulinemia, and ANA positivity
  
−
* Symptoms can persist or relapse over months (average 2 months, but up to 8)
  
   
  +
===Pathophysiology===
−
=== Stem cell transplantation ===
  
−
* Low risk until day 21 post-transplantation, when cell lines begin to return
  
−
* May present as asymptomatic viremia
  
−
* Most common symptomatic presentation is pneumonitis (an interstitial pneumonia)
  
−
* Can also present with GI involvement
  
   
  +
*Persists in CD34-positive cells, including monocytes and other tissues
−
=== Solid-organ transplantation ===
  
  +
*'''Immunomodulatory'''
−
* Tends to reactivate within the transplanted organ
  
  +
**Downregulates HLA in T cells, which predisposes to bacterial and fungal infections
−
* However, all can have GI involvement
  
  +
**Increased risk of transplant rejection
  +
**Increased risk of atherosclerosis
   
−
=== Advanced HIV ===
 +
===Risk Factors===
−
* Coinfection is common, with 90% CMV seropositivity in HIV-positive men
  
−
* Advanced HIV disease carries increased risk of severe CMV disease
  
−
* CMV '''retinitis''' is the most common form in AIDS
  
−
** Classic white fluffy retinal infiltrate with areas of hemorrhage
  
−
* Can cause '''polyradiculopathy''' and '''myopathy''', with back pain and subacute flaccid paralysis
  
−
** CSF will be abnormal
  
−
* Can cause '''esophagitis'''
  
−
* Can cause '''colitis''', with diarrhea, often fever, and occasionally hematochezia
  
−
** On sigmoidoscopy, has plaque-like pseudomembranes, serpiginous ulcers, and erosions
  
−
** Can occasionally present with a mass lesion that can cause partial obstruction
  
−
* Rarely, pancreatitis, cholecystitis,
  
   
  +
*Crowding
−
=== Complications ===
  
  +
*Immunosuppression; refer to specific scenarios below
−
* '''Pneumonitis'''
  
−
** Can cause an interstitial pneumonia
  
−
** Severe in SCT patients, mild in mononucleosis patients
  
−
* '''Hepatitis'''
  
−
** Usually mild
  
−
** Can include granulomatous hepatitis in the context of mononucleosis
  
−
* '''[[Guillain-Barré syndrome]]'''
  
−
** Sensory and motor palsies in the extremities and cranial nerves
  
−
** Resolves over months
  
−
* '''Meningoencephalitis'''
  
−
** Headache, photophobia, lethargy, and pyramidal tract dysfunction
  
−
** May have concurrent motor and sensory palsies
  
−
* '''Myocarditis'''
  
−
** Rare
  
−
* '''Thrombocytopenia and hemolytic anemia'''
  
−
** Common in congenital infection, and occasionally seen in adults
  
−
* '''Rashes'''
  
−
** Can cause maculopapular or rubelliform rashes following treatment with amipicillin
  
   
  +
==Clinical Manifestations==
−
== Investigations ==
  
−
* CBC showing leukopenia or pancytopenia
  
−
* Mild elevation in liver enzymes
  
−
* CMV-IgG positive
  
−
* Detectable CMV DNA in peripheral blood, though it can rise during intercurrent illness
  
   
−
== Diagnosis ==
 +
===Children===
−
* '''Serology'''
  
−
** IgG useful for prior exposure (suggesting latent infection)
  
−
** IgG avidity can confirm recent infection
  
−
** IgM >300 U/mL can help diagnose acute infection
  
−
* '''Quantitative PCR''' is most useful for diagnosis and monitoring response to treatment
  
−
** Can be done on blood, BAL, urine, saliva, etc.
  
−
** Standards for reporting are defined by WHO
  
−
** However, can shed CMV asymptomatically during an acute illness, so must be taken within the clinical context
  
−
** Sensitivity/specificity for CMV disease depends on the laboratory methods and cutoff used
  
−
* '''Microscopy''' of tissue biopsy or cytology may demonstrate large nuclear inclusions, and can use immunofluorescence to pp65 antigen to confirm diagnosis
  
−
* '''Viral culture''' can be done with human fibroblast cells, but is slow
  
   
  +
*Often asymptomatic when young
−
== Management ==
  
−
* Antivirals
  
−
** First-line: [[Is treated by::valganciclovir]] or [[Is treated by::ganciclovir]]
  
−
*** Measure baseline CBC first due to risk of cytopenias
  
−
** Second-line, if cytopenias: [[Is treated by::foscarnet]]
  
−
** Third-line: [[Is treated by::cidofovir]], [[Is treated by::maribavir]], [[Is treated by::letermovir]]
  
−
* At McMaster, expect 1-log drop within 2 weeks (lab-dependent)
  
−
* Continue treatment until PCR is negative
  
   
  +
===Infectious Mononucleosis===
−
== Prophylaxis ==
  
−
* '''Solid-organ transplant'''
  
−
** Donor+/Recipient– high risk for reactivation, the the donor organ infecting the recipient
  
−
** Donor–/Recipient+ intermediate risk
  
−
** Donor+/Recipient+ intermediate risk
  
−
** Donor–/Recipient– lowest risk
  
−
** High and intermediate risk patients get '''prophylaxis''' with valganciclovir 900 mg po bid for some amount of duration...
  
−
* '''Hematologic stem cell transplant'''
  
−
** Donor+/Recipient+ high risk for reactivation
  
−
** Donor–/Recipient+ high risk
  
−
** Donor+/Recipient– intermediate risk
  
−
** Donor–/Recipient– lowest risk
  
−
** '''Preemptive monitoring''' with weekly CMV DNA PCR starting week 2
  
−
* Treat if greater than threshold (1425 at McMaster) or if rising titre with symptoms
  
   
  +
*CMV causes 21% of IM
−
== Complications ==
  
  +
*Fever, lymphadenopathy, and lymphocytosis
−
* Even when dormant, can cause mild immunosuppression that predisposes to fungal infections
  
  +
*Often mild liver abnormalities
−
* Asymptomatic shedding in lungs during intercurrent illness
  
  +
*Occasionally cold agglutinin disease, RF positivity, cryoglobulinemia, and ANA positivity
−
* Viremia with influenza-like illness
  
  +
*Symptoms can persist or relapse over months (average 2 months, but up to 8)
−
* End-orgam damage
  
  +
−
** CMV colitis
  
  +
===Asymptomatic Viremia===
−
** Retinitis in AIDS patient (CD4 < 50-100)
  
  +
−
** Organ inflammation of solid-organ transplants
  
  +
*May have asymptomatic viremia with any intercurrent illness, of no significance
−
** Pneumonitis in stem cell transplants
  
  +
  +
===Immunodeficient Patients===
  +
====Stem Cell Transplantation====
  +
  +
*See also [[CMV after hematopoietic stem cell transplantation]]
  +
*Low risk until day 21 post-transplantation, when cell lines begin to return, up to about 120 days
  +
*May present as asymptomatic viremia
  +
*Most common symptomatic presentation is '''pneumonitis''' (an interstitial pneumonia), which has high mortality
  +
**Onset over less than 2 weeks, with fever, non-productive cough, and dyspnea
  +
**More common with [[GVHD]]
  +
*Can also present with GI involvement
  +
  +
====Solid Organ Transplantation====
  +
  +
*See also [[CMV after solid organ transplantation]]
  +
*Tends to reactivate within the transplanted organ (lungs, liver, kidney)
  +
*However, all can have [[CMV colitis|colitis]]
  +
*The CMV syndrome is another non-specific manifestation that requires viremia plus two of:
  +
**Fever >38ºC for >2 days
  +
**New or worsened fatigue or malaise
  +
**Leukopenia or neutropenia
  +
**>5% reactive lymphocytes
  +
**Thrombocytopenia <100,000 (or <20% of initial platelet count if it was <115,000)
  +
**Elevated transaminases
  +
  +
====Advanced HIV====
  +
  +
*Coinfection is common, with 90% CMV seropositivity in HIV-positive men
  +
*Advanced HIV disease carries increased risk of severe CMV disease
  +
*CMV '''retinitis''' is the most common form in AIDS
  +
**Classic white fluffy retinal infiltrate with areas of hemorrhage
  +
*Can cause '''polyradiculopathy''' and '''myopathy''', with back pain and subacute flaccid paralysis
  +
**CSF will be abnormal
  +
*Can cause '''esophagitis''' and '''colitis'''
  +
*Rarely, pancreatitis and cholecystitis
  +
  +
====Other Immunosuppression====
  +
  +
*Most common implicated medications include [[cyclophosphamide]], [[MMF]], and [[azathioprine]]
  +
*Highest-risk medications include [[alemtuzumab]], [[fludarabine]], and [[2-chlorodeoxyadenose]] (CDA)
  +
*Others include [[OKT3 antiserum]] and [[ATG]]
  +
*Unmatched transplant, transplant rejection, [[GVHD]], umbilical cord blood transplantation are also risk factors
  +
*Neither [[prednisone]] nor [[tacrolimus]] appears to cause reactivation
  +
  +
===Congenital CMV===
  +
  +
*See [[congenital CMV]]
  +
  +
===Complications===
  +
  +
*'''Pneumonitis''', most common in HSCT and lung transplant
  +
**Can cause an interstitial pneumonia
  +
**Severe in SCT patients, mild in mononucleosis patients
  +
*'''Hepatitis''', most common in liver transplant
  +
**Usually mild
  +
**Can include granulomatous hepatitis in the context of mononucleosis
  +
*'''[[Guillain-Barré syndrome]]'''
  +
**Sensory and motor palsies in the extremities and cranial nerves
  +
**Resolves over months
  +
*'''Meningoencephalitis'''
  +
**Headache, photophobia, lethargy, and pyramidal tract dysfunction
  +
**May have concurrent motor and sensory palsies
  +
*'''Myocarditis'''
  +
**Rare
  +
*'''Thrombocytopenia and hemolytic anemia'''
  +
**Common in congenital infection, and occasionally seen in adults
  +
*'''Rashes'''
  +
**Can cause maculopapular or rubelliform rashes following treatment with amipicillin
  +
*'''Colitis''', in anyone, including older age
  +
**Symptoms include diarrhea, often fever, and occasionally hematochezia
  +
**On sigmoidoscopy, has plaque-like pseudomembranes, serpiginous ulcers, and erosions
  +
**Can occasionally present with a mass lesion that can cause partial obstruction
  +
  +
==Investigations==
  +
  +
*CBC showing leukopenia or pancytopenia
  +
*Mild elevation in liver enzymes
  +
*CMV-IgG positive
  +
*Detectable CMV DNA in peripheral blood, though it can rise during intercurrent illness
  +
  +
==Diagnosis==
  +
  +
*'''Serology'''
  +
**IgG
  +
***Useful for prior exposure (suggesting latent infection)
  +
***IgG avidity can confirm recent infection (avidity increases with time since primary infection)
  +
**IgM
  +
***>300 U/mL can help diagnose acute infection
  +
***Usually positive by 6 weeks after primary infection, but can remain positive for as long as 12 months
  +
***False positives, including from [[rheumatoid factor]], [[EBV]] infection, [[lupus]]
  +
{| class="wikitable"
  +
!IgG
  +
!IgM
  +
!Avidity
  +
!Interpretation
  +
|-
  +
| +
  +
|–
  +
|N/A
  +
|past infection, low risk for congenital infection
  +
|-
  +
| +
  +
| +
  +
|high
  +
|past infection, low risk for congenital infection
  +
|-
  +
| +
  +
| +
  +
|low
  +
|primary maternal infection within the past 3 months
  +
|-
  +
|–
  +
|–
  +
|N/A
  +
|either no infection, or repeat in 4 weeks
  +
|}
  +
  +
  +
  +
*'''Quantitative PCR''' is most useful for diagnosis and monitoring response to treatment
  +
**Can be done on blood, BAL, urine, saliva, etc.
  +
**Standards for reporting are defined by WHO, but results are still lab-specific
  +
**Can be undetectable, less than lab cutoff, or quantified in IU/mL
  +
**However, can shed CMV asymptomatically during an acute illness, so must be taken within the clinical context
  +
**Sensitivity/specificity for CMV disease depends on the laboratory methods and cutoff used
  +
*'''Microscopy''' of tissue biopsy or cytology may demonstrate large nuclear inclusions, and can use immunofluorescence to pp65 antigen to confirm diagnosis
  +
*'''Viral culture''' can be done with human fibroblast cells, but is slow
  +
  +
==Management==
  +
===Antivirals===
  +
  +
*First-line: [[Is treated by::valganciclovir]] or [[Is treated by::ganciclovir]]
  +
**Measure baseline CBC first due to risk of cytopenias
  +
*Second-line, if cytopenias: [[Is treated by::foscarnet]]
  +
*Third-line: [[Is treated by::cidofovir]], [[Is treated by::maribavir]], [[Is treated by::letermovir]]
  +
*New or experimental: [[maribavir]], [[brincidofovir]], and [[letermovir]]
  +
  +
===Duration===
  +
  +
*Depends on the clinical site of infection, which usually resolves over several weeks
  +
*In transplant patients, viremia is treated until negative viral load (not just undetectable)
  +
  +
===Resistance===
  +
  +
*See [[antiviral resistance in CMV]]
  +
*Antiviral resistance in CMV is uncommon
  +
*Mutations in UL97 are uncommon and confer resistance to [[ganciclovir]] and [[valganciclovir]]
  +
*Mutations in UL54 are rare and confer resistance to [[ganciclovir]], [[foscarnet]], and [[cidofovir]]
  +
  +
==Prevention==
  +
===Transplantation===
  +
  +
*See also [[CMV after solid organ transplantation]] and [[CMV after hematopoietic stem cell transplantation]]
  +
*Risk of reactivation is determined by the specific transplantation and the donor/recipient serostatus
  +
*Asymptomatic viremia precedes CMV disease by about a week
  +
*'''Solid organ transplant'''
  +
**Donor+/Recipient– high risk, with the the donor organ infecting the recipient
  +
**Donor–/Recipient+ intermediate risk
  +
**Donor+/Recipient+ intermediate risk
  +
**Donor–/Recipient– lowest risk
  +
**High and intermediate risk patients get '''prophylaxis''' with [[valganciclovir]] 900 mg po bid for about 6 months
  +
*'''Hematologic stem cell transplant'''
  +
**Donor±/Recipient+ high risk
  +
**Donor+/Recipient– intermediate risk
  +
**Donor–/Recipient– lowest risk
  +
**'''Preemptive monitoring''' with weekly CMV DNA PCR starting week 2 or 3
  +
***Treat if greater than threshold (1451 at McMaster) or if rising titre with symptoms
  +
***Expect 1-log drop within 2 weeks (lab-dependent)
  +
***Continue treatment until PCR is negative
   
 
[[Category:Herpesviridae]]
  
[[Category:Herpesviridae]]

Latest revision as of 08:48, 18 October 2023

Background

Microbiology

  • A dsDNA virus and the largest member of the Herpesviridae family
  • DNA in the nucleoprotein core is embedded in matrix proteins and pp65 antigen, which is surrounded by lipid envelope
  • UL54 encodes DNA polymerase and is highly conserved
  • UL97 encodes a tyrosine kinase required to phosphorylate (and therefore activate) ganciclovir
  • May have four genotypes

Antiviral Resistance

  • See antiviral resistance in CMV
  • Inherent acyclovir resistance
  • Tyrosine kinase mutation UL97 confers resistance to (val)ganciclovir
  • Polymerase mutation UL54 confers resistance to (val)ganciclovir and to foscarnet

Epidemiology

  • Transferred by droplets and blood transfusions (though less now that we leukoreduce donor blood)
  • 50 to 80% of people are CMV-IgG seropositive
    • Increases with age
    • Higher in poor countries1 and First Nations2

Pathophysiology

  • Persists in CD34-positive cells, including monocytes and other tissues
  • Immunomodulatory
    • Downregulates HLA in T cells, which predisposes to bacterial and fungal infections
    • Increased risk of transplant rejection
    • Increased risk of atherosclerosis

Risk Factors

  • Crowding
  • Immunosuppression; refer to specific scenarios below

Clinical Manifestations

Children

  • Often asymptomatic when young

Infectious Mononucleosis

  • CMV causes 21% of IM
  • Fever, lymphadenopathy, and lymphocytosis
  • Often mild liver abnormalities
  • Occasionally cold agglutinin disease, RF positivity, cryoglobulinemia, and ANA positivity
  • Symptoms can persist or relapse over months (average 2 months, but up to 8)

Asymptomatic Viremia

  • May have asymptomatic viremia with any intercurrent illness, of no significance

Immunodeficient Patients

Stem Cell Transplantation

  • See also CMV after hematopoietic stem cell transplantation
  • Low risk until day 21 post-transplantation, when cell lines begin to return, up to about 120 days
  • May present as asymptomatic viremia
  • Most common symptomatic presentation is pneumonitis (an interstitial pneumonia), which has high mortality
    • Onset over less than 2 weeks, with fever, non-productive cough, and dyspnea
    • More common with GVHD
  • Can also present with GI involvement

Solid Organ Transplantation

  • See also CMV after solid organ transplantation
  • Tends to reactivate within the transplanted organ (lungs, liver, kidney)
  • However, all can have colitis
  • The CMV syndrome is another non-specific manifestation that requires viremia plus two of:
    • Fever >38ºC for >2 days
    • New or worsened fatigue or malaise
    • Leukopenia or neutropenia
    • >5% reactive lymphocytes
    • Thrombocytopenia <100,000 (or <20% of initial platelet count if it was <115,000)
    • Elevated transaminases

Advanced HIV

  • Coinfection is common, with 90% CMV seropositivity in HIV-positive men
  • Advanced HIV disease carries increased risk of severe CMV disease
  • CMV retinitis is the most common form in AIDS
    • Classic white fluffy retinal infiltrate with areas of hemorrhage
  • Can cause polyradiculopathy and myopathy, with back pain and subacute flaccid paralysis
    • CSF will be abnormal
  • Can cause esophagitis and colitis
  • Rarely, pancreatitis and cholecystitis

Other Immunosuppression

Congenital CMV

Complications

  • Pneumonitis, most common in HSCT and lung transplant
    • Can cause an interstitial pneumonia
    • Severe in SCT patients, mild in mononucleosis patients
  • Hepatitis, most common in liver transplant
    • Usually mild
    • Can include granulomatous hepatitis in the context of mononucleosis
  • Guillain-Barré syndrome
    • Sensory and motor palsies in the extremities and cranial nerves
    • Resolves over months
  • Meningoencephalitis
    • Headache, photophobia, lethargy, and pyramidal tract dysfunction
    • May have concurrent motor and sensory palsies
  • Myocarditis
    • Rare
  • Thrombocytopenia and hemolytic anemia
    • Common in congenital infection, and occasionally seen in adults
  • Rashes
    • Can cause maculopapular or rubelliform rashes following treatment with amipicillin
  • Colitis, in anyone, including older age
    • Symptoms include diarrhea, often fever, and occasionally hematochezia
    • On sigmoidoscopy, has plaque-like pseudomembranes, serpiginous ulcers, and erosions
    • Can occasionally present with a mass lesion that can cause partial obstruction

Investigations

  • CBC showing leukopenia or pancytopenia
  • Mild elevation in liver enzymes
  • CMV-IgG positive
  • Detectable CMV DNA in peripheral blood, though it can rise during intercurrent illness

Diagnosis

  • Serology
    • IgG
      • Useful for prior exposure (suggesting latent infection)
      • IgG avidity can confirm recent infection (avidity increases with time since primary infection)
    • IgM
      • >300 U/mL can help diagnose acute infection
      • Usually positive by 6 weeks after primary infection, but can remain positive for as long as 12 months
      • False positives, including from rheumatoid factor, EBV infection, lupus
IgG IgM Avidity Interpretation
+ – N/A past infection, low risk for congenital infection
+ + high past infection, low risk for congenital infection
+ + low primary maternal infection within the past 3 months
– – N/A either no infection, or repeat in 4 weeks


  • Quantitative PCR is most useful for diagnosis and monitoring response to treatment
    • Can be done on blood, BAL, urine, saliva, etc.
    • Standards for reporting are defined by WHO, but results are still lab-specific
    • Can be undetectable, less than lab cutoff, or quantified in IU/mL
    • However, can shed CMV asymptomatically during an acute illness, so must be taken within the clinical context
    • Sensitivity/specificity for CMV disease depends on the laboratory methods and cutoff used
  • Microscopy of tissue biopsy or cytology may demonstrate large nuclear inclusions, and can use immunofluorescence to pp65 antigen to confirm diagnosis
  • Viral culture can be done with human fibroblast cells, but is slow

Management

Antivirals

Duration

  • Depends on the clinical site of infection, which usually resolves over several weeks
  • In transplant patients, viremia is treated until negative viral load (not just undetectable)

Resistance

Prevention

Transplantation

  • See also CMV after solid organ transplantation and CMV after hematopoietic stem cell transplantation
  • Risk of reactivation is determined by the specific transplantation and the donor/recipient serostatus
  • Asymptomatic viremia precedes CMV disease by about a week
  • Solid organ transplant
    • Donor+/Recipient– high risk, with the the donor organ infecting the recipient
    • Donor–/Recipient+ intermediate risk
    • Donor+/Recipient+ intermediate risk
    • Donor–/Recipient– lowest risk
    • High and intermediate risk patients get prophylaxis with valganciclovir 900 mg po bid for about 6 months
  • Hematologic stem cell transplant
    • Donor±/Recipient+ high risk
    • Donor+/Recipient– intermediate risk
    • Donor–/Recipient– lowest risk
    • Preemptive monitoring with weekly CMV DNA PCR starting week 2 or 3
      • Treat if greater than threshold (1451 at McMaster) or if rising titre with symptoms
      • Expect 1-log drop within 2 weeks (lab-dependent)
      • Continue treatment until PCR is negative

References

  1. ^  Michael J. Cannon, D. Scott Schmid, Terri B. Hyde. Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection. Reviews in Medical Virology. 2010;20(4):202-213. doi:10.1002/rmv.655.
  2. ^  Jutta K. Preiksaitis, R. P. Bryce Larke, Glory J. Froese. Comparative seroepidemiology of cytomegalovirus infection in the Canadian Arctic and an Urban center. Journal of Medical Virology. 1988;24(3):299-307. doi:10.1002/jmv.1890240307.

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