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 (though less now that we leukoreduce donor blood)
* 50 to 80% of people are CMV-IgG seropositive
** Increases with age
** Higher in poor countries[[CiteRef::cannon2010re]] and First Nations[[CiteRef::preiksaitis1988co]]


*See [[antiviral resistance in CMV]]
=== Pathophysiology ===
*Inherent acyclovir resistance
* Persists in CD34-positive cells, including monocytes and other tissues
*Tyrosine kinase mutation UL97 confers resistance to (val)ganciclovir
* Downregulates HLA in T cells, which predisposes to bacterial and fungal infections
*Polymerase mutation UL54 confers resistance to (val)ganciclovir and to foscarnet


=== Risk Factors ===
===Epidemiology===
* Crowding


*Transferred by droplets and blood transfusions (though less now that we leukoreduce donor blood)
== Clinical Presentation ==
*50 to 80% of people are CMV-IgG seropositive
* Often asymptomatic when young
**Increases with age
**Higher in poor countries[[CiteRef::cannon2010re]] and First Nations[[CiteRef::preiksaitis1988co]]


===Pathophysiology===
=== Infectious mononucleosis syndrome ===
* 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)


*Persists in CD34-positive cells, including monocytes and other tissues
=== Stem cell transplantation ===
*'''Immunomodulatory'''
* Low risk until day 21 post-transplantation, when cell lines begin to return, up to about 120 days
**Downregulates HLA in T cells, which predisposes to bacterial and fungal infections
* May present as asymptomatic viremia
**Increased risk of transplant rejection
* Most common symptomatic presentation is '''pneumonitis''' (an interstitial pneumonia), which has high mortality
**Increased risk of atherosclerosis
** Onset over less than 2 weeks, with fever, non-productive cough, and dyspnea
** More common with [[GVHD]]
* Can also present with GI involvement


===Risk Factors===
=== Solid-organ transplantation ===
* Tends to reactivate within the transplanted organ
* However, all can have GI involvement


*Crowding
=== Advanced HIV ===
*Immunosuppression; refer to specific scenarios below
* 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,


==Clinical Manifestations==
=== Other immunosuppression ===
* Most common implicated medications include [[cyclophosphamide]] and [[azathioprine]]
* Others include [[OKT3 antiserum]]
* Neither [[prednisone]] nor [[tacrolimus]] appears to cause reactivation


=== Congenital CMV ===
===Children===
* See [[congenital CMV]]


*Often asymptomatic when young
=== Complications ===
* '''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


===Infectious Mononucleosis===
== 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


*CMV causes 21% of IM
== Diagnosis ==
*Fever, lymphadenopathy, and lymphocytosis
* '''Serology'''
*Often mild liver abnormalities
** IgG useful for prior exposure (suggesting latent infection)
*Occasionally cold agglutinin disease, RF positivity, cryoglobulinemia, and ANA positivity
** IgG avidity can confirm recent infection
*Symptoms can persist or relapse over months (average 2 months, but up to 8)
** 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


===Asymptomatic Viremia===
== 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]]
* At McMaster, expect 1-log drop within 2 weeks (lab-dependent)
* Continue treatment until PCR is negative
* Consider resistance if CMV DNA titres not decreasing despite appropriate treatment
** Resistance genotyping available


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


===Immunodeficient Patients===
== Complications ==
====Stem Cell Transplantation====
* Even when dormant, can cause mild immunosuppression that predisposes to fungal infections

* Asymptomatic shedding in lungs during intercurrent illness
*See also [[CMV after hematopoietic stem cell transplantation]]
* Viremia with influenza-like illness
*Low risk until day 21 post-transplantation, when cell lines begin to return, up to about 120 days
* End-orgam damage
*May present as asymptomatic viremia
** CMV colitis
*Most common symptomatic presentation is '''pneumonitis''' (an interstitial pneumonia), which has high mortality
** Retinitis in AIDS patient (CD4 < 50-100)
**Onset over less than 2 weeks, with fever, non-productive cough, and dyspnea
** Organ inflammation of solid-organ transplants
**More common with [[GVHD]]
** Pneumonitis in stem cell transplants
*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 12:48, 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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