Cytomegalovirus: Difference between revisions
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m (Aidan moved page Cytomegalovirus (CMV) to Cytomegalovirus without leaving a redirect) |
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+ | ==Background== |
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− | = Cytomegalovirus (CMV) = |
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+ | ===Microbiology=== |
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− | = Definition = |
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+ | *A dsDNA virus and the largest member of the [[Herpesviridae]] family |
||
− | * Human herpesvirus (DNA virus) transferred by respiratory droplets and blood transfusions that lies dormant in white blood cells |
||
+ | *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=== |
||
− | = Epidemiology = |
||
+ | *See [[antiviral resistance in CMV]] |
||
− | * 80% of people are CMV-IgG positive |
||
+ | *Inherent acyclovir resistance |
||
+ | *Tyrosine kinase mutation UL97 confers resistance to (val)ganciclovir |
||
+ | *Polymerase mutation UL54 confers resistance to (val)ganciclovir and to foscarnet |
||
+ | ===Epidemiology=== |
||
− | = Risk Factors = |
||
+ | *Transferred by droplets and blood transfusions (though less now that we leukoreduce donor blood) |
||
− | * Crowding |
||
+ | *50 to 80% of people are CMV-IgG seropositive |
||
+ | **Increases with age |
||
+ | **Higher in poor countries[[CiteRef::cannon2010re]] and First Nations[[CiteRef::preiksaitis1988co]] |
||
+ | ===Pathophysiology=== |
||
− | = Presentation = |
||
+ | *Persists in CD34-positive cells, including monocytes and other tissues |
||
− | * Asymptomatic when young |
||
+ | *'''Immunomodulatory''' |
||
− | * Mono-like or influenza-like illness when older |
||
+ | **Downregulates HLA in T cells, which predisposes to bacterial and fungal infections |
||
+ | **Increased risk of transplant rejection |
||
+ | **Increased risk of atherosclerosis |
||
+ | ===Risk Factors=== |
||
− | = Investigations = |
||
+ | *Crowding |
||
− | * CBC showing leukopenia or pancytopenia |
||
+ | *Immunosuppression; refer to specific scenarios below |
||
− | * Mild elevation in liver enzymes |
||
− | * CMV-IgG positive |
||
− | * Detectable CMV DNA in peripheral blood, though it can rise during intercurrent illness |
||
+ | ==Clinical Manifestations== |
||
− | = Management = |
||
+ | ===Children=== |
||
− | * First-line: valganciclovir or ganciclovir |
||
− | ** Measure baseline CBC first |
||
− | * Second-line, if cytopenias: foscarnet |
||
− | * Third-line: cidofovir, marabavir |
||
− | * At McMaster, expect 1-log drop within 2 weeks (lab-dependent) |
||
+ | *Often asymptomatic when young |
||
− | = Prophylaxis = |
||
+ | ===Infectious Mononucleosis=== |
||
− | * 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 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 |
||
+ | *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=== |
||
− | * Even when dormant, can cause mild immunosuppression that predisposes to fungal infections |
||
− | * Asymptomatic shedding in lungs during intercurrent illness |
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− | * Viremia with influenza-like illness |
||
− | * End-orgam damage |
||
− | ** CMV colitis |
||
− | ** Retinitis in AIDS patient (CD4 < 50-100) |
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− | ** Organ inflammation of solid-organ transplants |
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− | ** Pneumonitis in stem cell transplants |
||
+ | *May have asymptomatic viremia with any intercurrent illness, of no significance |
||
− | = Resistance = |
||
+ | ===Immunodeficient Patients=== |
||
− | * Inherent acyclovir resistance |
||
+ | ====Stem Cell Transplantation==== |
||
− | * Tyrosine kinase mutation UL97? confers resistance to (val)ganciclovir |
||
+ | |||
− | * Polymerase mutation U54? confers resistance to (val)ganciclovir and foscarnet |
||
+ | *See also [[CMV after hematopoietic stem cell transplantation]] |
||
− | * Consider resistance if CMV DNA titres not decreasing despite appropriate treatment |
||
+ | *Low risk until day 21 post-transplantation, when cell lines begin to return, up to about 120 days |
||
− | * Resistance genotyping available |
||
+ | *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" |
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+ | !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
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
- 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
- IgG
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: valganciclovir or ganciclovir
- Measure baseline CBC first due to risk of cytopenias
- Second-line, if cytopenias: foscarnet
- Third-line: cidofovir, maribavir, 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
References
- ^ 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.
- ^ 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.