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Cytomegalovirus

2019-10-24T14:01:05Z

Anna: /* Prevention of disease in transplant patients */

== Background ==

=== 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

=== Antiviral resistance ===
* 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 countries[[CiteRef::cannon2010re]] and First Nations[[CiteRef::preiksaitis1988co]]

=== 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

== Clinical Presentation ==

=== Children ===
* Often asymptomatic when young

=== 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)

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

=== Immunodeficient patients ===
==== 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 ====
* Tends to reactivate within the transplanted organ (lungs, liver, kidney)
* However, all can have colitis

==== 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]]
* 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
** 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, 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]]

=== Resistance ===
* Consider resistance if CMV DNA titres not decreasing despite appropriate treatment
* Resistance genotyping available

=== Prevention of disease in transplant patients ===
* 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

== Complications ==
* Even when dormant, can cause mild immunosuppression that predisposes to fungal infections
* Asymptomatic shedding in lungs during intercurrent illness
* Viremia with influenza-like illness
* End-orgam damage
** CMV colitis
** Retinitis in AIDS patient (CD4 < 50-100)
** Organ inflammation of solid-organ transplants
** Pneumonitis in stem cell transplants

[[Category:Herpesviridae]]

Cytomegalovirus

2019-10-24T13:58:34Z

Anna: /* Prevention of disease in transplant patients */

== Background ==

=== 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

=== Antiviral resistance ===
* 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 countries[[CiteRef::cannon2010re]] and First Nations[[CiteRef::preiksaitis1988co]]

=== 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

== Clinical Presentation ==

=== Children ===
* Often asymptomatic when young

=== 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)

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

=== Immunodeficient patients ===
==== 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 ====
* Tends to reactivate within the transplanted organ (lungs, liver, kidney)
* However, all can have colitis

==== 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]]
* 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
** 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

== 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]]

=== Resistance ===
* Consider resistance if CMV DNA titres not decreasing despite appropriate treatment
* Resistance genotyping available

=== Prevention of disease in transplant patients ===
* 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 (1454 at McMaster) or if rising titre with symptoms
*** Expect 1-log drop within 2 weeks (lab-dependent)
*** Continue treatment until PCR is negative

== Complications ==
* Even when dormant, can cause mild immunosuppression that predisposes to fungal infections
* Asymptomatic shedding in lungs during intercurrent illness
* Viremia with influenza-like illness
* End-orgam damage
** CMV colitis
** Retinitis in AIDS patient (CD4 < 50-100)
** Organ inflammation of solid-organ transplants
** Pneumonitis in stem cell transplants

[[Category:Herpesviridae]]