Cytomegalovirus infection

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

CMV infection is caused by cytomegalovirus which belongs to the family Herpesviridae. Transmission of CMV occurs from person to person and results in activation of the immune system. Patients often present with a mononucleosis-like presentation with particularly severe complications in immunocompromised individuals and rarely in immunocompetent individuals. Reactivation can occur in response to inflammatory stimuli, physiologic stress and immunosuppressionrwhicheleasinevirions that can infect new cells causing CMV end organ infection. CMV infection can affect the eye, gastrointestinal tract and the central nervous system. Common complications of CMV infection in immunocompromised patients include CMV retinitis, CMV colitis, CMV encephalitis and CMV pneumonia. CMV is associated with increased risk of graft versus host disease, myelosuppression, and invasive bacterial and fungal infections increasing morbidity and mortality of the patients. Antiviral therapy is the primary treatment of choice. The duration of therapy and the antiviral agents are selected based on the severity of the disease, location of the disease and the level of immunosuppression of the patient. Ganciclovir and valganciclovir are the most commonly used antiviral drugs for the treatment of CMV infection.

In 1881, Ribbert described the presence of inclusion bodies in the cells in sections of kidney of a still born. In 1960, Thomas H.Weller from Harvard University, coined the term “cytomegalovirus” and isolated the virus from the urine sample of an infant with generalized disease.

Cytomegalovirus infection may be classified based on the organ system involved into the following: CMV retinitis, CMV colitis, CMV esophagitis, CMV pneumonitis, and CMV encephalitis.

Transmission of CMV occurs from person to person and primary CMV infection causes activation of the immune system and resulting in a mononucleosis like presentation and its complications in immunocompromised individuals and few immunocompetent individuals. Reactivation can occur in response to inflammatory stimuli, physiologic stress and immunosuppression releasing new virions that can infect new cells causing CMV end organ infection.

CMV infection is caused by cytomegalovirus. It belongs to order Herpesvirales, in the family Herpesviridae, in the subfamily Betaherpesvirinae.

CMV infection can affect the eye, gastrointestinal tract, and the central nervous system. Diagnosis of CMV requires differentiation of infections and diseases presenting with similar features. The majority of patients with CMV end organ infection are immunosuppressed. Therefore CMV infection must be suspected in all the patients presenting with immunosuppression and differentiated from other conditions known to affect immunocompromised patients.

Cytomegalovirus infection is seen approximately 40-90% of the world population, however, only manifests in serious complications in immunocompromised patients.

Patients with the following conditions or undergoing the following procedures are at a higher risk for developing symptomatic cytomegalovirus infection: solid organ transplant, hematological stem cell transplant, AIDS, and existing T-cell deficiency.

There is no standard screening recommended for cytomegalovirus infection due to the high seroprevalence.

Primary CMV infection takes place in childhood and early adolescence is asymptomatic. After the resolution of the primary infection CMV is latent in the mononuclear leukocytes. Reactivation in immunocompetent patients presents with mononucleosis like syndrome, but severe infection can occur in elderly and critically ill patients. Common complications of CMV infection in immunocompromised patients include CMV retinitis, CMV colitis, CMV encephalitis, CMV pneumonia and CMV myocarditis. CMV is associated with increased risk of graft versus host disease, myelosuppression, and invasive bacterial and fungal infections increasing morbidity and mortality of the patients.

Primary infection in majority of patients have a mononucleosis like presentation. Patients with immunosuppression have symptoms related to the affected organ system. Retinitis presents with blurred vision and floaters. Colitis presents with abdominal pain and bloody diarrhea. Pneumonitis is usually asymptomatic. Neurologic infection presents with altered mental status and focal neurological deficits.

The appearance of the patient depends on the stage of the disease. The patient may look very healthy or be ill-looking and cachectic. On fundus examination fluffy yellow-white retinal lesions, with or without intraretinal hemorrhages can be demonstrated in patients with CMV retinitis. Abdominal distension and tenderness can be present on examination in patients with CMV colitis. In patients with CMV encephalitis altered mental status and focal neurological deficits are present.

There are no specific laboratory findings associated with CMV infection. Elevated ESR and a low lymphocyte count may be present in patients with complications. Diagnosis is usually done by demonstration of the inclusion bodies from the tissue biopsies or by a positive PCR for CMV DNA.

There are no EKG changes associated with cytomegalovirus infection.

Chest X-Ray in cytomegalovirus pneumonitis demonstrates diffuse pulmonary interstitial infiltrates.

CT scan of the abdomen in patients with CMV colitis demonstrates colonic thickening. On brain CT, the presence of periventricular enhancement is suggestive of ventriculoencephalitis which is a common (but non-specific) finding in CMV encephalitis.

Periventricular enhancement is present in patients with ventriculoencephalitis on brain MRI.

There are no echocardiography findings associated with CMV infection.

CMV infection is diagnosed by demonstration of intranuclear inclusion bodies and a positive PCR, therefore there are no other specific imaging findings for CMV infection.

Other diagnostic studies helpful for the diagnosis of CMV infection include upper GI endoscopy, colonoscopy, serology and PCR.

Antiviral therapy is the primary modality of treatment. Duration of therapy and the antiviral agents are selected based on the severity of the disease, location of the disease and the level of immunosuppression. Ganciclovir and valganciclovir are the commonly used antiviral drugs for the treatment of CMV infection.

Surgical intervention is not recommended for the management of cytomegalovirus infection.

Primary prevention measures for CMV infection include regular hand washing to reduce the spread of infections. Healthcare providers should follow standard precautions to prevent nosocomial transmission particularly to immune compromised individuals.

Secondary prevention of CMV infection includes preemptive treatment with antiviral agents in asymptomatic patients with positive blood PCR for CMV DNA.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Qasim Salau, M.B.B.S., FMCPaed [2]

Transmission of CMV occurs from person to person and primary CMV infection causes activation of the immune system and resulting in a mononucleosis like presentation with hepatitis in immunocompromised individuals and few immunocompetent individuals. Reactivation can occur in response to inflammatory stimuli, physiologic stress and immunosuppression releasing new virions that can infect new cells causing CMV end organ infection.

• Transmission of CMV occurs from person to person.^[1]
• Infection requires close, intimate contact with a person excreting the virus in their saliva, urine, blood, tears, and semen.
• The shedding of virus may take place intermittently, without any detectable signs, and without causing symptoms.
• CMV can be sexually transmitted and can also be transmitted via breast milk, transplanted organs, and rarely from blood transfusions.^[2]

• Primary CMV infection causes activation of the immune system and results in a mononucleosis like presentation and its complications in immunocompromised individuals and few immunocompetent individuals.^{[3][4][5][6][7]}
• In majority of immunocompetent people, primary CMV infection is sub clinical and asymptomatic.
• Following primary infection the virus persists in a latent form in the host tissues invading the immune system.^[8]
• Reactivation can occur in response to inflammatory stimuli, physiologic stress and immunosuppression releasing new virions that can infect new cells causing cmv end organ infection.
• T-cells play a role in controlling the replication of the virus.
• In patients with T-cell deficiency the viral replication is uncontrolled and results in excessive shedding of the virus.
• Reactivation of the virus results in the release of cytokines such as TNF-α and IFN-γ resulting in inflammation.

• Patients with polymorphisms in the genes coding for mannose binding lectin and ficolin-2 are at a higher risk of developing CMV infection.^[9]

• Symptomatic cytomegalovirus is associated with HIV infection in majority of patients.^[10][11]

• CMV infection demonstrates the presence of intranuclear inclusion bodies. These inclusion bodies stain dark pink on an H&E stain, and are also called “Owl’s Eye” inclusion bodies.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Cytomegalovirus (from the Greek cyto-, “cell”, and megalo-, “large”) is a genus of viruses in the order Herpesvirales, in the family Herpesviridae, in the subfamily Betaherpesvirinae. Human and monkeys serve as natural hosts. There are currently eight species in this genus including the type species human herpesvirus 5. Diseases associated with HHV-5 include mononucleosis, and pneumonias.^[2][3] It is typically abbreviated as CMV.

The species that infects humans is commonly known as human CMV (HCMV) or human herpesvirus-5 (HHV-5), and is the most studied of all cytomegaloviruses.^[4] Within Herpesviridae, CMV belongs to the Betaherpesvirinae subfamily, which also includes the genera Muromegalovirus and Roseolovirus (HHV-6 and HHV-7).^[5] It is related to other herpesviruses within the subfamilies of Alphaherpesvirinae that includes herpes simplex viruses (HSV)-1 and -2 and varicella-zoster virus (VZV), and the Gammaherpesvirinae subfamily that includes Epstein–Barr virus.^[4]

All herpesviruses share a characteristic ability to remain latent within the body over long periods. Although they may be found throughout the body, CMV infections are frequently associated with the salivary glands in humans and other mammals.^[5] Other CMV viruses are found in several mammal species, but species isolated from animals differ from HCMV in terms of genomic structure, and have not been reported to cause human disease.

Group: dsDNA
Order:Herpesvirales

Family: Herpesviridae

Sub-Family: Betaherpesvirinae

Genus: Cytomegalovirus

Species:

• Aotine herpesvirus 1
• Cebine herpesvirus 1
• Cercopithecine herpesvirus 5
• Human herpesvirus 5>
• Macacine herpesvirus 3
• Panine herpesvirus 2
• Papiine herpesvirus 3
• Saimiriine herpesvirus 4

Several species of Cytomegalovirus have been identified and classified for different mammals.^[5] The most studied is Human cytomegalovirus (HCMV), which is also known as Human herpesvirus 5 (HHV-5). Other primate CMV species include Chimpanzee cytomegalovirus (CCMV) that infects chimpanzees and orangutans, and Simian cytomegalovirus (SCCMV) and Rhesus cytomegalovirus (RhCMV) that infect macaques; CCMV is known as both Panine herpesvirus 2 (PaHV-2) and Pongine herpesvirus-4 (PoHV-4). SCCMV is called Cercopithecine herpesvirus-5 (CeHV-5) and RhCMV, Cercopithecine herpesvirus 8 (CeHV-8). A further two viruses found in the night monkey are tentatively placed in the Cytomegalovirus genus, and are called Herpesvirus aotus 1 and Herpesvirus aotus 3. Rodents also have viruses previously called cytomegaloviruses that are now reclassified under the genus Muromegalovirus; this genus contains Mouse cytomegalovirus (MCMV) is also known as Murid herpesvirus 1 (MuHV-1) and the closely related Murid herpesvirus 2 (MuHV-2) that is found in rats. In addition, there many other viral species with the name Cytomegalovirus identified in distinct mammals that are as yet not completely classified; these were predominantly isolated from primates and rodents.

Viruses in Cytomegalovirus are enveloped, with icosahedral, Spherical to pleomorphic, and Round geometries, and T=16 symmetry. The diameter is around 150-200 nm. Genomes are linear and non-segmented, around 200kb in length.^[2]

Viral replication is nuclear, and is lysogenic. Entry into the host cell is achieved by attachment of the viral glycoproteins to host receptors, which mediates endocytosis. Replication follows the dsDNA bidirectional replication model. DNA templated transcription, with some alternative splicing mechanism is the method of transcription. Translation takes place by leaky scanning. The virus exits the host cell by nuclear egress, and budding. Human and monkeys serve as the natural host. Transmission routes are contact, urine, and saliva.^[2]

The CMV promoter is commonly included in vectors used in genetic engineering work conducted in mammalian cells, as it is a strong promoter and drives constitutive expression of genes under its control.^[6]

• Viralzone: Cytomegalovirus
• ICTV

Template:Baltimore classification Template:Viral diseases

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

CMV infection can affect the eye, gastrointestinal tract and the central nervous system. Diagnosis of CMV requires differentiation of infections and diseases presenting with similar features. Majority of the patients with CMV end organ infection are immunosuppressed. Therefore CMV infection must be suspected in all the patients presenting with immunosuppression.

Cytomegalovirus retinitis must be differentiated from tuberculosis, fungal infections, toxoplasmosis and syphilis:

The symptoms of colitis such as bloody diarrhea and abdominal pain are seen are seen in all forms of colitis. The table below differentiates among the common causes of colitis.^[2][3] Cytomegalovirus colitis is diagnosed by demonstration of intranuclear inclusion bodies on colonic biopsy.

Cytomegalovirus infection presents with confusion and altered mental status. It must be differentiated from other disorders presenting with similar features. The following table is a list of disorders and their differentiating features:

Cytomegalovirus infection is more common among immunocompromised patients who are at high risk for other fungal, bacterial, and viral infections. It should be differentiated from the following diseases:

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Worldwide, approximately 40,000 to 90,000 per 100,000 individuals are seropositive for Cytomegalovirus infection.

• Worldwide, approximately 40,000 to 90,000 per 100,000 individuals are seropositive for Cytomegalovirus infection. ^[1]
• CMV seroprevalence in developing countries reaches more than 90% by adolescence and exceeds 95% by early adulthood

• In the United States, 35%-90% of women entering their childbearing years are seropositive, and thus, they are not susceptible to primary CMV infection.

• Seroprevalence is age-dependent 58.9% of individuals aged 6 and over are infected with CMV.
• 90.8% of individuals aged 80 and over are positive for CMV.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Patients with the following conditions are at a higher risk for developing symptomatic cytomegalovirus infection include patients with solid organ transplant, hematological stem cell transplant, AIDS and existing T-cell deficiency.

• Patients with the following conditions are at a higher risk for developing symptomatic cytomegalovirus infection:^[1]
  • Solid organ transplant
  • Hematological stem cell transplant^[2]
  • AIDS
  • T-cell deficiency
  • Elderly age
  • Critically ill patients
  • Patients with malignancy
  • Patients with burn injuries^[3]
• Patients with the following risk factors are at a higher risk to be seropositive for cytomegalovirus infection:^[4]
  • Female sex
  • Foreign birthplace
  • Low income
  • Overcrowding
  • Low education and socioeconomic status

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aravind Kuchkuntla, M.B.B.S[2]

Primary CMV infection takes place in childhood and early adolescence is asymptomatic. After the resolution of the primary infection CMV is latent in the mononuclear leukocytes. Reactivation in immunocompetent patients presents with mononucleosis like syndrome, but severe infection can occur in elderly and critically ill patients. Common complications of CMV infection in immunocompromised patients include CMV retinitis, CMV colitis, CMV encephalitis, CMV pneumonia and CMV myocarditis. CMV is associated with increased risk of graft versus host disease, myelosuppression, and invasive bacterial and fungal infections increasing morbidity and mortality of the patients.

Primary CMV infection which occurs in childhood and early adolescence is asymptomatic. After the resolution of the primary infection, CMV is latent in the mononuclear leukocytes. Reactivation of the virus can occur during states of stress and immunosuppression. Reactivation in immunocompetent patients presents with a mononucleosis like syndrome. If left untreated, severe infection can occur in elderly and critically ill patients. They present with clinical manifestations affecting the gastrointestinal tract and the central nervous system. Retinitis and pneumonitis are uncommon in immunocompetent patients when compared to immunocompromised patients. Reactivation of CMV infection in immunocompromised patients results in CMV end organ infection affecting multiple organs.^[1]

Common complications of CMV infection in immunocompromised patients include:^[1]

• CMV retinitis can result in blindness
• CMV colitis can progress to bowel perforation and fatal diverticular bleeding^[2]
• CMV encephalitis is a rapidly progressive condition leading to death
• CMV pneumonia
• CMV myocarditis
• CMV hepatitis
• Increased risk of secondary bacterial and fungal infections
• Increased risk of cardiovascular related mortality^[3]

Complications in critically ill immunocompetent patients include:

• Increased mortality rate
• Prolonged intensive care unit and hospital length of stay
• Prolonged mechanical ventilation
• Nosocomial infections
• Endothelial cell dysfunction can cause portal or femoropopliteal vascular thrombosis

Complications of CMV infection in organ transplant patients:^[4]

• Acute allograft rejection and failure
• Death

CMV disease is common in patients with solid organ transplantation causing significant morbidity and mortality. CMV is associated with increased risk of graft versus host disease, myelosuppression, and invasive bacterial and fungal infections increasing morbidity and mortality of the patients.^[5][6]