Home > D. Systemic pathology > Infectious diseases > cytomegalovirus

cytomegalovirus

Wednesday 14 April 2004

Digital cases

- PX:29514 : Neonatal CMV pneumonia

Transmission

Transmission of CMV can occur by several mechanisms, depending on the age group affected.

These include the following:
- Transplacental transmission from a newly acquired or primary infection in a mother who does not have protective antibodies ("congenital CMV").
Transmission of the virus through cervical or vaginal secretions at birth or, later, through breast milk from a mother who has active infection ("perinatal CMV").
- Transmission through saliva during preschool years, especially in day care centers. Toddlers so infected readily transmit the virus to their parents.
- Transmission by the venereal route is the dominant mode after about 15 years of age, but spread may also occur via respiratory secretions and the fecal-oral route.
- Iatrogenic transmission can occur at any age through organ transplants or by blood transfusions.

Pathology

Cytomegalovirus (CMV), a β-group herpesvirus, can produce a variety of disease manifestations, depending on the age of the host, and, more important, on the host’s immune status. The major envelope glycoprotein of CMV binds to epidermal growth factor receptor;60 it is not known if the virus uses this and other receptors to gain entry into different cell types in natural infections. CMV infects and remains latent in white blood cells and can be reactivated when cellular immunity is depressed. CMV causes an asymptomatic or mononucleosis-like infection in healthy individuals but devastating systemic infections in neonates and in immunocompromised patients. As its name implies, cytomegalovirus produces enlargement of infected cells. Infected cells exhibit gigantism of both the entire cell and its nucleus. Within the nucleus is a large inclusion surrounded by a clear halo (owl’s eye).

CMV can induce transient but severe immunosuppression. Mouse CMV can infect dendritic cells and impair their function and maturation and their ability to stimulate T-cell responses, and it appears that human CMV also can infect dendritic cells and alter their function.65,67 Similar to other herpesviruses, CMV can elude immune responses by down-modulating MHC class I and II molecules and producing homologues of TNF receptor, IL-10, and MHC class I receptors.

Interestingly, CMV can both activate and evade natural killer cells by inducing ligands for activating receptors and class I-like proteins that engage inhibitory receptors. Thus, CMV can both hide from immune defenses and actively suppress immune responses.

Morphology

The characteristic enlargement of infected cells can be appreciated histologically. Prominent intranuclear basophilic inclusions spanning half the nuclear diameter are usually set off from the nuclear membrane by a clear halo.

Within the cytoplasm of these cells, smaller basophilic inclusions can also be seen. In the glandular organs, the parenchymal epithelial cells are affected; in the brain, the neurons; in the lungs, the alveolar macrophages and epithelial and endothelial cells; and in the kidneys, the tubular epithelial and glomerular endothelial cells. Affected cells are strikingly enlarged, often to a diameter of 40 μm, and they show cellular and nuclear polymorphism.

Disseminated CMV causes focal necrosis with minimal inflammation in virtually any organ.

Congenital Infections

Infection acquired in utero may take many forms. In approximately 95% of cases, it is asymptomatic. However, sometimes when the virus is acquired from a mother with primary infection (who does not have protective immunoglobulins), classic cytomegalic inclusion disease (CID) develops.

CID resembles erythroblastosis fetalis. Affected infants may suffer intrauterine growth retardation, be profoundly ill, and manifest jaundice, hepatosplenomegaly, anemia, bleeding due to thrombocytopenia, and encephalitis. In fatal cases, the brain is often smaller than normal (microcephaly) and may show foci of calcification.

The infants who survive usually bear permanent effects, including mental retardation, hearing loss, and other neurologic impairments. The congenital infection is not always devastating, however, and may take the form of interstitial pneumonitis, hepatitis, or a hematologic disorder. Most infants with this milder form of CID recover, although a few develop mental retardation later.

Uncommonly, a totally asymptomatic infection may be followed months to years later by neurologic sequelae, including delayed-onset mental retardation and hearing deficits.

Perinatal Infections

Infection acquired during passage through the birth canal or from breast milk is asymptomatic in the vast majority of cases, although, uncommonly, infants may develop an interstitial pneumonitis, failure to thrive, skin rash, or hepatitis.

These children have acquired maternal antibodies against CMV, which reduce the severity of disease. Despite the lack of symptoms, many of these patients continue to excrete CMV in their urine or saliva for months to years. Subtle effects on hearing and intelligence later in life have been reported in some studies.

Cytomegalovirus mononucleosis

In healthy young children and adults, the disease is nearly always asymptomatic. In surveys around the world, 50% to 100% of adults demonstrate anti-CMV antibodies in the serum, indicating previous exposure.

The most common clinical manifestation of CMV infection in immunocompetent hosts beyond the neonatal period is an infectious mononucleosis-like illness, with fever, atypical lymphocytosis, lymphadenopathy, and hepatomegaly accompanied by abnormal liver function test results, suggesting mild hepatitis. Most patients recover without any sequelae, although excretion of the virus may occur in body fluids for months to years.

Irrespective of the presence or absence of symptoms following infection, a person once infected becomes seropositive for life. The virus remains latent within leukocytes, which are the major reservoirs.

CMV in Immunosuppressed Individuals

This occurs most commonly in three groups of patients:

- Recipients of solid organ transplants (heart, liver, kidney) from seropositive donors. These patients typically receive immunosuppressive therapy, and the CMV is usually derived from the donor organ, but reactivation of latent CMV infection in the host may also occur.
- Recipients of allogeneic bone marrow transplants. These patients are immunosuppressed not only because of immunosuppressive therapy but also because of poor marrow function until it is engrafted. In this setting, there is usually reactivation of latent CMV in the recipient.
- Patients with AIDS. These immunosuppressed individuals have reactivation of latent infection and are also infected by their sexual partners. CMV is the most common opportunistic viral pathogen in AIDS.

In all these settings, serious, life-threatening disseminated CMV infections primarily affect the lungs (pneumonitis), gastrointestinal tract (colitis), and retina (retinitis); the central nervous system is usually spared.

In the pulmonary infection, an interstitial mononuclear infiltrate with foci of necrosis develops, accompanied by the typical enlarged cells with inclusions.

The pneumonitis can progress to full-blown acute respiratory distress syndrome. Intestinal necrosis and ulceration can develop and be extensive, leading to the formation of pseudomembranes and debilitating diarrhea.

CMV retinitis, by far the most common form of opportunistic CMV disease, can occur either alone or in combination with involvement of the lungs and intestinal tract.

Diagnosis of CMV infections is made by demonstration of characteristic morphologic alterations in tissue sections, viral culture, rising antiviral antibody titer, detection of CMV antigens, and qualitative or quantitative PCR-based detection of CMV DNA.

The PCR-based methods have revolutionized the approach to monitoring patients after transplantation.

Synopsis

- cytomgegalic inclusion

Pathology

- CMV infections

  • CMV fetopathy
  • CMV pneumonitis
  • CMV colitis
  • CMV hepatitis

Videos

- Congenital hepatic CMV disease by Washington Deceit

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References

- Khanna R, Diamond DJ. Human cytomegalovirus vaccine: time to look for alternative options. Trends Mol Med. 2005 Dec 6; PMID: 16337831

- Cinatl J, Scholz M, Kotchetkov R, Vogel JU, Doerr HW. Molecular mechanisms of the modulatory effects of HCMV infection in tumor cell biology. Trends Mol Med. 2004 Jan;10(1):19-23. PMID: 14720582