Causative Agent Of Cytomegalovirus

Cytomegalovirus Disease

Cytomegalovirus (CMV) is a member of the herpesvirus family, which includes herpes simplex virus, Epstein-Barr virus, and varicella-zoster virus, any of which can cause troublesome symptoms in patients with immunodeficiency. CMV, like other her-pesviruses, is commonly acquired early in life and then remains latent. With impairment of the immune system, the infection activates and can cause severe symptoms.

Symptoms

Symptoms of cytomegalovirus disease follow a pattern similar to that of toxoplasmosis. Acute infections in immunocompe-tent individuals are usually without symptoms, but adolescents

Table 29.8 Toxoplasmosis

Symptoms

In healthy individuals: sore throat, fever, enlarged lymph nodes, rash; with fetal infections: miscarriage, stillbirth, birth defects, epilepsy, mental retardation, retinitis; in immunodeficient individuals: confusion, poor coordination, weakness, paralysis, seizures, coma

Incubation period

Usually indeterminate

Causative agent

Toxoplasma gondii, a protozoan infectious for most warm-blooded animals. Sexual reproduction occurs in the intestinal epithelium of cats, the definitive hosts. Infected cats discharge oocysts with their feces. Ingested organisms are released from the oocysts, multiply rapidly, spread throughout the body. As immunity develops, infected cells become filled with the organisms, resulting in tissue cysts, which remain viable and infectious for the lifetime of the animal

Pathogenesis

Organisms penetrate host cells causing necrosis. With development of immunity cell destruction stops, tissue cysts develop. Most healthy individuals have few or no symptoms unless the numbers of ingested organisms is very large. Organisms released from tissue cysts if immunity becomes impaired

Epidemiology

Occurs worldwide, less common in cold or dry locations. Infection acquired by ingesting oocysts from cat feces, or eating inadequately cooked meat

Prevention and treatment

Prevention: avoiding foods potentially contaminated with oocysts from cat feces, and not consuming inadequately cooked meat.Trimethoprim-sulfamethoxazole is given to immunodeficient persons with CD4+T lymphocyte counts below 100 cells per |l if they have antibodies to T. gondii indicating latent infection.Treatment: pyrimethamine with sulfadiazine, or alternative medication

758 Chapter 29 HIV Disease and Complications of Immunodeficiency and young adults sometimes develop illness resembling infectious mononucleosis, with fever, fatigue, and enlarged lymph nodes and spleen for weeks or months.

Severe damage can occur to the fetus if the mother develops an acute infection during pregnancy. This condition is known as congenital cytomegalic inclusion disease and is characterized by jaundice, large liver, anemia, eye inflammation, and birth defects. The vast majority of infected infants appear normal at birth, but 5% to 25% manifest hearing loss, mental retardation, or other abnormalities later in life.

Blindness is one of the most feared complications of cytomegalovirus disease in immunodeficient individuals. Other symptoms include fever, loss of appetite, painful joints and muscles, rapid, difficult breathing, ulcerations of the gastrointestinal tract with bleeding, lethargy, paralysis, dementia, and coma.

Causative Agent

Human cytomegalovirus is an enveloped, double-stranded DNA virus that looks like other herpesviruses on electron micrographs but has a larger genome. Its name (cyto for "cell" and megalo for "large") derives from the fact that cells infected by the virus are two or more times the size of uninfected cells. Infected cells show a large intranuclear inclusion body surrounded by a clear halo, inspiring its description as an "owl's eye" (figure 29.15). The envelope is acquired as the virion buds from the nuclear membrane.

There are many different strains of the virus detected by the patterns of endonuclease digests, and antigenic differences also occur. Like other herpesviruses, CMV can cause lysis of the infected cell or become latent and subject to later reactivation. ■ genomic typing, p. 257

Pathogenesis

In cytomegalovirus disease, a wide variety oftissues, including eye (figure 29.16), central nervous system, and liver, are susceptible to infection. Once cell entry has occurred, the viral genome can exist in a latent non-infectious form, in a slowly replicating form, or as a fully productive infection. Control of viral gene expression depends partly on the type of cell infected. Monocytes allow low levels of infectious virus production. The CMV genome is ordi-

Figure 29.15 Cytomegalovirus Infected cells showing "owl's eye" appearance of intranuclear inclusions.

Figure 29.16 Cytomegalovirus (CMV) Retinitis, a Common Cause of Blindness in Persons with AIDS Photograph of a CMV-infected retina as it appears when viewed through the eye's pupil using an ophthalmoscope.

Figure 29.15 Cytomegalovirus Infected cells showing "owl's eye" appearance of intranuclear inclusions.

Figure 29.16 Cytomegalovirus (CMV) Retinitis, a Common Cause of Blindness in Persons with AIDS Photograph of a CMV-infected retina as it appears when viewed through the eye's pupil using an ophthalmoscope.

narily quiescent in T and B lymphocytes, expressing some viral genes but not producing viral DNA. Integration of viral DNA into the host cell genome probably does not occur. If CMV-infected T cells are also infected with HIV, productive CMV infection occurs. Fully productive infection of a wide variety of tissues occurs during acute infections, causing tissue necrosis. Transplanted organs and blood transfusions can transmit the disease, indicating that virus-producing cells are present or that non-producing cells in the blood or organ start producing infectious CMV under conditions of immune suppression. Cellular immunity probably plays a role in suppressing production of infectious virus as well as in lysis of infected cells. In cells infected with CMV, however, transfer ofMHC molecules to the cell surface is impaired, and therefore, CMV antigens are not recognized as being "foreign." CMV infection is associated with an increase in CD8+ cells and a decrease in CD4+ cells, thus enhancing the effect of HIV infection. Latent infections activate with AIDS, organ transplants, and other immunodeficient states. Also, immunodeficient subjects are highly susceptible to newly acquired infection. ■ MHC molecules, p. 407

Epidemiology

CMV is found worldwide. One U.S. study found that more than 50% of adults 18 to 25 years old and more than 80% of people over 35 years had been infected. Infection is lifelong. Infants born with CMV infection and those who acquire it shortly after birth excrete the virus in their saliva and urine for months or years. Virus is found in semen and cervical secretions in the absence of symptoms, and sexual intercourse is a common mode of transmission in young adults. Up to 15% of pregnant women secrete the virus, and 1% of newborn infants have CMV in their urine. Breast milk, blood, and tissue transplants may contain CMV and be responsible for transmission. Almost all prostitutes and promiscuous gay men are infected with CMV. CMV spreads readily in day care centers.

Prevention and Treatment

There is no approved vaccine for preventing cytomegalovirus disease. The use of condoms is effective in decreasing the risk of sexual transmission. People with HIV disease or other immunodeficiency syndromes or who lack CMV antibody should avoid contact with day care centers if possible and, in any case, should wash their hands if exposed to saliva, urine, or feces. Tissue and blood donors can be screened for antibody to CMV. Those who have anti-CMV antibody are assumed to be infected and should not donate to those lacking antibody to CMV. The anti-herpesviral medication ganciclovir, given orally, halves the incidence of CMV retinitis in HIV disease patients with low CD4+ cell counts and positive tests for CMV antibody. A ganciclovir implant designed to release the medication into the eye over a long period also delays the progression to blindness.

Combination drug therapy with the antiviral drugs ganci-clovir and foscarnet can reduce the severity of CMV disease. They inhibit CMV DNA polymerase, the enzyme responsible for assembling viral DNA, at different sites. Both medications have serious side effects, mainly bone marrow suppression with ganciclovir and kidney impairment with foscarnet. ■ DNA polymerase, p. 171

The main features of cytomegalovirus disease are presented in table 29.9.

29.3 Infectious Complications of Acquired Immunodeficiency 759

Mycobacterial Diseases

Initial exposure to Mycobacterium tuberculosis, the cause of tuberculosis, usually causes an asymptomatic infection that is controlled by the immune system and becomes latent. As might be expected, defects in cellular immunity are associated with reactivation of latent tuberculosis, which commonly results in unrestrained disease in AIDS and other immunodeficiencies. Mycobacterium tuberculosis is not the only mycobacterium that causes disease in immunodeficient people. Disease has been reported due to M. kansasii, M. scrofulaceum, M. xenopi, M. szulgai, M. ganavense, M. haemophilum, M. celatum, and others. This section discusses disease caused by organisms of Mycobacterium avium complex, next to M. tuberculosis the most common mycobacterial opportunists complicating immunodeficiency diseases.

Symptoms

The vast majority of Mycobacterium avium complex (MAC) infections in immunologically normal people are asymptomatic. Elderly people, especially those with underlying lung disease from smoking and those with alcoholism, develop a chronic cough productive of sputum and sometimes lesions in the lungs resembling tuberculosis. Children sometimes develop chronic enlargement of lymph nodes on one side of their neck, easily treated by surgical removal of the affected nodes. Patients with AIDS and other severe immunodeficiencies have slowly progressing symptoms ranging from chronic cough productive of sputum to fever, drenching sweats, marked weight loss, abdominal pain, and diarrhea.

Causative Agent

Mycobacterium avium complex is a group of mycobacteria consisting of two closely related species, M. avium and M. intracellular. More than two dozen strains of these acid-fast rods fall into the MAC, distinguishable by serological tests, optimum growth temperature, and host range. Their growth rate is almost as slow as that of M. tuberculosis, but they are easily distinguished by using biochemical tests and nucleic acid probes. ■ tuberculosis, p. 580

Pathogenesis

MAC organisms enter the body via the lungs and the gastrointestinal tract. They are phagocytized by macrophages, but resist destruction because they inhibit acid production in the phago-some. Surviving organisms multiply within phagocytes and are carried by the bloodstream to all parts of the body. When cellular immunity is intact, most organisms are destroyed, and disease is localized. With profound immunodeficiency, the disease spreads throughout the body. In these patients, there is persistent bacteremia, occasionally with counts as high as 1 million per milliliter of blood. The small intestine contains macrophages packed with the bacteria, and infected tissues (figure 29.17) may resemble leprosy, sometimes containing more than 100 billion of the acid-fast bacteria per gram of tissue. Despite the presence of enormous numbers of the bacteria, there is little or no inflammatory reaction, and the clinical effect is a slow decline in the patient's well-being rather than a quickly lethal effect. One cause of deterioration may be activation of HIV replication when HIV-infected macrophages are infected with MAC. ■ leprosy, p. 670

Table 29.9 Cytomegalovirus Disease

Symptoms

Symptoms rare in immunocompetent individuals, but sometimes an infectious mononucleosis-like illness develops. Infection of the mother during pregnancy can result in disease of the newborn. Immunocompromised individuals may experience blindness, lethargy, dementia, coma and brain damage

Incubation period

In immunocompetent adults, 20 to 60 days

Causative agent

Cytomegalovirus, a member of the herpesvirus family

Pathogenesis

Many tissues susceptible to infection, damage, especially eyes, brain, and liver. CMV latent infection can reactivate, produce infectious virions, tissue necrosis. CD4+T-lymphocyte count is depressed and thus can enhance HIV disease

Epidemiology

Common worldwide; lifelong infection. More than 50% of 18- to 25-year-olds are infected. Infants with congenital infections and those infected shortly after birth shed the virus for months or years. Body fluids, including breast milk, blood, urine, semen, and vaginal secretions, can transmit the disease. Almost all prostitutes and promiscuous homosexual men are infected with CMV

Prevention and treatment

No vaccine available. Condoms decrease transmission. CMV-negative immunodeficient persons advised to avoid day care centers, wash their hands following contact with bodily fluids of infants. Blood and tissue transplants are tested for CMV before being given to CMV-negative individuals.The antiviral medication ganciclovir is considered for immunodeficient individuals who have antibody to CMV and whose CD4+T-lymphocyte count falls below 50 cells per |l. Treatment: ganciclovir plus foscarnet

760 Chapter 29 HIV Disease and Complications of Immunodeficiency

760 Chapter 29 HIV Disease and Complications of Immunodeficiency

Eosinofilos
Figure 29.17 Acid-Fast Stain Showing Massive Numbers of MAC Bacteria Infecting Cells

Epidemiology

MAC organisms are widespread in natural surroundings and have been found in food, water, soil, and dust. In the United States, they are most prevalent in the Southeast, parts of the Pacific Coast, and the North Central region. Some strains are important pathogens of chickens and pigs. In AIDS patients, they are the most common bacterial cause of generalized infection. It is not known whether infection in AIDS patients is mostly newly acquired or a reactivation of latent disease. Most infections are from environmental sources rather than from person-to-person spread.

Prevention and Treatment

No effective measures are available to prevent exposure to MAC organisms. For HIV patients whose CD4 + count is below 50 cells/ml, the antibacterial medication clarithromycin is recommended to help prevent MAC disease. If MAC bacteremia develops, patients must be given two or more medications together, such as clarithromycin plus ethambutal.

The main features of MAC disease are presented in table 29.10.

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Responses

  • Marco
    What is the causative agent for cytomegalovirus?
    1 year ago
  • Maxima
    What is the causative agent of cytomegalovirus infection?
    7 days ago
  • Johannes
    Where does the causative agent of mono replicate?
    4 days ago

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