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litis, myelitis, gastrointestinal disease

" Diseases shciwn occur less commonly alter reactivation of a latent infection.

" Diseases shciwn occur less commonly alter reactivation of a latent infection.

megalic inclusion disease (CID) (Fig. 20-9). The classic syndrome is not always seen in its entirety. The infant is usually small, with petechial hemorrhages, jaundice, hepatosplenomegaly, microcephaly, encephalitis, and sometimes choriorentinitis and/or inguinal hernia. The abnormalities of the brain and eyes are associated with mental retardation, cerebral palsy, impairment of hearing, and rarely impairment of sight, Many of these infants require special care for life. Socially and educationally important intellectual or perceptual deficits such as hearing loss, subnormal IQ, epilepsy, and behavioral problems may not become apparent until as late as 2-4 years after birth.

Mononucleosis

Most infections acquired after birth, by whatever route, are subclinical. Not uncommonly, however, a syndrome resembling EB virus mononucleosis but milder is seen, particularly in young adults and in recipients of blood transfusions. Typically, the patient presents with prolonged fever and on examination is found to have splenomegaly, abnormal liver function tests, and lymphocytosis, often with "atypical lymphocytes" such as those observed with EB virus infections (see below). In contrast to EB virus mononucleosis, however, pharyngitis and lymphadenopathy are uncommon, and heterophil antibody is absent.

Other Clinical Presentations

Cytomegalovirus infections may be widely disseminated and may present in a wide variety of more serious forms, particularly in immunocompromised patients (e.g., AIDS patients or recipients of organ transplants) or in premature infants following blood transfusion. Almost any organ may be seriously affected. The most important presentations are interstitial pneumonia, hepatitis, chorioretinitis, arthritis, carditis, chronic gastrointestinal infection, and various CNS diseases, especially encephalitis, Guillain-Barré syndrome, and transverse myelitis.

Fig. 20-9 Congenital cytomegalic inclusion disease Features are retardation of growth, microcephaly, thrombocytopenia, and hepatosplenomegaly The edge of the liver has been marked (Courtesy Di K Hayes.)

Laboratory Diagnosis

Laboratory confirmation of cytomegalic inclusion disease (CID) in a newborn infant is of great importance as it affects the medical and educational management of the child and facilitates parental counseling. Further, life-threatening CMV infections in immunocompromised persons are becoming increasingly common, and early diagnosis is needed to instigate appropriate antiviral therapy. In particular clinical circumstances it may be important not only to detect CMV but to discern whether the patient is undergoing an active acute infection rather than a latent or chronic low-grade infection, and if so, whether that acute episode is a primary infection of exogenous origin or an endogenous reactivation of a persistent infection in that individual. Because virus can be detected intermittently in urine or saliva of asymptomatic carriers, these specimens are suitable only for epidemiologic surveys or for detection of virus (or viral DNA or viral antigen) in newborn infants with suspected CID. The more relevant specimen in other clinical situations is blood leukocytes, because cell-associated viremia, especially if high-titer, correlates with invasive disease. Quantitative assays for virus load are likely lo be developed and used to assess the need for prompt antiviral therapy. Other specimens appropriate to particular clinical presentations include bronchoalveolar lavage and various organs taken at biopsy or autopsy.

Cytomegalovirus is isolated in cultured human fibroblasts; sensitivity can be increased by sedimenting the specimen onto the cells by low-speed centrif-ugation. The virus replicates very slowly, a single cycle having a latent period of 36-48 hours. Moreover, new virus tends to remain cell-associated, with

Clinical Features

Infectious Mononucleosis (Glandular fever)

In young children EBV infections are asymptomatic or very mild. However, when infection is delayed until adolescence, as happens in developed countries, the result is often infectious mononucleosis. Following a long incubation period (4-7 weeks), the disease begins insidiously with headache, malaise, and fatigue. The clinical presentation is protean, but three regular features are fever, pharyngitis, and generalized lymphadenopathy. The fever is high and fluctuating, and the pharyngitis is characterized by a white or grey malodorous exudate covering the tonsils and may occasionally be so severe as to obstruct respiration. The spleen is often enlarged and liver function tests abnormal. Occasionally a rash may appear, especially following treatment with ampiciilin; the reason for this strange association is unknown. The disease usually lasts for 2-3 weeks, but convalescence may be very protracted.

An extraordinary range of further developments can occasionally occur. Neurologic complications include the Guillain-Barré syndrome, Bell's palsy, meningoencephalitis, and transverse myelitis. Other complications include hemolytic anemia, thrombocytopenia, carditis, nephritis, or pneumonia.

Infection in Immunocompromised Hosts

A variety of syndromes associated with uncontrolled progression of infection occur in individuals with congenital or acquired inability to mount an adequate immune response to EBV. For example, a rare fatal polyclonal B-cell proliferative syndrome caused by EBV infection occurs in families with an X-linked recessive immunodeficiency associated with a reducedabilityjujsyiv thesize interferon 7 (X-hnked lymphopwhfeiative syndrome). There is an inexorable expansion of virus-infected B cells and suppression of normal bone marrow cells, and about half of the boys die within a month from sepsis or hemorrhage; the remainder develop dysgammaglobulinemia or die from malignant B-cell lymphomas.

Much more common is progressive hpnphoprohferal ive disease, seen in transplant recipients, immunodeficient children, or AIDS patients. In these immunocompromised individuals, the absence of cell-mediated immunity permits unrestrained replication of EBV, acquired exogenously or reactivated from the latent state. Some of the infections present as mononucleosis, but others are atypical, presenting, for example, as pneumonitis or hepatitis. Infants with AIDS develop a lymphocytic interstitial pneumonitis; adults with AIDS may develop EBV-associated lymphoproliferative conditions of various kinds.

Burkift's Lymphoma and Nasopharyngeal Carcinoma

The reader is referred to Chapter 11 for a discussion of the highly malignant neoplasms Burkift's lymphoma and nasopharyngeal carcinoma and their relationship to EBV.

Laboratory Diagnosis

The clinical picture of infectious mononucleosis is so variable that laboratory confirmation is required. This rests on (1) differential white blood cell counts; (2) heterophil antibodies, and (3) EBV-specific antibodies. By the second week o( the illness, white blood cells total 10,000-20,000 per cubic millimeter or even higher, Lymphocytes plus monocytes account for 60-80% of t his number. Of these, at least 10%, and generally more than 25%, are "atypical lymphocytes" (large pleomorphic blasts with deeply basophilic vacuolated cytoplasm and lobulated nuclei, Fig 20-8B), which persist for 2 weeks to several months.

Many years ago Paul and Bunnell made the empirical observation that sera from glandular fever patients agglutinate sheep erythrocytes. It is now clear that the agglutinins are just one of the heterophil lgM antibodies elicited by EBV infection. The Paul-Bunnell test is still a valid diagnostic aid, however. Sera are first absorbed with guinea pig kidney cells to remove Forssman antibody (and serum-sickness antibodies, which are rare these days) Commercially available horse erythrocyte slide agglutination kits are convenient, although heterophile antibodies are made /;/ vivo for only a month, results are often negative in children, and neither sensitivity nor specificity is high. Another assay for heterophile antibodies is the ox red cell hemolysin test, which requires no serum absorption and is specific but remains positive for only a month or two.

The EBV-specific antibodies offer a more reliable indicator of infection now that ElAs have become available to replace the cumbersome immunofluorescence readout that was previously employed. IgM antibody against the EBV capsid antigen VCA develops to high titer early in the illness and declines rapidly over the next 3 months or so; it therefore represents a good index of primary infection. However, because IgM assays tend to be plagued by false positives and negatives, the trend is toward using a panel of genetically cloned EBV antigens to screen for IgG antibodies and considering the resulting profile. Because antibodies to EBNA first appear a month or more after onset of disease and then persist, a rising titer is diagnostic. (It should be noted, however, that antibody to EBNA-1 is specifically missing from many immunocompromised patients with severe chronic active infection.) On the other hand, antibodies against the early antigen EA-D are diagnostic of acute, reactivated, or chronic active infection, as they decline rapidly and are not detectable in asymptomatic carriers. IgG (or total) antibodies against VCA represent the most convenient measure of past infection and immune status.

Isolation of virus is rarely used as a diagnostic procedure because no known cell line is fully permissive for EBV The only method for "growing" EBV in vitro is to inoculate infected oropharyngeal secretions or peripheral blood leukocytes onto umbilical cord lymphocytes and to demonstrate the immortalization of the latter to produce a lymphoblastoid cell line that can be stained successfully with fluoresceinated monoclonal antibody against EBNA. The other problem with virus isolation (or use of PCR to detect viral DNA in infected cells) for routine diagnosis of EBV-induced disease is that such a high proportion of asymptomatic individuals carry the latent genome and/or shed virus for life.

Epidemiology

Following an attack of mononucleosis, virus is found in saliva for several months, and more sensitive assays reveal that most EBV-seropositive people secrete the virus in lower titer thereafter, continuously or intermittently, probably for life Chronic shedding is highest in less developed countries, in young children, in early pregnancy, and in immunocompromised patients EBV is ubiquitous in most developing countries. Almost all infants become infected in the first year or two of life, probably by salivary exchange, contamination of eating utensils, and perhaps also by respiratory aerosols. At this age almost all infections are subclinical; glandular fever is virtually unknown in the Third World. By way of contrast, in countries with higher standards of living many persons reach adolescence before first encountering the virus. The intimate osculatory contact involved in kissing is the principal means of transmission; hence, mononucleosis is a disease of 15-25 year olds. Some 80% of people eventually acquire infection and are permanently immune.

As with CMV, conventional respiratory transmission of EBV by droplets does not appear to be significant. For example, casual roommates of mononucleosis patients are not at increased risk; closer contact seems to be required. By analogy with CMV it may be reasonable to speculate that EBV can also be transmitted by sexual intercourse. Male homosexuals have a very high rate of seropositivity. Blood transfusions can also rarely transmit the virus.

Control

Chemotherapy

Unfortunately none of the present armory of nucleoside analogs has been unequivocally shown to have any effect on EBV infections

Vaccines

If a successful vaccine could be developed against EBV it may be feasible to prevent not only mononucleosis but also nasopharyngeal carcinoma (see Chapter 11) However, formidable barriers will delay progress. A conventional live or inactivated vaccine is a long way off since the virus has yet to be grown satisfactorily in cultured cells. Research has commenced on "subunit" and recombinant vaccines based on the major membrane glycoprotein complex gp350/gp220, and live vaccinia or attenuated varicella virus constructs containing the corresponding gene.

Herpes B Virus

Macaque monkeys suffer from infection with an alphaherpesvirus known variously as herpes B virus, herpesvirus simiae, or cercopithecine herpesvirus 1. Its natural history is very like that of HSV-1 infection in humans. A number of fatal cases of ascending paralysis and encephalitis in animal handlers have followed the bite of a monkey, and herpes B virus is a continuing risk to personnel working with primates, as in zoos or laboratories.

Further Reading

Ad lor, S P (199(1) New insights into human cylomegaloviral infections Prog. Med Virol 37, J 36 Casería, M r, and Hall, C B (1993) Human herposvirus-6 Awiit. Rev Med 44, 377. Chou, S (1992) Cytomegalovirus infection Cnn Opht hiferl Dis 5, 427

Corey, L-, and Spear, P. G (1986) Infections with herpes simplex viruses N l.ngl J Med 314, 686 and 749

Croen, K D. (1991) Latency of the human herpesviruses. Atnnt Rev Med 42, 61

Croen, K. D , and Straus, S E (1991) Varicella-zoster virus latency Antut Rev Miirnfrid/ 45,265

Davison, A ) (1991). Varicella-zoster virus /. Gen Virol 72,475

Davison, A f., ed (1993) HSV and other alphaherpesviruses Senim Virol 4,123

DemmJor, G J. (1991) Summary of a workshop on surveillance for congenital cytomegalovnus disease Rev Infect Dis 13, 315. Epstein, M A , and Achong, B. G , eds (1986). "The Epstein Ban Virus: Recent Advances " Heinemann, London

Evans, A. S , ed (1989). "Viral Infections of Humans' Epidemiology and Control," 3rd Ed ,

Chapters 8, 10, 14, and 25-28. Plenum, New York Fields, B N , Knipe, D M„ Chanock, R M., Hirsch, M. S., Melnick, J. L , Monath, T P., and Rouman, B , eds (1990) "Fields Virology," 2nd Ed , Chapters 64-73, pp. 1787-2054 Raven, New York

Galasso, G. j , Whitley, R.), and Merigan, T C , ed (1990) "Antiviral Agents and Viral Diseases of Man," 3rd Ed., Chapters 6-8, 13, 14, 16, 17, and 19. Raven, New Yoik. Cers/mrt, A. (1987) Live attenuated varicella vaccine. Amu/ Rei> Med 38, 41 Ho, M (1991) "Cytomegaloviruses Biology and Infection," 2nd Ed. Plenum, New York Hyman, R W (1987) "Natural History of Varicella-Zoster Viius " CRC Press, Boca Raton, Florida.

Jones, J F., and Straus, S E (1991) Chronic Epstein-Barr virus infection Amu/ Rev Med 42,195 Landini, M P (1993) New approaches and perspectives in cytomegalovirus diagnosis. Prog Med Virol 40, 157

Lope/., C-, Mori, R,, Roizman, B , and Whitley, R W. (1990) "Immunobiology and Prophylaxis of

Human Herpesvirus Infections " Plenum, New York McDougall, J. D , ed (1990). Cytomegaloviruses. Curr Top Microbiol Immunol 154. McGeoch, D. J. (1989). The genomes of human herpesviruses; contents, relationships, and evolution Annu Rev Microbiol. 43, 235. Meyers, J. D (1991) Prevention and treatment of cytomegalovirus infections Annu Rev Med 42, 179

Nahmias, A. J., Dowdle, W R , and Schina/i, R F, eds (1986) "The Human Herpesviruses " Elsevier, New York.

Okano, M , Thiele, G. M , Davis, } R , Grieison, 11. L , and Purtilo, D T (1988). EpsteiivBarr virus and human diseases. Recent advances in diagnosis Clin. Microbiol. Rev 1, 300. Okano, M., Matsumoto, S , Osato, T, Sakiyama, Y, Thiele, G. M , and Purtilo, D 1 (1991)

Severe chronic active Epstein-Barr virus infection syndrome. Clin Microbiol Rev 4, 129. Ostrove, J M. (1990) Molecular biology of varicella-zoster virus. Adv Virus Res 38, 45 Pellett, P E , Black, J B , and Yamamoto, M (1992) Human herpesvirus 6—the virus, and the search for its role as a human pathogen Adv Virus Res 41, 1 Rodman, 8 , ed (1982-1985) "The Herpesviruses," Vols 1 -5. Plenum, New York. Roizman, B. (1991). Herpesviruses tn "Encyclopedia of Human Biology" (R Dulbecco, ed,), Vol

4, p. 187 Academic Press, Orlando, Florida. Roizman, B , and Sears, A. E. (1987) An inquiry into the mechanisms of herpes simplex virus latency Annu Rev Microbiol. 41, 543 Roizman, B., and Sears, A. E. (1990) Herpes simplex viruses and their replication In "Fields Virology" (B. N Fields, D M Knipe, R M. Chanock, M S Hirsch, ] I Melntck, I V Monath, and Roizman, B , eds.), 2nd Ed , p 1795 Raven, New York Roizman, B , Desrosiers, R C , Fleckenstein, B., Lopez, C , Minson, A C , and Studdert, M J.

(1992). The family Hcrpsi'iriifiii"-An update Arch Vmtl 123, 425 Rouse, B T , ed (1992) Herpes Simplex Virus Pathogenesis, Immunobiology and Control Gfrr

Top Microbiol Immunol 179. Rubin, R. H , ed (1990) Cytomegalovirus Infections Epidemiology, Diagnosis, and Treatment

Strategies Rev Infect Dis 12 iSupid 7) Schlossberg, D , ed (1989). "Infectious Mononucleosis," 2nd Ed. Springer-Verlag. Berlin. Stevens,] G (1989) Human herpesviruses A consideration of the latent state. Murobiot Rev 53, 318.

Straus, S. E (1988) The chronic mononucleosis syndrome. / Infect I>s 157, 405

Straus, S E (1992). Acute progressive Epstein Ban virus infections Annu Rev Med 43, 437

■BBS Chapter 21

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