C

The Revised Authoritative Guide To Vaccine Legal Exemptions

Vaccines Have Serious Side Effects

Get Instant Access

Blood

" Only the commonly occurring serotypes are listed, those most commonly associated with particular syndromes are in bold type

" Only the commonly occurring serotypes are listed, those most commonly associated with particular syndromes are in bold type

Ocular Infections

Pharyngoconjunctival fever tends to occur in outbreaks, for example, at children's summer camps where "swimming pool conjunctivitis" may occur with or without pharyngitis, fever, and malaise. Adenoviruses 3, 4, and 7 are commonly responsible. Type 4 has caused a number of nosocomial outbreaks of conjunctivitis or pharyngoconjunctival fever among hospital staff.

Epidemic keratoconjunctivitis is a more severe eye infection, commencing as a follicular conjunctivitis and progressing to involve the cornea (keratitis). Originally reported in industrial workers exposed to dusl and trauma, the disease was once known as "shipyard eye." Highly contagious and often occurring in epidemic form, the infection is caused by members of subgenus D. Type 8 was the principal agent until 1973 when type 19 temporarily took over until, in 1976, type 37 suddenly appeared, spread worldwide, and today remains (with type 8) the predominant cause of epidemic keratoconjunctivitis. During epidemics, nosocomial spread can readily occur in eye clinics.

Genitourinary Infections

Cervicitis and urethritis are common manifestations of venereal infection with type 37, which was first identified in prostitutes. Cystitis, seen mainly in young boys, is caused by type 11 and more rarely by type 21. In its acute hemorrhagic form cystitis is characterized by hematuria as well as dysuria and frequency of micturition. Adenoviruses commonly establish asymptomatic persistent infection of the kidney and may be shed in the urine for months or years. This is observed particularly in immunocompromised individuals, such as renal transplant recipients.

Enteric Infections

Gastroenteritis in infants is commonly caused by two recently discovered adenovirus serotypes, 40 and 41. These enteric adenoviruses, previously visualized by electron microscopy in feces but regarded as uncultivable, can now be grown in cultured cells. Their recovery from outbreaks of gastroenteritis, including in day-care centers, and significantly more frequently from symptomatic patients than from controls, confirms that they do indeed cause the disease. However, many other adenoviruses that replicate in the intestine or in the throat are excreted asymptomatically in the feces for weeks or months, hence carefully controlled studies are required before assigning them an etiologic Tole in gastroenteritis.

Infections in Immunocompromised Patients

Adenoviruses may cause life-threatening infections in at least three groups of immunocompromised patients. In children with severe combined immune deficiency disease the common serotypes of subgenera A, B, and C can cause serious conditions such as pneumonia or meningoencephalitis. Kidney, liver, or bone marrow transplant recipients, and patients with AIDS, often shed subgenus B serotypes such as 11, 34, or 35 in urine for prolonged periods, and AIDS patients also excrete the recently described subgenus D serotypes (43-47) in feces.

Laboratory Diagnosis

Depending on the clinical presentation, appropriate specimens for diagnosis include feces; pharyngeal swab, nasopharyngeal aspirate, transtracheal aspirate, or bronchial lavage; conjunctival swab, corneal scraping, or tears; genital secretions; urine; and tissues from biopsy (e.g., of liver or spleen) or autopsy (e.g., lung or brain).

Enzyme immunoassay (EIA) is emerging as the diagnostic method of choice for the detection of soluble viral antigen in feces or nasopharyngeal secretions A monoclonal antibody (MAb) to a hexon epitope common to all adenovirus serotypes (or polyclonal serum) suffices to identify the family; then, if desired, a type-specific MAb can be used to identify the particular adenovirus concerned. Reliable reagents are now available commercially, and the EIA should give 90-95% specificity and 70-90% sensitivity compared with the more laborious process of isolation of the virus in cultured cells. Even the so-called noncultivable adenoviruses can be identified by this method, or by immunoelectron microscopy.

Immunofluorescence can be employed to demonstrate adenoviral antigen in cells Irom the respiratory tract, eye, urine, or biopsy or autopsy material, following low-speed centrifugation of the specimen and then fixation of the pelleted cells.

Virus isolation is still the approach of most diagnostic and reference laboratories. Propagation of adenoviruses in cultured cells is time-consuming because many serotypes are very slow-growing. Human malignant cell lines such as HeLa, HEp-2, KB, or A-549 cells, or diploid human embryonic fibroblasts (HDF) derived, for example, from lung or tonsil, are the substrates of choice. The fastidious enteric adenoviruses 40 and 41 have only recently been cultivated in viiro and require special cell lines such as Graham-293 or special conditions (e.g., low-serum medium). The common adenoviruses (types 1-7) generally produce cytopathic effects (CPE) within 1-2 weeks; the cells become swollen, rounded, and retractile, cluster together like a bunch of grapes, and reveal characteristic basophilic intranuclear inclusions after staining (Fig. 19-2). Other serotypes, however, especially those of subgenera A and D, grow very slowly, and CPE, often nonclassical, may not become evident for a month. Confirmation of the isolate as an adenovirus can be made by immunofluorescence on the (fixed) cell monolayer. Appropriate type-specific antisera, or MAbs directed to type-specific epitopes on the fiber, can then be chosen to type the isolate by hemagglutination inhibition and/or neutralization.

Fig. 19-2 Cytopathic effects induced by adenoviruses (hematoxylin and eosin stain, magnification x400). (A) Normal monolayer of HEp-2 cells 1 lonzonlal arrow marks cell in mitosis and the vertical arrow marks phagocytosed cell debris, not to be confused with viral Inclusion bodies. (U) Cytopathic effects induced by adenovirus in HEp-2 cells Note distended cells containing basophilic intranuclear inclusions (arrows), which consist of masses of virions (see Fig 19-1C") Threads of chromatin sometimes radiate from the nuclear inclusions to the periphery of the nucleus (Courtesy I Jack )

Fig. 19-2 Cytopathic effects induced by adenoviruses (hematoxylin and eosin stain, magnification x400). (A) Normal monolayer of HEp-2 cells 1 lonzonlal arrow marks cell in mitosis and the vertical arrow marks phagocytosed cell debris, not to be confused with viral Inclusion bodies. (U) Cytopathic effects induced by adenovirus in HEp-2 cells Note distended cells containing basophilic intranuclear inclusions (arrows), which consist of masses of virions (see Fig 19-1C") Threads of chromatin sometimes radiate from the nuclear inclusions to the periphery of the nucleus (Courtesy I Jack )

Epidemiology

Although mainly associated with disease of the respiratory tract and eye, and olten transmitted by respiratory droplets or contact, adenoviruses probably spread principally via the enteric (fecal-oral) route. Long-term family studies have demonstrated thai, following infection of young children, very large numbers of adenovirus particles are shed in feces (10'1 virions per gram) over a period of several months and succeed in infecting about half of all susceptible members of the same family. Doubtless this explains the endemicity of the common members of subgenus C (1, 2, 5) and the fact that most children acquire one or more of these viruses by the age of 2 years. About half of such infections are subclinical, the others presenting as pharyngitis or pharygocon-junctival fever. The enteric adenoviruses of subgenus A and many of those of subgenus D are generally isolated from feces, whereas those of subgenus F may spread exclusively via the fecal-oral route. Adenoviruses 40 and 41 have been clearly demonstrated to cause gastroenteritis in children year-round, with occasional outbreaks, for example, in schools or hospitals. Adenoviruses may be responsible for about 10% of cases of gastroenteritis in children

Respiratory spread, via droplets or contact, occurs particularly in the case of the so-called epidemic serotypes of subgenera B and E, which are responsible for outbreaks of pharyngoconjunctival fever in children (types 3, 4, 7) or ARD in military recruits (4, 7) in late winter and spring. Altogether adenoviruses have been calculated to cause 5-10% of respiratory viral infections.

Eye infections may be acquired in several ways, including transfer of respiratory secretions on fingers following infection via the respiratory or alimentary routes. However, two important direct routes ol entry to the eye are well established. Outbreaks of "swimming pool conjunctivitis" (with or without pharyngoconjunctival fever) often occur in children during the summer. In addition, a number of major outbreaks of epidemic keratoconjunctivitis have been traced to the surgeries of particular ophthalmologists or hospitals whose aseptic technique leaves something to be desired. These iatrogenic infections are attributable to contaminated towels, ophthalmic solutions, and instruments such as tonometers. Hand-to-eye transfer is also particularly important.

Adenoviruses of subgenus B are also commonly excreted in urine, whereas subgenus D types 19 and 37 can presumably be transmitted venereally (as well as by contact, in eye infections) because they cause genital infections of males and females.

Overall, fewer than half of the 47 types of adenoviruses currently known have been unequivocally demonstrated to cause any disease. This applies particularly to the 29 members of subgenus D. Serotypes 1-8 comprise about 90% of isolates worldwide

Control

Fecal-oral spread of adenoviruses within families can be reduced by personal hygiene Chlorination of swimming pools, drinking water, and wastewater largely removes the risk of outbreaks from these communal sources. Prevention of contact spread of eye infections by ophthalmologists and nurses in eye clinics demands that special attention be paid to early identification and segregation of epidemic keratoconjunctivitis patients, hand washing, separate paper towels and ophthalmic solutions, and adequate disinfection of equipment. Similar precautions should also be taken to minimize the possibility of nosocomial outbreaks in wards where a patient with a severe adenovirus infection is being nursed.

Vaccine

The regularity of outbreaks of ARD in U.S. military recruits prompted the development in the 1960s of a vaccine for protection of this particular population. The approach was novel. Live virulent virus is enclosed in a gelatin-coated capsule and given by mouth. In this way the virus bypasses the throat, in which it would normally cause disease, but is released in the intestine, where it grows without producing disease. Because of lymphocyte recirculation, such vaccines induce mucosal immunity in the respiratory tract as well as in the intestinal tract. When the two important serotypes, 4 and 7, cultured in human fibroblasts, are combined in such a live vaccine, they grow in the gut with little or no mutual interference and produce highly effective immunity to challenge. This experience has Jed to intensive research on the possible use of recombinant adenoviruses for protection against a range of infections in which mucosal immunity plays an important role.

Further Reading

Doerffler, W., ed (1984) The Molecular Biology of Adenoviruses, Vols. 1-3 Curr Top Microbiol

Immunol 109, 110, and 111. Doerffler, W., ed. (1986). "Adenovirus DNA- The Viral Genome and Its Expression " Nijhoff, Boston.

Flint, S J (1986) Regulation of adenovirus mRNA function Adv. Virus Res 31, 169

Fox, J F., Hall, C E., and Cooney, M K (1977) The Seattle Virus Watch VII Observations of adenovirus infections Am. j Epidemiol 105, 362. Ginsberg, H. S., ed (1984) "The Adenoviruses " Plenum, New York

Hierholzer, J. C. (1989) Adenoviruses hi "Diagnostic Procedures for Viral, Rickettsial and Chlamydial Infections" (N. ) Schmidt and R W. Emmons, eds ), 6th td , p 219 American Public Health Association, Washington, D.C Hicrhoker, |. C, Wigand, R, Anderson, L J, Adrian, T, and Gold, J. W M (1988). Adenoviruses from patients with AIDS. A plethora of serotypes and a description of five new serotypes of subgenus D (types 43-47) }. Infect- D« 158, 804 Horwitz, M. S (1990). Adenoviridae and their replication In "Fields Virology" (13 N Fields, D M. Kmpe, R. M. Chanock, M S Hirsch, ) L Melnick, T. P. Monath, and B Rouman, eds ), 2nd Ed , p 1679 Raven, New York Nevins, J. R (1987) Regulation of early adenovirus gene expression Microbiol Rev 51, 419 Schmitz, H., Wigand, R , and Heinnrh, W (1983) Worldwide epidemiology of human adenovirus infections. Am. I Epidemiol 117, 455 Waddell, G (1988) Adenoviridae' The adenoviruses In "Laboratory Diagnosis of Infectious Diseases Principles and Practice Volume II Viral, Rickettsial and Chlamydial Diseases" (E. H. Lennette, P Halonen, and F. A. Murphy, eds ), p 284. Springer-Verlag, Berlin and New York

Waddell, G , Allard, A , lohansson, M , Svensson, L , and Uhnoo, I (1987) Enteric adenoviruses Ciha I mind Si/uip 128, 63 Warren, D , Nelson, K E , Farrar, J A , flurwit/, L , Hierliol/er, J C , Ford, E , and Anderson, L J (1989). A large outbreak of epidemic keratoconjunctivitis Problems in controlling nosocomial spread. I Infcit Dis 160, 938

Was this article helpful?

0 0

Post a comment