Vol. 17, No. 25
THE JOHNS HOPKINS MICROBIOLOGY NEWSLETTER
Monday, June 22, 1998
A. Provided by Carmela Groves, R.N., M.S., Chief, Division of Outbreak Investigation, Maryland Department of Health and Mental Hygiene.
From June 12, 1998 to June 18, 1998, 4 outbreaks have been reported to the Maryland Department of Health and Mental Hygiene. Three of the four were foodborne gastroenteritis associated with food service facilities; was scabies associated with a long term care facility.
B. The Johns Hopkins Hospital. Information provided by Dr. Edward Weir, Dept. of Pathology.
Patient History: The patient was a sexually active 17-year-old male who was spending the summer working as a counselor at a YMCA camp in western Virginia. He had presented to the camp infirmary with complaints of fever, chills, muscle aches, headache, sore throat, and sore eyes of several days duration. He was also noted to have a mild dry cough and nasal congestion. Physical exam revealed a temperature of 38.8oC, an erythematous pharynx with swollen tonsils, and inflamed, injected conjuctivae remarkable for multiple, small, nodular excrescences bilaterally. In addition, a maculopapular rash appeared to be fading from the patient's back and upper and lower extremities. The patient was reported to be responsible for cleaning the camp swimming pool, organizing evening barbecues, and leading hiking expeditions. Four other campers/counselors also presented to the infirmary with similar symptomatology. The patient was symptomatically treated and sent home. Cultures from both a conjunctival swab and the patient's throat showed positive growth seven days later.
Organism: The above patient was suffering from pharyngoconjunctival fever caused by adenovirus infection. Adenoviruses are nonenveloped, double-stranded DNA viruses of the family Adenoviridae, genus Mastadenovirus. Forty-nine distinct serotypes have been recognized as pathogens in man. On the basis of DNA homology studies and hemagglutination patterns, each serotype has been classified into one of six subgroups (A to F). All adenoviruses are approximately 80 nm in diameter and icosahedral in shape with a genome molecular weight of 20 to 25 x 106 daltons. In each virion are located 240 hexons and 12 pentons. The hexons are dispersed on the triangular faces and edges, and the pentons are located in the vertices of the icosahedron. Each penton consists of a base and a fiber that is a rodlike outward projection of variable length with a terminal knob. Together, the penton base and fiber are toxic to cells and also contain type-specific antigens that give rise to serum-neutralizing antibodies. The fiber, which contains the viral attachment proteins, can act as a hemagglutinin and thus elicit hemagglutinin inhibition antibodies. The genus-specific antigen is the principle determinant on the hexon, but it resides on the internal part of the capsid and thus does not elicit protective antibodies. The adenovirus genes are transcribed from both DNA strands at different times during the replication cycle. Most of the transcribed RNA is processed into several individual mRNAs in the nucleus. Early proteins promote cell growth and include a DNA polymerase that is involved in the replication of the genome. Adenovirus also encodes proteins that suppress host immune and inflammatory responses. Late proteins, which are synthesized after the onset of viral DNA replication, are primarily structural in function.
Adenoviruses infect epithelial cells lining respiratory and enteric organs. Viremia may occur after local replication of the virus, with subsequent spread to visceral organs and possible death. One virus cycle takes approximately 32 to 36 hours and produces 10,000 virions. In this process, the viral fiber proteins interact with cell surface receptors, and virions enter the cell by means of endocytosis. The virus lyses the endosomal vesicle, and the capsid delivers the DNA genome to the nucleus. The viral fiber proteins determine the target cell specificity among adenovirus serotypes. The toxic activity of the penton base protein can result in inhibition of cellular protein synthesis, cell rounding, and tissue damage. Antibody is important for causing lytic adenovirus infections to resolve and protects the person from reinfection with the same serotype. Cell-mediated immunity is important in limiting virus outgrowth; immunosuppressed people suffer recurrent disease.
Clinical Disease: Adenoviruses are spread exclusively by human-to-human transmission, mainly by respiratory or fecal-oral contact. They primarily infect children and less commonly infect adults. Infection with reactivated virus occurs in immunocompromised patients. Several distinct clinical syndromes are associated with adenovirus infection. Acute febrile pharyngitis and pharyngoconjunctival fever are frequently attributed to adenovirus. Pharyngitis alone occurs in young children, particularly those younger than three years of age. Affected patients typically have mild influenza-like symptoms including nasal congestion, cough, coryza, malaise, fever, chills, myalgia, and headache which may last 5 to 10 days. Pharyngoconjunctival fever occurs more often in outbreaks that involve older children. Acute respiratory tract disease is a syndrome of fever, cough, pharyngitis, and cervical adenitis. It occurs primarily among military recruits due to serotypes 4 and 7. Other respiratory tract diseases include laryngitis, croup, and bronchiolitis. Adenovirus also can cause a pertussis-like illness in children and adults that consists of a prolonged clinical course and true viral pneumonia. Eye infections frequently manifest in the form of a follicular conjunctivitis in which the mucosa of the palpebral conjunctiva develops nodules and both conjunctivae (palpebral and bulbar) become inflamed. Such conjunctivitis may occur sporadically or in outbreaks that can be traced to a common source (e.g., swimming pools). Epidemic keratoconjunctivitis may be an occupational hazard for industrial workers exposed to dust, debris, and foreign bodies. Adenovirus is a major cause of acute viral gastroenteritis. Serotypes 40, 41, and 42 (Group F enteric adenoviruses) account for episodes of diarrhea in infants and 15% of the cases of nosocomial gastroenteritis. These serotypes rarely result in fever or respiratory disease. Other clinical presentations associated with adenovirus infection include intussusception in young children, acute hemorrhagic cystitis in bone marrow transplant recipients, musculoskeletal disorders, and genital and skin diseases. Immunocompromised individuals are especially at risk for adenovirus infections of the lung and the liver.
Laboratory Diagnosis: The isolation of most adenovirus types is best accomplished in cell cultures derived from epithelial cells (e.g., primary human embryonic kidney cells, HeLa cells, etc.). The virus causes a lytic infection with characteristic inclusion bodies within 2 to 20 days. Recovery of virus from cell culture requires an average of six days but may take as long as 3 weeks. For the results of virus isolation to be significant, the isolate should be obtained from a site or secretion relevant to the disease symptoms. Isolation of adenovirus from the throat of a patient with pharyngitis is usually diagnostic if laboratory findings eliminate other common causes of pharyngitis, such as Streptococcus pyogenes. Immunoassays, including fluorescent antibody and enzyme-linked immunosorbent assays, the polymerase chain reaction (PCR), and DNA probe analysis can be used to detect and type and group the virus in clinical samples and tissue cultures. A novel PCR method has been recently developed and validated for diagnosis in the Johns Hopkins Microbiology Lab. Enzyme immunoassay, PCR, DNA probe analysis, and immunoelectron microscopy are used to identify enteric adenovirus serotypes 40, 41, and 42, which have fastidious growth requirements in available cell cultures. The histologic hallmark of adenovirus infection is a dense, central intranuclear inclusion within an infected epithelial cell that consists of viral DNA and protein. Serologic assays such as complement fixation, hemagglutination inhibition, enzyme immunoassay, and neutralization techniques have been used to detect type-specific antibodies after adenovirus infection. However, a fourfold rise in the antibody level between acute and convalescent serum specimens, or seroconversion, must occur for active infection to be diagnosed. Serological testing is rarely used except to confirm the significance of a fecal or upper respiratory tract isolate by identifying its serotype.
Treatment: There is no known treatment for adenovirus infection. Live oral vaccines have been used to prevent infections with adenovirus 4 and 7 in military recruits, but they are not used in civilian populations. The widespread use of live adenovirus vaccines has not yet been instituted because of the large number of serotypes and because members of some species of the adenovirus family have been shown to be oncogenic in mice. However, genetically engineered subunit vaccines could be prepared and used in the future.
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