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Murray et al., Microbiology
5th Ed., Chapters 59
Brief review of paramyxovirus virus structure, properties and classification.
Discussion of human parainfluenza virus infections, disease, epidemiology, prevention and treatment.
Discussion of respiratory syncytial virus infections, disease, epidemiology, prevention and treatment.
Discussion of human metapneumovirus infections, disease, epidemiology, prevention and treatment.
Brief review of adenovirus structure, properties and classification
Discussion of adenovirus infections, disease, epidemiology, prevention and treatment.
The common cold
Parainfluenza viruses are important viral pathogens causing upper and lower respiratory infections in adults and children. They are second to respiratory syncytial virus cause of lower respiratory tract disease in young children.
Big Picture Book of Viruses
|Figure 1. Structure of a paramyxovirus||
Parainfluenza viruses are relatively large viruses of about 150-300 nm in diameter. They have a spherical or pleomorphic shape (figure 1 and 2). The RNA is negative sense, unsegmented and single stranded (ss). The nucleocapsid core is filamentous or herringbone-like, has helical RNA tightly associated with Nucleoprotein (NP) Phosphoprotein (P) and Large protein (L)
These are enveloped viruses with a host-derived lipid bilayer associated with two virus-specific glycoproteins:
Matrix (M) protein, located just within the envelope, is hydrophobic
Transmission electron micrograph of parainfluenza virus. Two intact particles and free filamentous nucleocapsid. CDC/Dr. Erskine Palmer
Cell lines such as primary Rhesus monkey kidney epithelial Cells (PRMK), LLC-MK-2, and human embryonic kidney cells are used. Cytopathic effects occur such as rounding, bridging, cell lysis, and syncytium formation.
Hemadsorption (due to the interaction of viral hemagglutinin with specific erythrocyte receptors on guinea pig red cells) can be observed at 4° C. This may be seen even before the appearance of cytopathic effects and has been used for early diagnosis (especially PIV-1 and PIV-3).
The first step in the infection cycle involves attachment of the virus to host cell sialic acid receptors. This is mediated by viral attachment protein, a function served by the HN glycoprotein.
Next, the F protein catalyzes fusion of the viral envelope and host cell membrane, resulting in uncoating and release of the nucleocapsid structure into the host cell cytoplasm.
For transcription and protein synthesis to occur, first mRNA is formed with the help of RNA-dependent RNA polymerase which must be supplied by the virus. The polymerase function is carried out by the P and L proteins, and possibly also the NP. The genome is replicated by formation of a full-length positive sense RNA template onto which a negative sense RNA is then transcribed.
Assembly of the nucleocapsid occurs and M proteins are then associated with the viral glycoprotein modified cell membranes. Mature virions are released from host cell membranes by budding.
|Figure . Weekly reports of parainfluenza type 1 in the US. Seasonal variation. CDC||
Primary infections and re-infections occur but most infections are asymptomatic, especially in older children and adults. The incubation period is 2 to 6 days. Reinfections are clinically less severe, most commonly involve the upper respiratory tract and occur throughout life.
Fever and a spectrum of respiratory infections are caused by PIVs:
Particularly severe and persistent infections are known to occur in immunocompromized children and adults in whom prolonged viral shedding is seen.
Most HPIV infections are mild and self-limiting. There is no specific treatment and no anti-virals are available. Supportive treatment for croup includes humidification of air and racemic epinephrine (Racemic epinephrine is a 1:1 mixture of the dextrorotatory and levorotatory isomers of epinephrine. The L form is the active component) . Corticosteroids may be used in moderate to severe cases.
Immunity following infection is short lived. The role of antibody is not clear since reinfection has been seen even with high levels of antibody. Cell-mediated immunity is probably more important for limiting infection.
Asymptomatic shedding is common, making it difficult to contain spread of infection. Hand washing and preventing contamination of surfaces with respiratory secretions are important for limiting nosocomial spread.
RESPIRATORY SYNCYTIAL VIRUS
Classification and structure
Family Paramyxoviridae, genus Pneumovirus.
Infection of cells by RSV often results in syncytium formation, hence the name. The virus was first discovered in chimpanzees (Chimpanzee Coryza Virus) and accidental infection in humans led to its recognition as a human pathogen.
These are spherical or pleomorphic enveloped viruses (100-350 nm) with single-stranded, negative sense linear RNA. There are two non-structural and eight structural proteins.
The envelope has 2 glycoproteins: F protein, the fusion protein, is important for fusion of viral particles to target cells and fusing infected cells to neighboring cells to form syncytia. G protein, which is highly glycosylated, is important for viral attachment to host cells. Antigenic variations in the type of G protein determine the subgroup (A or B). RSV lacks H/N proteins, unlike other members of the family Paramyxoviridae.
These viruses survive on surfaces for up to 6 hours, on gloves for less than 2 hours. They rapidly lose viability with freeze-thaw cycles, in acidic conditions and with disinfectants.
RSV attaches (via the G protein) to cells of nasal mucosa and upper respiratory tract. The F protein allows fusion of the viral envelope with the host cell plasma membrane. The virus can also infect the eye. Infected cells may undergo necrosis and syncytia form through cell-cell fusion (which is often cell with cultured cells). Cell to cell transfer of virus leads to spread from upper to lower respiratory tract.
Mucosa edema occurs and there is increased mucin secretion. There is also cell necrosis that leads to sloughing of debris. Smaller airways (bronchioles) become plugged with debris and mucin; bronchoconstriction also occurs. Peribronchial lymphocytes may infiltrate the tissue.
immune response also induces some of the pathological changes. IgE
response in some individuals is linked to airway hyper-reactivity.
Cell-mediated immunity and humoral response limits the severity of the
RSV has a worldwide distribution and and is an important cause of lower respiratory tract disease in young infants. Most children have had an RSV infection by age 4 years. RSV is the most frequent cause of bronchiolitis but is an infrequent cause of croup.
Out breaks are seasonal occurring from late fall through spring (November to May), the virus being transmitted via large droplets, through fomites and via the hands. RSV can survive on surfaces for up to six hours. Viral shedding continues for less than 1 to 3 weeks but longer in immuno-compromised hosts.
75,000 to 125,000 infants are hospitalized each year in the US because of RSV infections. These account for 50 to 90% of hospitalizations for bronchiolitis.
Nosocomial spread is common. Viral shedding can last for up to three weeks and infants can show a high titer of shed virus, especially initially (107 viral particles per ml). Asymptomatic viral shedding is also observed. There is prolonged shedding in immunocompromized individuals.
Transmission electron micrograph of respiratory syncytial virus. Long
filamentous form. CDC/Dr. Erskine Palmer
|Figure . Weekly reports of RSV isolation in the US||
The incubation period is 4 to 6 days (range: 2 to 8 days). First, there is an upper respiratory infection (‘bad cold’) in older children and adults with clinical features of fever, rhinitis, pharyngitis. Lower respiratory infection (bronchiolitis and/or pneumonia) may occur after the upper respiratory infection and results in the clinical features of cough, tachypnea, respiratory distress, hypoxemia, cyanosis. The cough can persist for 3 weeks.
In young infants one may observe apnea, lethargy, irritability, poor feeding, otitis media and croup.
Radiological examination may show atelectasis, streaking, hyperinflation and perihilar infiltrates, especially in the right middle and upper lobes.
Severe infections occur in
infants (especially less than 35 weeks gestation and those with chronic lung
disease), children with cyanotic congenital heart disease, and
immunocompromized hosts. There are up to 3000 deaths per year in the
Nasal washings, nasal aspirates or swabs should be transported on ice and processed immediately. Rapid diagnosis is carried out using DFA, IFA, ELISA.
Viral culture is carried out in cell lines such as HeLa, Hep-2, Monkey Kidney cells. Cytopathic effects are usually seen in 2-5 days. Shell vial technique with immunofluorescence is useful.
Treatment is usually supportive by the provision of fluids, oxygen, humidification of air, respiratory support. Steroids and bronchodilators have not proved useful.
Ribavirin (Virazole) (see
chemotherapy) , a guanosine analogue
(aerosol) has been used with some efficacy but is used only in persons
at high risk for severe disease (premature and immunocompromized infants).
Hand washing is important as is isolation and cohort nursing. Health care providers should wear protective gear, i.e. gowns, gloves, masks and goggles
Synagis package insert (pdf file)
RespiGam package insert (pdf file)
Negative-stain electron micrographs of human metapneumovirus.
(Photograph courtesy of Dr. Charles Humphrey of CDC/NCID/IDPA
Published in JID 2002;185:1660-3)
This virus (Pneumovirinae subfamily, Paramyxoviridae family) is closely related to RSV and was first recognized as a pathogen in the Netherlands in 2001. Its role in upper and lower respiratory tract infections is now being recognized world-wide and it may cause 5% of respiratory illness in children. There is often co-infection with RSV.
Metapneumovirus is ubiquitous and, by the age of five, most people are seropositive and have thus been infected by the virus. Many infections are asymptomatic but the virus can cause both upper and lower respiratory tract infections with symptoms of a cold, otitis media, pneumonia or bronchitis. There can also be pneumonia in marrow recipients that can possibly be fatal.
There are distinct epidemics in the winter months. There are two main HMPV
types (A and B), each with 2 subtypes (A1, A2; B1, B2) and allfour of these
circulate in the population with the dominant strain varying.
Medical Microbiology, 3rd Ed.-1998; Mosby (Murray et al)
Manual Of Clinical Microbiology, 6th Ed.-1995; ASM Press (Murray, Baron, Pfaller)
2000 Red Book; American Academy of Pediatrics
Textbook of Pediatric Infectious Diseases, 4th ed. 1998 (R.D. Feigin and J. D. Cherry)
"adenovirus" because they were first isolated in 1953 from
tissue cultures of human adenoidal tissue.
Adenoviruses belong to family Adenoviridae, genus Mastadenovirus.
They are further classified into 6 subgroups (A through F), based on hemagglutinating properties and DNA homology.
About 47 serotypes have been isolated from humans.
|Figure Structure of adenovirus||
|Adenovirus © Dr Linda M Stannard, University of Cape Town, South Africa, 1995 (used with permission).||
Virus primarily attacks mucoepithelial cells of the conjunctiva, respiratory tract, gastrointestinal and genitourinary tracts. Attachment to host cell receptor occurs via the fiber protein. The virus replicates in the cytoplasm of host cells, but viral DNA replicates within the host cell nucleus. Early and late phases of replication occur, followed by assembly and release of virions.
Three types of infections occur in target cells:
Adenovirus also replicates in associated lymphoid tissues, and subsequent viremia can cause secondary infection in visceral organs.
Inefficient (error-prone) replication of the virus results in many excess antigenic components. These are liberated into the culture fluid in vitro as soluble antigens and lead to formation of basophilic staining intra-nuclear inclusion bodies in cells.
Adenoviruses are stable in the environment and to low pH, bile, and proteolytic enzymes - These properties make it possible for them to replicate to high titers in the GI tract.
Almost half of adenoviral infections are subclinical
Most infections are self-limited and induce type-specific immunity
Incubation period is 2-14 days; for
gastroenteritis usually 3-10 days
Different clinical syndromes have been described:
Rare results of adenovirus infections include- Meningitis, encephalitis, arthritis, skin rash, myocarditis, pericarditis, hepatitis. Fatal disease may occur in immunocompromised patients, as a result of a new infection or reactivation of latent virus
|Figure . Weekly reports of respiratory adenovirus in the US. Seasonal variation. CDC||
Endemic, epidemic and sporadic infections occur. Outbreaks have been noted in military recruits, swimming pool users, residential institutions, hospitals, day care centers etc.
Transmission is by droplets, the fecal-oral route (direct and through poorly chlorinated water) or fomites
Many infections are subclinical
Infections are most communicable in the first few days of illness, however infective period continues since clinical infection may be followed by intermittent and prolonged rectal shedding
Secondary attack rate within families is up to 50%;
Adenovrius outbreaks are seasonal: Respiratory disease mainly occurs in late winter through early summer. Pharyngoconjunctival and EKC infections occur in the summer months while GI disease does not seem to be seasonal
Clinical specimens, such as swabs (nasopharyngeal, conjuncticval, rectal, or other) and washings, corneal scrapings, stool, urine or biopsy and autopsy materials etc. should be transported in viral transport medium.
Viral Isolation in cell cultures is carried out in HeLa, human embryonic kidney (HEK) and human fetal diploid cells (HDFL). A549 cells lines are used for types 1-39.
Subgroup F (serotypes 40, 41) do not grow well in these cell lines, but do grow in Graham-293 (a modified HEK cell line).
Shell vial culture technique aids in faster detection.
Cytopathic effects include swelling and rounding of cells. Cells may become refractile and clustered into irregular clumps.
Isolation of virus from a pharyngeal specimen is more suggestive of a current clinical infection than from fecal specimen.
Rapid detection of enteric types (serotypes 40, 41) is by ELISA or immunofluorescnece antibody. Immune EM (aggregation with sera) may also be used
Other detection methods in current use include electron microscopy, polymerase chain reaction and nucleic acid probes.
Serology is mainly used for
Contact precautions, respiratory precautions in health care settings
Adequate chlorination of swimming pools
Sterilization / disinfection of ophthalmologic equipment and use of single dose vials of ophthalmic medications
Vaccine: There is a live, enteric coated, oral vaccine (against types 4, 7, 21)
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