The paramyxoviruses are a family of enveloped viruses containing negative sense single-stranded RNA as a single piece.
Parainfluenza, mumps, measles, NDV and simian virus 5 are indistinguishable when seen in the electron microscope, whereas the pneumoviruses (respiratory syncytial virus and metapneumovirus) have slightly longer surface spikes and are more difficult to visualize.
Functionally there are other differences. Parainfluenza viruses (1–4a, b), Newcastle disease virus (NDV) and mumps virus have a surface haemagglutinin and neuraminidase located on the same spike; measles virus spikes have haemagglutinin but no neuraminidase activity; while pneumoviruses have neither. In addition, measles virus has a haemolysin not possessed by the others. Respiratory syncytial (RS) virus has a large surface glycoprotein, G, which has a cell-attaching function similar to that of a haemagglutinin.
The replication of paramyxoviruses follows a common theme. After attachment, the F protein fuses the viral envelope to the cell membrane, becoming part of it and releasing the nucleocapsid into the cell. The negative-sense genome cannot act as messenger RNA (mRNA), making it necessary for the virus to carry its own RNA-dependent RNA polymerase. This polymerase produces subgenomic-sized mRNA transcripts, which are translated to produce some of the early virus-specific polypeptides. These include a second RNA polymerase, which copies the genome into full-length positive complementary strands that are, in turn, copied back into negative strands both for transcription into later mRNA (coding for structural proteins) and for incorporation into new virions. The virus haemagglutinin is incorporated into the cell membrane allowing the virus to bud off from the cell surface. Red blood cells will adsorb to the cell surface expressing the viral haemagglutinin (called haemadsorption) and this is used in the laboratory to identify virus-infected cells.
The paramyxoviruses are subdivided into two sub-genera, Paramyxoviruses and Rubulaviruses
Description: Mumps virus is a typical paramyxovirus, indistinguishable in EM appearance from parainfluenza viruses, measles virus and NDV, with a similar ribonucleocapsid, which may be the only virus-like material seen by electron microscopy. There is only one serotype, although monoclonal antibodies have shown minor variations in the various surface antigenic epitopes.
Clinical features and pathogenesis
Mumps is an ‘iceberg’ disease which, although common as a childhood infection, is often subclinical. Although the salivary glands are often involved, inapparent or minor infections are more common. The advent of MMR (mumps, measles, rubella) vaccine as a universal vaccine of childhood has resulted in a significant age-shift, with most clinical cases in the UK now occurring in university-age adults.
Infection is probably acquired by inhalation of droplets into the respiratory tract. The incubation period is 14–18 days, and is followed by a generalized illness with later localization in the salivary glands, usually the parotids. The generalized phase is the usual ‘flu-like’ illness with fever and malaise, followed by developing pain in the parotid glands, which then swell rapidly. Much of the swelling is due to blockage of the efferent duct of the parotid gland, and sucking a lemon in front of a sufferer is a refined form of torture although likely to be diagnostic!
Neurological involvement is common in mumps (in more than 50% of infections), although the majority of cases are not clinically apparent. However, clinical meningitis remains the most common serious complication of mumps, occurring in 1–10% of patients with mumps parotitis. Meningitis (like any other complication of mumps) can occur before, during, after or even in the absence of salivary gland involvement. Before the widespread use of the MMR vaccine, mumps virus and the enteroviruses accounted for most of the cases of aseptic meningitis in the UK. Mumps meningitis is rarely fatal and complete recovery is usual. Meningo-encephalitis has been described, but is much rarer, carries a poorer prognosis and may result in long-term neurological sequelae or death. Deafness and tinnitus have also been described as complications, but are very rare.
In prepubertal children the acute illness usually subsides in 4–5 days, with complete recovery. The best known complication, in postpubertal males, is orchitis. This, although painful and causing softening and atrophy of the affected testicle, is usually unilateral and rarely causes sterility. Oophoritis also occurs in girls, and should be distinguished from a ruptured ovarian cyst or acute appendicitis. Both orchitis and oophoritis usually develop as the parotitis resolves, and a history of previous parotid pain and swelling usually provides the clue.
The role of mumps in pancreatitis is difficult to establish. There may be abdominal pain in acute mumps but the levels of serum amylase do not correlate with the clinical picture. High levels may provide supportive evidence but are not diagnostic. Although uncomfortable, it is not fatal.
Detection and isolation
Typical mumps does not always require laboratory confirmation, but mild cases with little parotid swelling may not be noticed until complications develop. Demonstration of mumps virus RNA by genome amplification (e.g. RT-PCR) is the most sensitive test and should be considered for virus detection, especially in the cerebrospinal fluid (CSF) of patients with possible mumps meningitis. Isolation of the virus in cell culture (usually in monkey kidney or HEp2 cells) from throat swabs, saliva, urine or the CSF is possible, although not as sensitive as RT-PCR testing, and the virus may take up to a week to grow to detectable levels. Virus presence can be reliably confirmed by indirect immunofluorescent staining of cultured cells. Alternatively, neutralization or haemadsorption, which can be inhibited by specific antiserum, may be used to confirm the presence and identity of the virus.
The detection of nucleocapsid helix in CSF by electron microscopy (EM) is diagnostic of mumps; however, the small quantities of CSF usually taken for all assays make routine EM diagnosis of mumps meningitis impractical.
Serological confirmation of mumps in a child is most easily accomplished by testing salivary fluid (or serum) for the presence of mumps-specific IgM. In older adults, especially those with a history of MMR vaccination, there may not be an IgM response, but high titres of IgG are strongly suggestive if the clinical picture fits. There are a number of ELISA-based and complement fixation tests available; neutralization and haemagglutination inhibition tests are more complex and do not offer any advantages in routine diagnosis.
Mumps is a worldwide disease, with man the only known reservoir. In the absence of vaccination, most infections are in children of school age but, where MMR has been introduced, most infections occur in adults around 20–25 years of age. Infections in adults may be more severe and more likely to lead to complications. Although epidemics occur, mumps is less infectious than measles or chickenpox. Initial infection appears to confer lifelong immunity, and second infections do not occur.
Some, but not very reliable, protection can be given by passive immunization, which may prevent severe orchitis even when given at the stage of parotitis.
Mumps vaccine, based on the Jeryl Lynn or Urabe strains, has been available as a monovalent vaccine for some time, particularly in the USA, but is now widely incorporated into the triple MMR vaccine. All three components are live-attenuated viruses, and the mumps component induces good antibody levels, lasting long enough to suggest that the recipients will not become susceptible as adults. A few cases of mild post-vaccine meningitis have been described but have not caused serious concern.
Measles virus, a morbillivirus, is morphologically indistinguishable in the EM from other members of the group. The ribonucleoprotein helix is readily released from the virion and may, as with the others, be the only identifiable virus structure seen by electron microscopy. The virion structure differs from other paramyxoviruses:
o spikes carry a haemagglutinin but not a neuraminidase function
o the F protein is also a haemolysin.
There is only one serotype of measles virus and no subtypes have yet been recognized, although monoclonal antibodies show that there may be minor differences between wild and cultivated strains.
Human morbilliviruses are related to a number of animal strains. Canine distemper and rinderpest in cattle are well-known relatives, although a global campaign for the eradication of rinderpest has recently come to a successful conclusion. In the past few years other similar viruses have been isolated from seals (of several species), dolphins and porpoises, and an equine morbillivirus has reappeared that has apparently been transmitted to man in contact, fatally in one case. All are distinct and can cause serious illness in their natural species, although survivors develop solid immunity. There is partial cross-protection experimentally in ferrets between measles and canine distemper viruses.
Clinical features and pathogenesis
@Koplik's spots : Measles is an acute febrile illness, usually in childhood, after an incubation period of 10–12 days. The onset is ‘flu-like’, with high fever, cough and conjunctivitis. Koplik's spots (red spots with a bluish-white centre on the buccal mucosa) may be present at this stage.
After 1–2 days the acute symptoms decline, with the appearance of a widespread maculopapular rash. Viral antigen, but not infectious virus, may be found in the spots. The rash can be inhibited by local injections of immune serum, but does not appear at all in those who are severely immunocompromised (‘spotless measles’ – usually rapidly fatal), and this has been thought to point to an immunopathological (T cell-mediated) component of the rash.
The pneumonia is due to direct invasion by virus, but the role of virus in the other two complications is uncertain. Measles encephalitis can cause severe and permanent mental impairment in those it does not kill. It is rare but disastrous.
The mortality rate associated with uncomplicated measles in immunocompetent, well-nourished children is low but rises rapidly with malnourishment (particularly in Africa), in the immunocompromised and, to a much lesser extent, with age. The virus has also been devastating in isolated populations (such as the Inuit in Greenland some years ago) into which it was introduced as a ‘new’ disease.
Clinical diagnosis of measles therefore has a low sensitivity and specificity. Laboratory confirmation is best done by demonstration of measles-specific IgM in a venous blood or salivary sample (avoiding the need for venesection). It may also be possible to amplify the viral genome from a throat swab or other respiratory tract specimen using RT-PCR. In hospital, and particularly in immunocompromised patients in whom the disease is often rashless (and where the diagnosis may not be suspected at first), the diagnosis may be made rapidly by immunofluorescence on exfoliated respiratory cells in well-taken nasopharyngeal secretions. The presence of a large number of giant cells, particularly in patients on cytotoxic drugs, is a bad prognostic sign.
The virus may be isolated, though not readily, from blood or nasopharyngeal aspirates during the prodrome and until day 2 of rash, in human fibroblasts, primary monkey kidney cells and Vero cells. The virus can then be identified by neutralization or immunofluorescence.
Transmission is from person to person, probably by respiratory droplets, but the associated conjunctivitis may also be a source. Measles epidemics occur every 2 years in developed countries in the absence of widespread use of the vaccine. This periodicity is absent in isolated populations too small to maintain transmission (<400 000), in poverty and overcrowding, and following the widespread use of vaccine. The disease is ubiquitous throughout the world and, although a candidate for eradication, this may be difficult to achieve due to the likely high cost and the logistic challenges such a programme poses.
The first measles vaccine was a formalin-inactivated one.Measles vaccine is now combined with those against mumps and rubella to form the MMR vaccine. This combination of three attenuated viruses has been shown to induce good immunity to all three. Introduced initially in the USA, it is now the preferred vaccine in the UK for administration to children aged between 12 and 18 months, with a pre-school booster.
The attenuated measles vaccine, alone or in combination with mumps and rubella, has been shown to be effective and safe. Unfortunately, vaccine uptake fell in the UK due to fears over its safety, particularly as a possible cause of autism. These fears have now been shown to be unsubstantiated but measles reappeared when levels of herd immunity dropped.
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