Mumps

Mumps is caused by the mumps virus (MuV), scientific name Mumps orthorubulavirus, which belongs to the Orthorubulavirus genus in the Paramyxoviridae family of viruses.[20] Humans are the only natural host of the mumps virus. MuV's genome is made of RNA and contains seven genes that encode nine proteins. In MuV particles, the genome is encased by a helical capsid. The capsid is surrounded by a viral envelope that has spikes protruding from its surface. MuV particles are pleomorphic in shape and range from 100 to 600 nanometers in diameter.[6][21][22]

The replication cycle of MuV begins when the spikes on its surface bond to a cell, which then causes the envelope to fuse with the host cell's cell membrane, releasing the capsid into the host cell's cytoplasm.[6][23][24] Upon entry, the viral RNA-dependent RNA polymerase (RdRp) transcribes messenger RNA (mRNA) from the genome, which is then translated by the host cell's ribosomes to synthesize viral proteins. RdRp then begins replicating the viral genome to produce progeny.[6][24] Viral spike proteins fuse into the host cell's membrane, and new virions are formed at the sites beneath the spikes.[6][23][24] MuV then utilizes host cell proteins to leave the host cell by budding from its surface, using the host cell's membrane as the viral envelope.[23]

Twelve genotypes of MuV are recognized, named genotypes A to N, excluding E and M. These genotypes vary in frequency from region to region. For example, genotypes C, D, H, and J are more common in the western hemisphere, whereas genotypes F, G, and I are more common in Asia, although genotype G is considered to be a global genotype. Genotypes A and B have not been observed in the wild since the 1990s. MuV has just one serotype, so antibodies to one genotype are functional against all genotypes.[10] MuV is a relatively stable virus and is unlikely to experience antigenic shifting that may cause new strains to emerge.[3]

The mumps virus is mainly transmitted by inhalation or oral contact with respiratory droplets or secretions. In experiments, mumps could develop after inoculation either via the mouth or the nose. Respiratory transmission is also supported by the presence of MuV in cases of respiratory illness without parotitis, detection in nasal samples, and transmission between people in close contact.[6] MuV is excreted in saliva from approximately one week before to eight days after the onset of symptoms,[2] peaking at the onset of parotitis,[5] though it has also been identified in the saliva of asymptomatic individuals.[6]

Mother-to-child transmission has been observed in various forms. In non-human primates, placental transmission has been observed, which is supported by isolation of MuV from spontaneous and planned aborted fetuses during maternal mumps. MuV has also been isolated from newborns whose mother was infected. While MuV has been detected in breast milk, it is unclear if the virus can be transmitted through it.[6] Other manners of transmission include direct contact with infected droplets or saliva, fomites contaminated by saliva, and possibly urine.[5][11][13] Most transmissions likely occur before the development of symptoms and up to five days after such time.[5]

In susceptible populations, a single case can cause up to twelve new ones. The time period when a person is contagious lasts from two days before the onset of symptoms to nine days after symptoms have ceased. Asymptomatic carriers of the mump virus can also transmit the virus.[11] These factors are thought to be reasons why controlling the spread of mumps is difficult.[6] Furthermore, reinfection can occur after a natural infection or vaccination,[10] indicating that lifelong immunity is not guaranteed after infection.[15] Vaccinated individuals who are infected appear to be less contagious than the unvaccinated.[5]

The average number of new cases generated from a single case in a susceptible population, called the basic reproduction number, is 4–7. Given this, it is estimated that a vaccination rate between 79 and 100% is needed to achieve herd immunity. Outbreaks continue to occur in places that have vaccination rates exceeding 90%, however, suggesting that other factors may influence disease transmission. Outbreaks that have occurred in these vaccinated communities typically occur in highly crowded areas such as school and military dormitories.[25]

Many aspects of the pathogenesis of mumps are poorly understood and are primarily inferred based on observations from the clinical features of the disease and experimental infections in laboratory animals. These animal studies may be unreliable for various reasons, including unnatural methods of inoculation.[6] Following exposure, the virus infects epithelial cells in the upper respiratory tract that express sialic acid receptors on their surface. After initial infection, the virus spreads to the parotid glands, causing the signature parotitis.[16] It is thought that shortly after infection the virus spreads to lymph nodes, in particular T-cells, which results in the presence of viruses in the blood, called viremia.[2][6] Viremia lasts for 7–10 days, during which MuV spreads throughout the body.[11]

In mumps orchitis, infection leads to: parenchymal edema; congestion, or separation, of the seminiferous tubules; and perivascular infiltration by lymphocytes. The tunica albuginea forms a barrier against edema, causing an increase in intratesticular pressure that causes necrosis of the seminiferous tubules. The seminiferous tubules also experience hyalinization, i.e. degeneration into a translucent glass-like substance, which can cause fibrosis and atrophy of the testes.[11][13]

In up to half of cases, MuV infiltrates the central nervous system (CNS), where it may cause meningitis, encephalitis, or hydrocephalus. Mumps is rarely fatal, so few post-mortem analyses have been done to analyze CNS involvement. Of these, fluid buildup, congestion, and hemorrhaging in the brain, white blood cell infiltration in the perivascular spaces in the brain, reactive changes to glial cells and damage to the myelin sheaths surrounding neurons were observed. Neurons appear to be relatively unaffected.[6]

In laboratory tests on rodents, MuV appears to enter the CNS first through cerebrospinal fluid (CSF), then spreading to the ventricular system. There, MuV replicates in ependymal cells that line the ventricles, which allows the virus to enter the brain parenchyma. This often leads to MuV infecting pyramidal cells in the cerebral cortex and hippocampus. Infected ependymal cells become inflamed, lose their cilia, and collapse into CSF, which may be the cause of the narrowing of the cerebral aqueduct thought to cause mumps hydrocephalus.[6]

In humans, mumps hydrocephalus may be due to obstruction of the cerebral aqueduct with dilatation of the lateral and third ventricles, obstruction of the interventricular foramina, or obstruction of the median and lateral apertures. Ependymal cells have been isolated from CSF of mumps patients, suggesting that animals and humans share hydrocephalus pathogenesis. Hydrocephalus has also been observed in the absence of canal obstruction, however, indicating that obstruction may be a result of external compression by edematous tissue and not related to hydrocephalus.[6]

Deafness from mumps may be caused by MuV infection in CSF, which has contact with the perilymph of the inner ear, possibly leading to infection of the cochlea, or it may occur as a result of inner ear infection via viremia that leads to inflammation in the endolymph. Hearing loss may also be caused indirectly by the immune response. In animal studies, MuV has been isolated from the vestibular ganglion, which may explain vestibular symptoms such as vertigo that often co-occur with deafness.[6]

Even though MuV has just one serotype, significant variation in the quantity of genotype-specific sera needed to neutralize different genotypes in vitro has been observed.[15][26] Neutralizing antibodies in the salivary glands may be important in restricting MuV replication and transmission via saliva, as the level of viral secretion in saliva inversely correlates to the quantity of MuV-specific IgA produced.[2] The neutralizing ability of salivary IgA appears to be greater than serum IgG and IgM.[5]

It has been proposed that symptomatic infections in the vaccinated may be because memory T lymphocytes generated as a result of vaccination may be necessary but insufficient for protection. The immune system in general appears to have a relatively weak response to the mumps virus, indicated by various measures: antibody production appears to be predominately directed toward non-neutralizing viral proteins, and there may possibly be a low quantity of MuV-specific memory B lymphocytes. The amount of antibodies needed to confer immunity is unknown.[15]

In places where mumps is widespread, diagnosis can be made based on development of parotitis and history of exposure to someone with mumps. In places where mumps is less common, because parotitis has other causes, laboratory diagnosis may be needed to verify mumps infection.[10] A differential diagnosis may be used to compare symptoms to other diseases, including allergic reaction, mastoiditis, measles, and pediatric HIV infection and rubella.[3] MuV can be isolated from saliva, blood, the nasopharynx, salivary ducts,[8] and seminal fluid within one week of the onset of symptoms,[11] as well as from cell cultures.[10] In meningitis cases, MuV can be isolated from CSF.[16] In CNS cases, a lumbar puncture may be used to rule out other potential causes,[14] which shows normal opening pressure,[12] more than ten leukocytes per cubic millimeter, elevated lymphocyte count in CSF, polymorphonuclear leukocytes up to 25% of the time, often a mildly elevated protein level, and a slightly reduced CSF glucose to blood glucose ratio up to 30% of the time.[16]

Mumps-specific IgM antibodies in serum or oral fluid specimens can be used to identify mumps. IgM quantities peak up to eight days after the onset of symptoms,[10] and IgM can be measured by enzyme-linked immunosorbent assays (ELISA) 7–10 days after the onset of symptoms. Sensitivity to IgM testing is variable, ranging from as low as 24–51%[11] to 75% in the first week and 100% thereafter.[12] Throughout infection, IgM titres increase four-fold between the acute phase and recovery.[11] False negatives can occur in people previously infected or vaccinated, in which case a rise of serum IgG may be more useful for diagnosis. False positives can occur after infection of parainfluenza viruses 1 and 3 and Newcastle disease virus as well as recently after mumps vaccination.[8][18]

Antibody titers can also be measured with complement fixation tests, hemagglutination assays, and neutralization tests.[16] In vaccinated people, antibody-based diagnosis can be difficult since IgM oftentimes cannot be detected in acute phase serum samples. In these instances, it is easier to identify MuV RNA from oral fluid, a throat swab, or urine.[10] In meningitis cases, MuV-specific IgM can be found in CSF in half of cases, and IgG in a 30–90%, sometimes lasting for more than a year with increased white blood cell count. These findings are not associated with increased risk of long-term complications.[12][18] Most parotitis cases have elevated white blood cell count in CSF.[16]

Real-time reverse transcription polymerase chain reaction (rRT-PCR) can be used to detect MuV RNA from the first day symptoms appear, declining over the next 8–10 days.[10] rRT-PCR of saliva is typically positive from 2–3 days before parotitis develops to 4–5 days after and has a sensitivity of about 70%.[18] Since MuV replicates in kidneys, viral culture and RNA detection in urine can be used for diagnosis up to two weeks after symptoms begin,[12] though rRT-PCR used to identify the virus in urine has a very low sensitivity compared to virus cultures at below 30%.[18] In meningoencephalitis cases, a nested RT-PCR is able to detect MuV RNA in CSF up to two years after infection.[12]

In sialadenitis cases, imaging shows enlargement of the salivary glands, fat stranding, and thickening of the superficial cervical fascia and platysma muscles, which are situated on the front side of the neck. If parotitis occurs only on one side, then detection of mumps-specific IgM antibodies, IgG titer, or PCR is required for diagnosis.[7] In cases of pancreatitis, there may be elevated levels of lipase or amylase, an enzyme found in saliva and the pancreas.[12][16][27][28]

Mumps orchitis is usually diagnosed by white blood cell count, with normal differential white blood cell counts. A complete blood count can show above or below average white blood cell count and an elevated C-reactive protein level. Urine analysis can exclude bacterial infections. If orchitis is present with normal urine analysis, negative urethral cultures, and negative midstream urine, then that can indicate mumps orchitis. Ultrasounds typically show diffuse hyper-vascularity, increased volume of the testes and epididymis, lower than usual ability to return ultrasound signals, swelling of the epididymis, and formation of hydroceles. Echo color doppler ultrasound is more effective at detecting orchitis than ultrasound alone.[11]

Mumps is preventable with vaccination. Mumps vaccines use live attenuated viruses.[3] Most countries include mumps vaccination in their immunization programs, and the MMR vaccine, which also protects against measles and rubella, is the most commonly used mumps vaccine.[10] Mumps vaccination can also be done on its own[29] and as a part of the MMRV vaccine, which also provides protection against measles, rubella, chickenpox, and shingles. More than 120 countries have adopted mumps vaccination, but coverage remains low in most African, South Asian, and Southeast Asian countries.[26] In countries that have implemented mumps vaccination, significant declines in mumps cases and complications caused by infection such as encephalitis have been observed.[10] Mumps vaccines are typically administered in early childhood, but may also be given in adolescence and adulthood if need be.[8][26][30] Vaccination is expected to be capable of neutralizing wild-type MuVs not included in the vaccine since they do not appear to escape from vaccine-derived immunity.[15]

A variety of virus strains have been used in mumps vaccines, including the Jeryl Lynn (JL), Leningrad-3, Leningrad-3-Zagreb (L-Zagreb), Rubini, and Urabe AM9 strains. Some other less prominent strains exist that are typically confined to individual countries. These include the Hoshino, Miyahara, Torii, and NK M-46 strains that have been produced in Japan and the S-12 strain, which is used by Iran.[2][31] Mild adverse reactions are relatively common, including fever and rash,[8] but aseptic meningitis also occurs at varying rates.[2][31] Other rare adverse reactions include meningoencephalitis, parotitis, deafness from inner ear damage, orchitis, and pancreatitis.[18] Safety and effectiveness vary by vaccine strain:[2][31]

• Rubini is safe but because of its low effectiveness in outbreaks, its use has been abandoned.
• JL is relatively safe and has a relatively high effectiveness. However, the effectiveness is significantly lower in outbreaks. A modified version of JL vaccines is RIT 4385, which is also considered safe.
• Urabe and Leningrad-3 are both at least as effective as JL, but are less safe.
• L-Zagreb, a modified version of Leningrad-3, is considered safe and effective, including in outbreaks.

Mumps protection from the MMR vaccine is higher after two doses than one[32] and is estimated to be between 79% and 95%, lower than the degree of protection against measles and rubella. This, however, has still been sufficient to nearly eliminate mumps in countries that vaccinate against it as well as significantly reduce frequencies of complications among the vaccinated.[15] If at least one dose is received, then hospitalization rates are reduced by an estimated 50% among the infected.[26] Compared to the MMR vaccine, the MMRV vaccine appears to be less effective in terms of providing mumps protection.[33] A difficulty in assessing vaccine effectiveness is that there is no clear correlate of immunity, so it is not possible to predict if a person has acquired immunity from the vaccine.[15]

There is a lack of data on the effectiveness of a third dose of the MMR vaccine. In an outbreak in which a third dose was administered, it was unclear if it had any effect on reducing disease incidence, and it only appeared to boost antibodies in those who previously had little or no antibodies to mumps.[15] Contraindications for mumps vaccines include prior allergic reaction to any ingredients or to neomycin, pregnancy, immunosuppression, a moderate or severe illness, having received a blood product recently, and, for MMRV vaccines specifically, a personal or familial history of seizures.[8] It is also advised that women not become pregnant in the four weeks after MMR vaccination.[30] No effective prophylaxis exists for mumps after one has been exposed to the virus, so vaccination or receiving immunoglobulin after exposure does not prevent progression to illness.[8][11][12]

For people who are infected or suspected to be infected, isolation is important in preventing the spread of the disease.[4][30] This includes abstaining from school, childcare, work, and other settings in which people gather together. In health care settings, it is recommended that health care workers use precautions such as face masks to reduce the likelihood of infection and to abstain from work if they develop mumps. Additional measures taken in health care facilities include reducing wait times for mumps patients, having mumps patients wear masks, and cleaning and disinfecting areas that mumps patients use.[30] The virus can be inactivated by means of formalin, ether, chloroform, heat, or ultraviolet light.[8]

Mumps is usually self-limiting, and no specific antiviral treatments exist for it, so treatment is aimed at alleviating symptoms and preventing complications. Non-medicinal ways to manage the disease include bed rest, using ice or heat packs on the neck and scrotum, consuming more fluids, eating soft food, and gargling with warm salt water.[9][11] Anti-fever medications may be used during the febrile period,[14] excluding aspirin when given to children, which may cause Reye syndrome.[9] Analgesics may also be provided to control pain from mumps inflammatory conditions.[14] For seizures, anticonvulsants may be used. In severe neurological cases, ventilators may be used to support breathing.[12]

Intramuscular mumps immunoglobulin may be of benefit when administered early in some cases, but it has not shown benefit in outbreaks. Although not recommended, intravenous immunoglobulin therapy may reduce the rates of some complications.[11] Antibiotics may be used as a precaution in cases in which bacterial infection cannot be ruled out as well as to prevent secondary bacterial infection.[11][13] Autoimmune-based disorders connected to mumps are treatable with intravenous immunoglobulin.[14]

Various types of treatment for mumps orchitis have been used, but no specific treatment is recommended due to each method's limitations. These measures are primarily based around relieving testicular pain and reducing intratesticular pressure to reduce the likelihood of testicular atrophy.[11][13] Interferon-α2α interferes with viral replication, so it has been postulated to be useful in preventing testicular damage and infertility.[11] Interferon alfa-2b may reduce the duration of symptoms and incidence of complications.[13][14] In cases of hydrocele formation, excess fluid can be removed.[11]

Prognosis for most people who experience mumps is excellent as long-term complications and death are rare. Hospitalization is typically not required.[5] Mumps is usually self-limiting and symptoms resolve spontaneously within two weeks as the immune system clears the virus from the body.[6][11] In high-risk groups such as immunocompromised persons, prognosis is considered to be the same as for other groups.[5] For most people, infection leads to lifelong immunity against future infection. Reinfections appear to be more mild and atypical than the first infection.[11] The overall case-fatality rate of mumps is 1.6–3.8 people per 10,000, and these deaths typically occur in those who develop encephalitis.[6]

Mumps orchitis typically resolves within two weeks. In 20% of cases, the testicles may be tender for a few more weeks. Atrophy, or reduction of size, of the involved testicle occurs in 30–50% of orchitis cases, which may lead to abnormalities in sperm creation and fertility such as low sperm count, absence of sperm in semen, reduced sperm motility, reduced fertility (hypofertility) in 13% of cases, and rarely sterility. Hypofertility can, however, occur in cases without atrophy. Abnormalities in sperm creation can persist for months to years after recovery from the initial infection, the length of which increases as the severity of orchitis increases. Examination of these cases shows decreased testicular volume, tenderness of the testicles, and a feeling of inconsistency when handling the testicles. Infertility is linked to severe cases of orchitis affecting both testes followed by testicular atrophy, which may develop up to one year after the initial infection. Of bilateral orchitis cases, 30–87% experience infertility. There is a weak association between orchitis and later development of epididymitis and testicular tumors.[6][11][13]

Mumps meningitis typically resolves within 3–10 days without long-term complications.[8] In meningoencephalitis cases, higher protein levels in CSF and a lower CSF glucose to blood glucose ratio are associated with longer periods of hospitalization.[17] Approximately 1% of those whose CNS is affected die from mumps.[12][18] Post-infectious encephalitis tends to be relatively mild, whereas post-infectious encephalomyelitis has a case-fatality rate of up to ten percent.[18] Most cases of mumps deafness affect just one ear and are temporary, but permanent hearing loss occurs in 0.005% of infections.[6][14] Myocarditis and pericarditis that occur as a result of mumps may lead to endocardial fibroelastosis, i.e. thickening of the endocardium.[12][14] With extreme rarity, infertility and premature menopause have occurred as a result of mumps oophoritis.[6]

According to Chinese medical literature, mumps was recorded as far back as 640 B.C.[14] The Greek physician Hippocrates documented an outbreak on the island of Thasos in approximately 410 B.C. and provided a fuller description of the disease in the first book of Epidemics in the Corpus Hippocraticum.[6][34] In modern times, the disease was first described scientifically in 1790 by British physician Robert Hamilton in Transactions of the Royal Society of Edinburgh.[35] During the First World War, mumps was one of the most debilitating diseases among soldiers.[36] In 1934, the etiology of the disease, the mumps virus, was discovered by Claude D. Johnson and Ernest William Goodpasture. They found that rhesus macaques exposed to saliva taken from humans in the early stages of the disease developed mumps. Furthermore, they showed that mumps could then be transferred to children via filtered and sterilized, bacteria-less preparations of macerated monkey parotid tissue, showing that it was a viral disease.[6][34]

In 1945, the mumps virus was isolated for the first time. Just a few years later, in 1948, an inactivated vaccine using killed viruses had been invented. This vaccine provided only short-term immunity and was later discontinued and replaced in the 1970s with vaccines that have live but weakened viruses, which are more effective at providing long-term immunity than the inactivated vaccine. The first of these vaccines was Mumpsvax, licensed on 30 March 1967, which used the Jeryl Lynn strain. Maurice Hilleman created this vaccine using the strain taken from his then five-year-old daughter, Jeryl Lynn. Mumpsvax was later recommended for use in 1977, and the Jeryl Lynn strain continues to be used in vaccines today.[25][34]

Hilleman worked to combine the attenuated mumps vaccines with measles and rubella vaccines, creating the MMR-1 vaccine. In 1971, a newer version, MMR-2, was approved for use by the US Food and Drug Administration.[25] In the 1980s, countries started recognizing the benefit of receiving multiple doses, so a two-dose immunization schedule was widely adopted.[25][31] Including MMR-2, five MMR vaccines have been created since the 1960s, the others being Triviraten, Morupar, Priorix, and Trimovax. Since the mid-2000s, two MMRV vaccines have been in use: Priorix-Tetra and ProQuad.[2]

The United States began to vaccinate against mumps in the 1960s, with other countries following suit.[6] From 1977 to 1985, 290 cases per 100,000 people were diagnosed each year worldwide.[11] Although few countries recorded mumps cases after they began vaccination, those that did reported dramatic declines. From 1968 to 1982, cases declined by 97% in the U.S., in Finland cases were reduced to less than one per 100,000 people per year,[26] and a decline from 160 cases per 100,000 to 17 per 100,000 per year in England was observed from 1989 to 1995.[32] By 2001, there had been a 99.9% reduction in the number of cases in the U.S. and similar near-elimination in other vaccinating countries.[6]

In Japan in 1993, concerns over the rates of aseptic meningitis following MMR vaccination with the Urabe strain prompted the removal of MMR vaccines from the national immunization program, resulting in a dramatic increase in the number of cases.[2][6] Japan now provides voluntary mumps vaccination separately from measles and rubella.[29] Starting in the mid-1990s, controversies surrounding the MMR vaccine emerged. One paper connected the MMR vaccine to Crohn's disease in 1995, and another in 1998 connected it to autism spectrum disorders and inflammatory bowel disease. These papers are now considered to be fraudulent and incorrect, and no association between the MMR vaccine and the aforementioned conditions has been identified. Despite this, their publication led to a significant decline in vaccination rates, ultimately causing measles, mumps, and rubella to reemerge in places with lowered vaccination rates.[11][13][34]

Notable outbreaks in the 21st century include more than 300,000 cases in China in 2013[14] and more than 56,000 cases in England and Wales in 2004–2005. In the latter outbreak, most cases were reported in then 15–24 year olds who were attending colleges and universities. This age group was thought to be vulnerable to infection because of the MMR vaccine controversies when they were to be vaccinated and due to MMR vaccine shortages that had also occurred at that time.[11] Similar outbreaks in densely crowded environments have frequently occurred in many other countries, including the U.S., the Netherlands, Sweden, and Belgium.[25]