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INFECTIOUS DISEASE

BACTERIOLOGY IMMUNOLOGY MYCOLOGY PARASITOLOGY VIROLOGY

VIDEO LECTURE

 

VIROLOGY CHAPTER FOURTEEN  

MEASLES (RUBEOLA) AND MUMPS VIRUSES  

Dr. Margaret Hunt

 

En Español

 

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Logo image © Jeffrey Nelson, Rush University, Chicago, Illinois  and The MicrobeLibrary

READING:
Murray et al., Microbiology
 5th Ed., Chapters 56, 59, 63 (pp. 645-648)

Revised October 2008

TEACHING OBJECTIVES

Brief review of structure and properties of measles and mumps viruses. Discussion of viral pathogenesis and disease, epidemiology, prevention and treatment.

 

INTRODUCTION

Infections with measles, mumps and rubella viruses are confined to man and occur worldwide. They are all spread primarily via the aerosol route. Each of these viruses exists as a single serotype. MMR  (mumps, measles, rubella) vaccine contains live, attenuated forms of all three of these viruses.

Measles and mumps viruses belong to the Paramyxovirus Family and are enveloped, non-segmented, negative-sense RNA viruses with helical symmetry (figure 1A).

 

MMR1.jpg (65876 bytes) 
Figure 1A
Paramyxovirus structure 
PARAMYXOVIRUS FAMILY  
TABLE 1

GENUS

MEMBERS

  GLYCOPROTEINS

Paramyxovirus

human parainfluenza virus1 (HPIV 1)
human parainfluenza virus3 (HPIV 3)

HN, F

Rubulavirus

human parainfluenza virus2 (HPIV 2)
human parainfluenza virus4 (HPIV 4)
Mumps virus

HN, F

Morbillivirus

measles

H, F

Pneumovirus

respiratory syncytial virus

G, F


Figure 1B
Reported cases of measles in the United States 1960-96 CDC

MEASLES (RUBEOLA)  

The word measles is derived from the German word for blister.

Before the advent of the current measles vaccine, there were about 500,000 cases of measles in the United States per year; almost everyone got the measles. But since 1963, the number has fallen precipitously (figure 1B) with a low of  only 86 cases in 2001, all of which seem to be imported. In the less developed world, measles still takes its toll with an estimated 30 million illnesses and  770,000 measles-caused deaths in 2000 of which 58% were in Africa.

WEB RESOURCES

Mumps, measles and rubella vaccine
CDC

Measles, Mumps, and Rubella -- Vaccine Use and Strategies for Elimination of Measles, Rubella, and Congenital Rubella Syndrome and Control of Mumps: Recommendations of the Advisory Committee on Immunization Practices (ACIP)
CDC

 

 


PATHOGENESIS AND DISEASE
(figure 2)

Infection is via an aerosol route and the virus is very contagious. It replicates initially in the upper/lower respiratory tract, followed by replication in lymphoid tissues leading to viremia and growth in a variety of epithelial sites. The disease develops 1 - 2 weeks after infection.

Uncomplicated disease is characterized by the following:

  • Fever of 101 degrees Fahrenheit (38.3 C) or above

  • Respiratory tract symptoms: running nose (coryza) and cough

  • Conjunctivitis (table 2)

  • Koplik's spots on mucosal membranes (table 2) - small (1 - 3mm), irregular, bright red spots, with bluish-white speck at center. The patient may get an enormous number and red areas may become confluent (see below). 

  • Maculopapular rash which extends from face to the extremities. This seems to be associated with T-cells targeting infected endothelial cells in small blood vessels (table 2) (see below).
     

The infection is prostrating but recovery is usually rapid. The peak of infectiousness is before the onset of obvious symptoms (Koplik’s spots, rash). Note some virus shedding occurs during the disease phase, so spread of the virus to other individuals can be somewhat reduced by minimizing contact with others.

The cell mediated response is important since patients with agamma-globulinemia recover normally. Measles tends to be more severe in adults and the very young (under 5 years of age) and is less severe in older children and teenagers.

Complications of measles

If a patient has an impaired cell-mediated immune response, there is continued growth of the virus in the lungs leading to giant cell pneumonia (such patients may not have a rash). This is rare, but often fatal. The reason for the giant cells is that, since F protein can function at physiological pH, it can facilitate cell-cell fusion.

Since virus grows in epithelia of the nasopharynx, middle ear and lung, all of these sites may then be susceptible to secondary bacterial infection. Otitis media and bacterial pneumonia are quite common.

The outcome of the disease is affected by the nourishment of the patient and access to medical care. Measles is still a major killer in underdeveloped countries and several studies in areas with severe vitamin A deficiency problems have found that vitamin A treatment of children with measles has resulted in reduction in morbidity and mortality. Pneumonia accounts for 60% of deaths from measles.

One in 1000 cases may get encephalitis a few days after the rash disappears. Most patients (90%) survive encephalitis but there may be complications such as deafness, seizures and mental disorders.


 

measlepath.jpg (92279 bytes)  Figure 2 The pathogenesis of measles. The virus invades the body via blood vessels and reaches surface epithelium first in the respiratory tract where there are only 1-2 layers of epithelial cells then in mucosae (Koplik's spots) and finally in the skin (rash). Adapted from Mims et al. Medical Microbiology, 1993, Mosby
 

SUB-ACUTE SCLEROSING PAN ENCEPHALITIS

Very rarely (7 in 1,000,000 cases) the patient may get subacute sclerosing panencephalitis (SSPE). This develops 1 to 10 years after the initial infection. It is a progressive, usually fatal disease and those who survive are severely impaired mentally and physically. First signs are behavioral, followed by loss of motor control and coordination. There are jerky movements known as myoclonic seizures. As the disease progresses speech and swallowing are affected and vision may be impaired. The course of the disease may be a few weeks although it may also last for years.

Risk factors include acquiring primary measles at an early age (usually under two years). The incidence of SSPE has decreased since vaccination against measles was initiated. SSPE is associated with defective forms of the virus in the brain and so it is difficult to isolate infectious virus from such patients. Certain viral proteins are often not expressed,  the M protein being frequently absent.

 

Figure 3

A
measle-cell3.jpg (127172 bytes)   
B measle-cell2.jpg (142452 bytes) 
Histopathology of measles pneumonia.  Giant cells.  CDC/Dr. Edwin P. Ewing, Jr.  epe1@cdc.gov 

C measle1-ml.jpg (53290 bytes)
D measle2-ml.jpg (41111 bytes) 
Fusion of Measles Virus Infected Cells. Cell fusion occurring 2 hours (C)) and 5 hours (D) after infection of a human cell line. Cell nuclei become pyknotic, and by 5 hours, small syncytia fuse into giant ones which show beginning evidence of vacuolation. These syncytia will eventually die and detach from the cell monolayer, leaving behind a visible plaque.  © Linda E. Fisher
University of Michigan - Dearborn
Dearborn, Michigan and The Microbe Library

 

TABLE 2

CLINICAL ASPECTS OF MEASLES

Site of replication of virus

Symptoms in a well nourished child with good medical care

Symptoms in a malnourished child with poor medical care

Lung

Temporary respiratory illness

Pneumonia (life threatening)

Ear

Otitis media is quite common

Otitis media is experienced more often and is more severe

Oral mucosa

meas5.jpg (19608 bytes)  Koplik's spots   WHO/Immunization Action Coalition.

  Patient who presented with Koplik’s spots on palate due to pre-eruptive measles on day 3 of the illness
CDC/Dr. Heinz F. Eichenwald

Severe ulcerating lesions

Conjunctiva

meas1.jpg (56558 bytes)   Conjunctivitis Eyes of child with measles. CDC/Barbara Rice ber2@cdc.gov 

Severe corneal lesions. There may be secondary bacterial infections of the eyes and blindness may occur

Skin

meas2.jpg (55251 bytes)  Maculopapular rash  Face of boy with measles. Third day of rash.  CDC 
meas4.jpg (70484 bytes) This child shows a classic day-4 rash with measles. CDC/NIP/Barbara Rice
  This child with measles is displaying the characteristic red blotchy pattern on his buttocks during 3rd day of the rash CDC

Possibility of hemorrhagic rashes (black measles)

Intestinal tract

No lesion

Diarrhea which increases malnutrition, halts growth and impairs recovery

Urinary tract

Virus in urine

No further effect

Overall impact

Serious disease in a small proportion of patients

Major cause of infant death (estimates of 1.5 million deaths per year)

Adapted from Mims et al. Medical Microbiology, 1993

 

E measle3-ml.jpg (40179 bytes) 

F Measle4-ml.jpg (63838 bytes) CPE typical of measles virus infection of HeLa cells. The large syncytia, or multinucleated giant cells, result from fusion of cell membranes bearing viral glycoproteins. Also visible are inclusion bodies,  eosinophilic areas of altered staining in the cytoplasm. Cells stained with hematoxylin, a basic dye, and eosin, an acidic dye. © Maria-Lucia Rácz, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil  and The Microbe Library

G Indirect fluorescent antibody serological test for measles virus immunoglobulin G (IgG) antibody. All cells are counterstained with Evans blue which fluoresces orange red. Measles virus induces the fusion of infected cells resulting in a large multinucleated cell (syncytia).
Kristina M. Obom, Patrick J. Cummings, Maria A. DeBernardi, Gary Brooker , Johns Hopkins University
and The Microbe Library
 

 

OTHER CONSEQUENCES OF MEASLES INFECTION

Measles can cause temporary defects in the immune response; for example, tuberculin-positive individuals may temporarily give a negative response. There may be reactivation of herpes or exacerbation of tuberculosis with natural measles, but this does not seem to happen with the vaccine strain.

Measles virus replicates in the cytoplasm, but inclusions containing nucleocapsid protein can also accumulate in the nucleus. It is not known if this has any effect on the host cell, but histologically typically giant cells with cytoplasmic and nuclear inclusion bodies are seen (figure 3). There may also be nucleocapsid protein in the nucleus but the significance of this is unknown.
 

DIAGNOSIS

The clinical picture is the first part of diagnosis; that is exposure plus upper respiratory tract symptoms, Koplik's spots (table 2) and rash (which is usually quite characteristic for physicians familiar with measles). This diagnosis is confirmed by serodiagnosis, RT-PCR or isolation. Serodiagnosis by IgG levels is simpler than isolation but  two samples are needed, one 10 to 21days post rash, and so takes longer. There is now also an IgM test. It is recommended that all suspect cases in the United States be confirmed by laboratory testing
 

EPIDEMIOLOGY

Almost all infected individuals show signs of disease. There is only one serotype of measles and a single natural infection gives life-long protection. The main route of infection is via inhalation. Measles virus is highly contagious and the period of maximum contagiousness is the  2 to 3 day period before onset of the rash.
 

PREVENTION

There is an attenuated virus vaccine that is grown in chicken embryo fibroblast culture. It is currently recommended to give a first dose of  the vaccine at 12 to 15 months. If given earlier, the recipient does not mount a strong immune response to the vaccine. A second dose is administered at 4 to 6 years of age, before the recipient enters kindergarten or first grade. This reduces the proportion of persons who remain susceptible due to primary vaccine failure. The vaccine gives long term immunity and the vaccine virus does not spread from the vaccinee.


Immune serum globulin can be used for at risk patients during an outbreak; that is those less than 1 year old or with impaired cellular immunity.

Measles vaccine can cause problems (e.g. fatal giant cell pneumonia) in those with severely compromised cell-mediated immunity. No inactivated vaccine is available, due to past problems in which subsequent infection with naturally acquired measles was sometimes associated with an atypical, severe form of measles.
 

TREATMENT

No antiviral therapy available for primary disease. Complications should be treated appropriately.

 

 

 

MUMPS  

The name comes from the British word "to mump", that is grimace or grin. This results from the appearance of the patient as a result of parotid gland swelling although other agents can also cause parotitis. Clinically, mumps is usually defined as acute unilateral or bilateral parotid gland swelling that lasts for more than two days with no other apparent cause.

Mumps is caused by a paramyxovirus. There is one serotype of the virus and in an affected patient it can be found in most body fluids including cerebro-spinal fluid, saliva, urine and blood. The virus can be grown in cell cultures and in eggs.

WEB RESOURCES

CDC (requires Acrobat)
Association of State and Territorial Directors of Health Promotion and Public Health Education



PATHOGENESIS AND DISEASE

Mumps is very contagious and is probably usually acquired from respiratory secretions and saliva via aerosols or fomites. The virus is secreted in urine and so urine is a possible source of infection. It is found equally in males and females. Before 1967, most mumps patients were under 10 years of age but since the advent of the attenuated vaccine, the remaining cases occur in older people with almost half being 15 years of age or older.

mumppath.jpg (152968 bytes)  Figure 4 Pathogenesis of mumps  Adapted from Mims et al Medical Microbiology 1993. Mosby, 1993  

 

TABLE 3

CLINICAL ASPECTS OF MUMPS

Site of replication of virus Symptoms Notes
Salivary glands mumps.jpg (33840 bytes) Inflammation, parotitis, in a child with mumps. CDC/NIP/Barbara Rice 
Virus is shed in saliva from 3 days before to 6 days after symptoms
Salivary gland symptoms are often absent  or may be unilateral
Meninges

Brain

Meningitis

Encephalitis

Up to 7 days after parotitis Meningitis is found in about 10% of cases.
Encephalitis  is less common. Usually there is complete recovery; nerve deafness is a rare complication
Kidney Virus in urine No clinical consequences
Testis, ovary epididymo-orchitis; rigid tunica albuginea around testis makes orchitis more painful, more damaging in male Common in adults (20% in adult males), often unilateral; not a significant cause of sterility
Pancreas Pancreatitis Rare complication (There is a possible role in juvenile diabetes)
Mammary gland Virus detectable in milk; mastitis in 10% post-pubertal females  
Thyroid Thyroiditis Rare
Myocardium Myocarditis Rare
Joints Arthritis Rare
Adapted from Mims et al. Medical Microbiology, Mosby, 1993

 

Complications of mumps CDC

Virus infects upper/lower respiratory tract leading to local replication. The virus spreads to lymphoid tissue which, in turn, leads to viremia. The virus thus spreads to a variety of sites, including salivary, other glands and other body sites (including the meninges).

The average time to full manifestation of disease is 2 - 3 weeks but there may be fever, anorexia, malaise, myalgia during prodromal phase. Many mumps infections (up to 20%) result in no symptoms at all and about half of infections result only in the primary respiratory symptoms.

The symptoms of mumps (figure 4 and table 3) include:

  • Fever

  • Parotitis. Pain from parotitis swelling persists for 7 - 10 days. This is the most common feature of mumps and is seen in about 40% of patients. It may be unilateral or bilateral depending on which salivary glands are infected by the virus.

  • Meningitis.  Aseptic meningitis is usually mild. About three times as many males than females get this . In about half of patients the meningitis is asymptomatic. In symptomatic meningitis, which occurs in about 15% of patients, there is stiff neck and headache which usually resolves in  up to 10 days with no further problems. Mumps-related meningitis is more severe in adults. In very rare cases mumps can result in encephalitis.

  • Deafness.  Mumps was a leading cause of acquired deafness before the advent of mumps vaccines but nevertheless hearing loss is rare (one in every 20,000 mumps cases). It is usually unilateral. The patient may not, in fact, have overt mumps. Deafness may improve with time but is usually permanent.

  • Orchitis (testicular inflammation). This is especially severe in adolescent and adult males and occurs in about 50% of cases. Sometimes, it occurs along with parotitis. The painful swelling diminishes after about seven days but tenderness can last for weeks. In 70% of cases, orchitis is unilateral and results in some degree of testicular atrophy. Damage tends to be patchy and rarely causes infertility.

  • Pancreatitis. This is an infrequent side effect of mumps. There is transient hyperglycemia that resolves. However, there is very little evidence from controlled studies that mumps plays any role in diabetes mellitus although outbreaks of diabetes have been reported after mumps outbreaks.

  • Myocarditis.   Myocarditis is observed from electrocardiograms in a minority of patients but is usually otherwise asymptomatic.

  • Rare complications. These include nephritis, arthralgia (joint pain) and arthritis (joint inflammation)

Mumps is more severe in adults and it seems that cell-mediated immunity is important in recovery. On average, one person dies per year in the United States now that most people are vaccinated.

 

Mumps epidemiology CDC

 

Cases of mumps in the United States 1968-2001 CDC

Cases of mumps in the United States 1980-2001 CDC

Age distribution of mumps cases in the United States 1980-2000 CDC

MMR Vaccine -adverse reactions CDC

DIAGNOSIS

Approximately 30% of infections are sub-clinical. Parotitis is suggestive as it occurs in 30 - 40% of infections but there are other causes of parotitis. The disease is confirmed by isolating the virus, RT-PCR or by serology. Hemagglutination inhibition, radial hemolysis and complement fixation assays are rather insensitive. Better is enzyme immunoassay which detects IgM or IgG. The level of IgM rise during the prodromal phase and peak at about seven days. Normally, when testing for IgG a specimen is taken during the acute disease and then during the convalescent phase. The latter should show a higher antibody titer than the former.

Complement fixing antibody to the S (soluble) antigen (nucleocapsid protein) is seen for a few months after infection and is used to diagnose a recent infection. However, one needs to be careful as there is some cross reaction with other human parainfluenza virus nucleocapsid proteins. CF antibody to the viral envelope (V antigen) persists.
 

EPIDEMIOLOGY

Man is the only known natural host and the disease is found worldwide. There is no 'carrier state'. Since many (about 30%) infections are sub-clinical, spread is usually via these persons. Mumps is contagious from about 7days before the infection becomes clinically apparent  and continues until about 9 days afterwards.
 

PREVENTION

Until the development of the highly effective attenuated vaccine, mumps was a very common disease.; for example, there were 212,000 reported case in the United States in 1964. Occurrence dropped to about 3,000 cases by the mid 1980's which is about one case per 100,000 population. In 2001, there were 231 United States cases. In 1986/87, there was a jump in mumps in people in the 10 - 19 years age group (12,848 cases) which was attributable to the fact that these people were born before routine immunization. Vaccine failure may also have contributed.

The vaccine virus, which is made in chick embryo fibroblasts, does not spread to contacts and gives long-term immunity (greater than 95% efficacy with immunity lasting more than 25 years). It is usually given as MMR vaccine that contains three live, attenuated viruses: mumps, measles and rubella. It is also available as a single virus preparation or combined with the rubella vaccine. Normally, two doses separated by four weeks are recommended for children more than one year of age.

Vaccine is contraindicated in immunosuppressed patients and in pregnant women, although there is no evidence that the vaccine can damage the fetus. Also people who have severe allergic reactions after a previous mumps vaccination should not receive the MMR vaccine.

The virus is rapidly inactivated by organic solvents such as chloroform and ether (as would be expected of enveloped viruses) and also by UV light and formaldehyde.
 

TREATMENT

There is no  specific treatment for mumps.
 

MMR VACCINE AND AUTISM

There have been reports in the media linking autism to administration of the MMR vaccine. This was based on a small study (based on 12 children)  and larger studies have failed to establish such a link.

Among the findings in such studies reported by CDC (link) are:

  • There is no indication that measles vaccine contributes to the development of long-term neurological damage, including educational and behavioral deficits

  • There is no difference in the prevalence of autism among children born before the introduction of the MMR vaccine in Sweden and those born after the vaccine was introduced

  • In a 1999 study of 498 children with autism in the UK, it was found that the age at which they were diagnosed was the same regardless of whether they received the MMR vaccine before or after 18 months of age or whether they were never vaccinated. The first signs or diagnoses of autism were not more likely to occur within time periods following MMR vaccination than during other time periods. Also, there was no sudden increase in cases of autism after the introduction of MMR vaccine in the UK. Such a jump would have been expected if MMR vaccine was causing a substantial increase in autism.

     

WEB RESOURCES

Facts about autism

CDC

Facts about MMR vaccines and autism
CDC

See also:
The MMR-autism scare
- our story so far


 

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