General Pediatrics 4 (Licari) 18.10.

19
Sbob: Araki
Topics covered:
Rev: Paredes
• Varicella-Zoster
• Measles
• Rubella
• Mumps
• MMR(V) vaccinations

EXANTHEMATOUS VIRAL INFECTIONS

This lecture will discuss about viral infections, in particular exanthematous viral infections – Varicella-Zoster,
Measles, Rubella and Mumps – all of which are infections that can be prevented by a vaccination.

Varicella-Zoster General Features

Varicella-Zoster virus (VZV) may cause two distinct clinical diseases:
• Varicella, more commonly called chickenpox, is the primary infection and results from exposure of a
person susceptible to the virus. Chickenpox is a very common disease, it is ubiquitous and extremely
contagious. However, for the most part, it is a benign illness characterized by a generalized
exanthematous rash. It occurs seasonally and in epidemics.
• Recurrence of infection results in the more localized phenomenon known as herpes zoster, often
referred to as shingles, a common infection among the elderly, i.e. it is not so common in children.

VZV features and life cycle

VZV is an α-herpesvirus. It is neurotropic with similarities to herpes simplex virus. It has a double-stranded,
linear DNA that encodes approximately 75 proteins and has a lipid-containing envelope with glycoprotein spikes
(its main virulence factors).

The virus is believed to replicate first at the site of entry in the nasopharynx, and then spread to regional lymph
nodes.
A primary viremia occurs 4 to 6 days after infection. Then the infection disseminates to other organs, such as
the liver, spleen, and sensory ganglia. The latter is a place where it can live quietly and eventually reactivate to
cause shingles.
Further replication occurs in the viscera, followed by a secondary viremia, with viral infection of the skin
(localized exanthematous rash).

The virus can be cultured from mononuclear cells of an infected person from 5 days before to 1 or 2 days after
the appearance of the rash.

Seasonality
In temperate areas, varicella has a distinct seasonal fluctuation, with the highest incidence occurring in winter
and early spring. Incidence is highest between March and May and lowest between September and November.
Less seasonality is reported in tropical areas.
Herpes zoster has no seasonal variation and it can occur throughout the year.

Varicella (Chickenpox)
Chickenpox is highly contagious, with secondary household attack rates of >90% in susceptible individuals.
Transmission occurs in susceptible hosts:
• Via contact with aerosolized droplets from nasopharyngeal secretions of an infected individual, or
• By direct cutaneous contact with vesicle fluid from skin lesions (such as the conjunctiva). In case a child
has the rash, he/she is contagious to other children as long as vesicles are present.

1
The incubation period for varicella infection is 14 to 16 days (~ 2 weeks), although this interval can range from
10 to 21 days. The period of infectivity is generally considered to last from 48 hours prior to the onset of rash
until skin lesions have fully crusted. Thus, the child is not
contagious anymore when skin lesions are fully crusted.

Epidemiology: Varicella in Italy

The incidence has been halved, from 180 cases per 100 000
patients in 2003 to 99 per 100 000 patients in 2013 (fig. 1).
These cases are usually due to people who refuse to receive the
vaccination and those who are not protected from the
vaccination.1
Figure 1: Incidence of varicella in Italy
Natural History
(2003-2013)
Varicella is a benign, self-limited illness in immunocompetent
children (most cases).
In and immunosuppressed or immunocompromised individuals of any age the disease can be very severe,
usually life-threatening.

Clinical Manifestations (Uncomplicated Varicella)

The clinical manifestations of varicella in healthy children generally develop within 15 days after the exposure.
They typically include a prodrome period in which the child may have:

• fever
• malaise
• pharyngitis
• loss of appetite.

The prodrome period is then followed by the development of a generalized vesicular rash (fig. 2), usually within
24 hours, which is characterized by:

• Pruritus
• Successive crops over several days:
“starry sky”2 appearance due to the
concomitant lesions
• 200-500 lesions in 2 to 4 successive
crops in a healthy child

The natural history of the rash is the

following: macules → papules →
vesicles/blisters → pustules → crusted
papules3. Usually all these lesions are Figure 2: varicella rash
highly pruritic.

Prevention
Varicella is preventable by vaccination. In Italy, there is a mandatory vaccination against varicella (chickenpox).

1
From European Varicella Surveillance Report: As in previous years, the highest number of cases was seen in unvaccinated
children below the age of ten. However, when looking at the impact of disease, our findings showed that the highest
rates of hospitalizations or complications were in the very young (less than one year of age) and in the oldest (more than
15 years of age).
2
Because the blisters on the skin are in different stages of development at any given time, their distribution is sometimes
described as a "starry sky". They are concomitant due to the viremia caused by the infection. Successive crops appear
over several days, with lesions present in several stages of development. For example, macular lesions may be observed
in the same area of skin as mature vesicles.
3
Revisor note: the rash of chickenpox develops in crops with raised red spots arriving first, progressing to blisters that
burst, creating open sores, before crusting over.
2
Approximately 20% of children who receive one dose of varicella vaccine may develop a mild varicella infection,
known as "breakthrough disease", if exposed to VZV. It is a mild disease with less fever and a lower number of
lesions. It has currently not been established why these cases occur, but the hypothesis is that it may occur due
to an incomplete or a failure of the immune response of the child.

A report on the clinical and epidemiological characteristics of varicella in populations with increasing vaccine
coverage between 1997 and 2005 identified the following trends:
• In vaccinated children 1 to 14 years of age, varicella was more often mild and modified than in
unvaccinated children (e.g., less fever and a lower number of lesions)
• The accompanying rash was significantly more likely to be atypical in nature among vaccinated children
(e.g., maculopapular)
• Complications were less likely to be reported among vaccinated children than unvaccinated children
• Neurologic complications (e.g., encephalitis) continue to be rare

Complications4
Prior to the introduction of varicella vaccine in 1995, healthy children and adolescents accounted for 80% of
the estimated 9,300 annual varicella-related hospitalizations in the United States (CDC Pinkbook data). Since
1996, hospitalizations and deaths from varicella have declined more than 70% and 88%, respectively.

Complications of varicella are the following:

• Bacterial infection of skin lesions: varicella complications commonly involve the skin – there might be a
superinfection of the pustules and/or macules and/or blisters from Staphylococcus or Streptococcus
(Group A Streptococci may cause invasive disease). Skin complications may include impetigo5.
• Pneumonia: another common complication is pneumonia, either viral or bacterial. It is more common
to occur in children younger than 1 year of age due to the lower ability of their immune system to
respond to pathogens (i.e., immaturity of their immune response).
• Central nervous system manifestations:
- CNS complications range from aseptic meningitis to encephalitis.
- Involvement of the cerebellum, with resulting cerebellar ataxia, is the most common central
nervous system manifestation, which usually presents after the resolution of the skin lesions.
Cerebellar ataxia generally has a good outcome.
- Encephalitis is an infrequent complication of varicella (estimated 1.8 per 10,000 cases) and may
lead to seizures and coma.
- Diffuse cerebral involvement is more common in adults than in children.
• Reye syndrome: Reye syndrome occurs almost exclusively in children who take NSAIDS (FANS is Italian)
during the acute illness. This is the reason why it is not recommended for parents to give NSAIDS to
children in varicella. In order to decrease the child’s fever, it is recommended to use always
paracetamol6.
• Hospitalization: 2-3 per 1,000 cases (children)
• Death: 1 per 60,000 cases

Groups at Increased Risk of Complications

There are several groups of patients that are at a higher risk for developing complications of varicella:
• Persons older than 15 years
• Infants younger than 1 year

4
If a student is asked during the exam what are the most common complications of varicella infection, then he/she needs
to say that the most common ones involve the skin and the respiratory system. However, it is also important to remember
the CNS involvement, in particular cerebellar ataxia.
5
In case a child has impetigo around the eye, it is important to check whether the child has keratitis. Indeed, varicella is
one of the causes of keratitis and so it should be checked to avoid development of ulcers and loss of vision. In hospitalized
patients the infection might be caused by Staphylococci with antibiotic resistance. In this case one might use IV
vancomycin.
6
It is very important to remember that in case a child has varicella and fever, always use paracetamol and not ibuprofen,
otherwise there is a risk for Reye syndrome. This is valid also for EBV infection (from a student question). Moreover, in
general ibuprofen is not indicated when a child is dehydrated, as in cases such as gastroenteritis.
3
 • Immunocompromised persons: immunocompromised persons have a high risk of disseminated disease
(up to 40%). These persons may have multiple organ system involvement, and the disease may become
fulminant and hemorrhagic. The most frequent complications in immunocompromised persons are
pneumonia and encephalitis. Children with HIV infection are at increased risk for morbidity from
varicella and herpes zoster.
• Newborns of women with rash onset within 5 days before delivery to 2 days after delivery: the onset
of maternal varicella from 5 days before to 2 days after delivery may result in overwhelming infection
of the neonate and a fatality rate as high as 30%. This severe disease is believed to result from fetal
exposure to varicella virus without the benefit of passive maternal antibody. In contrast, infants born
to mothers with onset of maternal varicella 5 days or more prior to delivery usually have a benign
course, presumably due to passive transfer of maternal antibody across the placenta.

Diagnosis
The diagnosis of varicella (chickenpox) is usually clinical. However, in case there is a doubt, it is possible to do:
• Isolation of varicella virus from clinical specimen (skin swab, conjunctival swab)
• Rapid varicella virus identification using PCR (preferred, if available) or DFA (direct fluorescent antibody)
from the specimen
• Significant rise in varicella IgG by any standard serologic assay is seen only after 2-3 weeks of infection.

Serology is no so useful when there is an acute infection of a child and when the doctor needs to decide whether
the child may benefit from an antiviral therapy or not. Therefore, in case of a clinical doubt, it is preferable to
perform a skin swab / conjunctival swab / collection of a nasopharyngeal secretion and perform a PCR on the
specimen.

Examples of clinical doubts that require PCR7: if there is an immunocompromised child, or a child taking
corticosteroids from another reason (e.g., nephrotic syndrome), and the patient develops some macules and
pustules that are suspicious for chickenpox, then it is important to perform a PCR that can give definitive results
within few hours, which allows the doctor to start therapy within 24 hours in order to maintain the efficacy of
the treatment and to avoid complications. Another example for the use of PCR – if, for example, a doctor
suspects that one of the children in the onco-hematological ward might have a varicella infection, then it is
needed to perform PCR to have a final diagnosis as quick as possible and treat the child accordingly, and to
prevent the spreading of the infection to the other vulnerable children in the ward.

Immunity
Recovery from primary varicella infection usually results in lifetime immunity.
In otherwise healthy persons, a second occurrence of chickenpox is not common, but it can happen, particularly
in immunocompromised persons. Also shingles can occur after a primary infection. As with other viral diseases,
re-exposure to natural (wild) varicella may lead to reinfection that boosts antibody titers without causing clinical
illness or detectable viremia.

Treatment
• Supportive care (the most important one):
- Antihistamines are helpful for the symptomatic treatment of pruritus.
8
In children it is recommended to use 2nd generation antihistamines. The most commonly used
antihistamines used in the ward are cetirizine, desloratadine and levocetirizine. These drugs are
usually well-tolerated, they do not expose the child to the risk of long QT syndrome, which can be
seen in case of another antihistamine drug in between the 1st and 2nd generation of antihistamines.
Some pediatricians use 1st generation antihistamines (e.g., chlorphenamine) however, they are
generally not recommended because they pass the BBB, interacting with the histamine receptors
in the CNS, causing sedation of the child.
- Fingernails should be closely cropped to avoid significant excoriation and secondary bacterial
infection

7
Answer to a student’s question
8
Answer to a student’s question: “can you give an example of an antihistamine used in the clinical practice?”
4
 - Acetaminophen (paracetamol) should be used to treat fever, particularly in children (discourage
NSAIDs because of the uncertain association with streptococcal superinfection; salicylates should
be avoided since aspirin has been associated with the onset of Reye syndrome in the setting of a
viral infection)
• Antiviral Agents:
- The only antiviral that can be used in the clinical practice is acyclovir (and its analogues, such as
valacyclovir, famciclovir). These drugs are effective for the treatment of primary varicella in both
healthy and immunocompromised hosts.
Oral antiviral therapy is indicated for immunocompetent children and adolescents who are at
increased risk of developing complications from varicella (e.g., pneumonia, skin infection), since
antiviral therapy may theoretically reduce the risk of complications in these patients and is
generally well-tolerated. These individuals include9:
1. Unvaccinated adolescents (i.e., children ≥13 years of age), since these patients are
more likely to have severe disease compared with younger children
2. Secondary cases in household contacts, since these cases are usually more severe
than primary cases. For example, if the child has varicella and the mother or another
caregiver contracts the infection, usually the latter will have an infection that is
more severe than that of the child, and this is the reason why it is recommended to
use antivirals in these cases
3. Patients with a history of chronic cutaneous or pulmonary disorders, since
secondary bacterial infections may have severe consequences
4. Children taking intermittent oral or inhaled steroid therapy (the risk is greatest
when corticosteroids are administered during the incubation period). For example,
a child with nephrotic syndrome that takes steroids should be given antiviral
therapy for his/her varicella infection
5. Individuals taking chronic salicylates FANS10 (at risk of developing Reye syndrome).

Acyclovir
• Immunocompetent children and adolescents: oral treatment should be started within 24 hours after
the rash develops, if possible. For patients ≥2 years with normal renal function, 20 mg/kg per dose
(maximal dose 800 mg) four times daily for five days is given.
• Immunocompromised hosts / complications: recommended for those with an underlying malignancy
or HIV infection, as well as those who are receiving high-dose corticosteroid therapy for more than 14
days (e.g. ≥20 mg or ≥2 mg/kg body weight [for children who weigh <10 kg] of prednisone or equivalent)
or other immunosuppressive therapies. Children ≥1 year of age and adolescents are given acyclovir
1,500 mg/m2 per day in three divided doses, or 30 mg/kg/day in three divided doses (IV), for 10 days.

Prevention of spreading
• Exclusion of children from the community until all lesions have dried and crusted, usually 6 days after
onset of rash in immunocompetent people; may be longer in immunocompromised people
• Management of contacts: varicella vaccine should be administered by 3-5 days after exposure, and
varicella-zoster IG should be administered up to 96 hours after exposure when indicated11. IG and
acyclovir are suitable alternatives for health care personnel with contraindications to vaccination, such
as immunosuppression or pregnancy.
• Vaccination.

9
cf. "Groups at increased risk of complications"
10
E.g., a Kawasaki disease patient with coronary complications
11
If case of an immunodepressed child that had a contact with the virus, it is important to administer immediately the
vaccine and a specific IG for varicella. For example, the professor had a patient with Burton’s disease (X-linked
agammaglobulinemia) and one of the child’s friends had chickenpox. The patient was, of course, infected as well (he
developed some macules) and was hospitalized and given immediately the IG for varicella.
5
Herpes Zoster (Shingles)
Shingles is not so common in children however, it may happen in immunodepressed children, or can rarely
happen in healthy children.

Epidemiology
Reactivation of varicella zoster virus (VZV) is associated with:
• Aging
• Immunosuppression
• Intrauterine exposure
• Varicella at younger than 18 months of age

500,000 to 1 million episodes occur annually in the United States.

Lifetime risk of zoster is estimated to be 32%. 50% of persons living
until age 85 years will develop zoster.
Figure 3: herpes zoster

Clinical Manifestations
The virus is latent in the dorsal ganglia, it is then reactivated in some subjects (failed immune control), causing
shingles, and reaches to the skin. The disease usually causes a vesicular erythematous rash that is localized in a
specific dermatomal area (fig. 3) in contrast to the wide-spread, diffuse sky starry appearance of the varicella
rash.

Complications
Postherpetic neuralgia (PHN), or pain in the area of the occurrence that persists after the lesions have
resolved12, is a distressing complication of zoster. There is currently no adequate therapy available.
PHN may last a year or longer after the episode of zoster. Ocular nerve and other organ involvement with zoster
can occur, often with severe sequelae. This can be seen also in immunocompromised children.

The virus is latent in the dorsal ganglia, it is then reactivated by going through the ventral ramus to reach the
skin, causing zoster. The disease in the skin usually causes a vesicular erythematous rash that is localized in a
specific dermatomal area. Complications can occur in both varicella and zoster (fig. 413).

Figure 4: varicella complications and zoster complications

12
Remember that in case of a localized pain with no apparent skin lesion, it is important to think about PHN.
13
All items belonging to "Acute complications" in Zoster table were mentioned by the professor.
6
Measles
Measles is a highly contagious viral illness, which was first described in the 7th century.
Before a vaccine was available, infection with measles virus was nearly universal during childhood, and more
than 90% of persons were immune by age 15 years.
Measles is still a common and often fatal disease in developing countries and still endemic in some. The World
Health Organization estimates there were 145,700 deaths globally from measles in 201314.

The virus is a paramyxovirus that contains RNA. Hemagglutinin is an important surface antigen for the virus.
There is one antigenic type for measles virus. It is rapidly inactivated by heat, sunlight, acidic pH, ether, and
trypsin.

As in the case of VZV, there are still some cases of measles that are generally due to persons that refuse to the
vaccination.

Percentage distribution and incidence in Italy (per

1,000,000 inhabitants) of cases reported by age
group (from 1 January 2013 to 31 August 2019):
around 30% of patients (n=484) reported at least one
complication15.
The complication (fig. 5) that was the most frequent
was diarrhea (201 cases), followed by hepatitis /
increase in transaminases (186 cases), and
keratoconjunctivitis (133 cases). Around 5% of cases
developed a pneumonia.
Figure 5: complications of measles
Measles Surveillance
In Italy, measles is a disease subject to mandatory Class II notification (relevant disease because of its high
frequency and/or subject to control interventions). In other words, it is mandatory to report a case of measles.
Furthermore, integrated measles-rubella surveillance was introduced in 2013, as an evolution of the special
measles surveillance system started in 2007 (circular 20 February 2013 - establishment of an integrated
surveillance system for measles and rubella), which has permission to strengthen the surveillance of this
disease, in terms of timeliness of the notification and completeness of the collected data.
Given that measles and rubella affect the same age groups, have similar symptoms and can be difficult to
distinguish on a clinical basis, integrated surveillance also provides that cases of suspected measles that are
negative for confirmatory tests are tested for rubella and that vice versa, cases of suspected rubella that are
negative for results of confirmatory tests are tested for measles.

Pathogenesis
The virus is transmitted via the respiratory tract. Replication starts in the nasopharynx and regional lymph
nodes. Primary viremia occurs 2-3 days after exposure, and secondary viremia occurs 5-7 days after exposure,
with spread to tissues.
There is a temporal pattern: peak in late winter-spring16.
Communicability: 4 days before to 4 days after the rash onset.

14
More information about epidemiology at vaccinarsi.org and epicentro.iss.it
15
Very important percentage. The real problem is not measles infection per se, but the complications because they may
be life-threatening.
16
cf. like Varicella
7
Clinical Manifestations
Incubation period is 10-12 days, with a prodrome period of 2-4 days, characterized by Koplik’s spots17 (fig. 6)
which are little rash spots on the mucous membrane, together with a stepwise increase in fever, cough, coryza18
and conjunctivitis.
The rash (fig. 7) starts 2-4 days after the prodrome period, 14 days after exposure. The rash persists for 5-6 days
and begins on the face and upper neck, and then spreads down19. The rash is maculopapular and becomes
confluent. It eventually fades in the same order of appearance (first the face and upper neck, then the rest of
the body).

Measles viral infection can cause a variety of clinical syndromes,

including:
• Classic measles infection in immunocompetent patients
• Modified measles infection in patients with pre-existing but
incompletely protective anti-measles antibody
• Atypical measles infection in patients immunized with the killed
virus vaccine
• Neurologic syndromes following measles infection, including acute
disseminated encephalomyelitis "ADEM" (an immune-mediated Figure 6: Koplik’s spots
complication that usually occurs after 2 weeks from infection) and
subacute sclerosing panencephalitis (even years after the infection). These two are post-infective
complications, occurring weeks (ADEM) or years (panencephalitis) after the acute event.
• Severe measles infection
• Complications of measles, including secondary
infection, giant cell pneumonia, and measles
inclusion body encephalitis.

Complications
Around 30% of patients having measles will have at least
one of the complications of measles.
Complications of measles are most common among
children younger than 5 years of age and adults 20 years
of age and older.
The complications of measles are the following:
• Diarrhea (8%) Figure 7: measles rash
• Otitis media (7%)
• Pneumonia (6%)
• Encephalitis (0.1%)
• Seizures (0.6-0.7%)
• Death (0.2%)

Neurological Complications
Neurological complications associated with measles include:
• Encephalitis: It is an acute complication. encephalitis usually appears within a few days of the rash,
typically day 5 (range 1 to 14 days); symptoms may include fever, headache, vomiting, stiff neck,
meningeal irritation, drowsiness, convulsions, seizures and sometimes coma. Acute measles

17
Further information about Koplik’s spots: Koplik’s spots (or Koplik’s sign) are a prodromic viral enanthem of measles
manifesting 2-3 days before the measles rash itself. They are characterized as clustered, white lesions on the buccal
mucosa and are pathognomonic for measles. They are described as appearing like “grains of salt on a reddish
background”, and often fade as the maculopapular rash develops. Source: Wikipedia.
18
Coryza is an inflammation of the mucous membranes lining the nasal cavity, usually causing a running nose, nasal
congestion and loss of smell. Source: Wikipedia.
19
This kind of spreading pattern is typical of measles.
8
 encephalitis may also occur in the absence of rash20. Up to 1 per 1,000 measles cases have encephalitis,
which is fatal in 15% of cases.

• Acute disseminated encephalomyelitis (ADEM): ADEM is a demyelinating disease that occurs in about
1 per 1,000 measles cases. ADEM present during the recovery phase of measles, typically within 2 weeks
of the exanthem. ADEM is an immune-mediated post-infective encephalomyelitis which may be due to
measles, but also due to other causes, such as HHV-6, HHV-7, varicella, etc. In children, there is a very
important headache, they do not have the typical symptoms of meningitis, but usually complain about
a severe headache. In case a head CT is performed, lesions are not seen, but it is possible to see lesions
in ADEM with a contrast-MRI. Moreover, ADEM usually has a peculiar aspect in the EEG that can help
with the diagnosis. In case ADEM is diagnosed, doctors also search for autoantibodies in CSF and an
analysis for detection of the damage of the BBB (done in cases of Multiple Sclerosis and Guillain–Barré
syndrome as well).

• Subacute sclerosing panencephalitis (SSPE): SSPE is a rare degenerative central nervous system disease
believed to be due to persistent measles virus infection of the brain. The onset occurs an average of 7
years after measles (range 1 month to 27 years) and occurs in 5-10 cases per million reported measles
cases. The onset is insidious, with progressive deterioration of behavior and intellect, followed by ataxia
(awkwardness), myoclonic seizures, and eventually death. SSPE has been extremely rare since the early
1980s. SSPE is a late complication, which can occur years after the infection. It may also be a very rare
and late complication of the vaccination itself.

Complications During Pregnancy

Measles and rubella may cause fetal death in case the infection occurs during pregnancy. Measles illness during
pregnancy results in a higher risk of premature labor, spontaneous abortion, and low birth weight infants. Birth
defects (with no definable pattern of malformation) have been reported rarely, without confirmation that
measles was the cause.

Hemorrhagic Measles
A rare, but severe, fatal complication is hemorrhagic measles, which is characterized by high fever, seizures,
delirium, respiratory distress, and hemorrhage into the skin and mucous membranes.
Remember to check for coagulation factors because some children with immunodepression may develop
hemorrhagic measles. When a doctor sees petechiae or other signs of hemorrhage in a skin of a child having
measles, it is very serious because the child has a high risk of death from hemorrhagic complications due to
measles.

Measles in the Immunocompromised Patient

Measles in an immunocompromised person can be severe with a prolonged course. It is reported almost
exclusively in persons with T-cell deficiencies (certain leukemias, lymphomas, and acquired immunodeficiency
syndrome [AIDS]). It may occur without the typical rash, and a patient may shed the virus for several weeks
after the acute illness.

Measles in Developing Countries

Measles in developing countries has resulted in high attack rates among children younger than 12 months of
age. Measles is more severe in malnourished children, particularly those with vitamin A deficiency.
Complications include diarrhea, dehydration, stomatitis, inability to feed, and bacterial infections (skin and
elsewhere). The case-fatality rate may be as high as 25%.
Measles is also a leading cause of blindness in African children.

Diagnosis
• Isolation of measles virus from urine, nasopharynx, blood, throat
• Significant rise in measles IgG by any standard serologic assay (e.g., EIA, HI)

20
In case of an acute encephalitis, it is important to perform lumbar puncture and PCR to search for bacteria, viruses and
measles as well, even in the absence of skin manifestations in vaccinated children.
9
 • Positive serologic test for measles IgM antibody

As with VZV, measles can be diagnosed through a laboratory diagnosis by taking a clinical specimen and
performing a PCR. In contrast to VZV, measles is not so simple (as varicella) to diagnose clinically. Moreover,
measles rash and rubella rash are very similar to each other, and it is important to differentiate between the
two by performing PCR. Another reason for which it is important to perform a laboratory diagnosis in the case
of measles is due to the need to isolate the patient in the hospital in case it is indeed measles.

Treatment
The treatment of measles is supportive; there is no specific antiviral therapy approved for treatment of measles.
Supportive therapy includes:
• Antipyretics
• Fluids
• Treatment of bacterial superinfections, such as bacterial pneumonia and otitis media21
• Treatment of other complications, such as seizures and respiratory failure, may also be necessary.

Rubella

Rubella, from Latin, means “little red”. Rubella is also known as “German measles” because it is similar to the
rash seen in measles and was first detected in Germany in the 18th century (and thought to be a variant of
measles). It was first described as a distinct clinical entity in German literature. Congenital rubella syndrome
(CRS) was described by Gregg in 1941. The virus was first isolated in 1962 by Parkman and Weller.

Rubella virus is a togavirus, an RNA virus, and there is one antigenic type of the rubella virus. The virus is
inactivated by lipid solvents, trypsin, formalin, ultraviolet light, low pH, heat, and amantadine.

Cases of post-natal rubella has decreased after the

introduction of the first vaccine (fig. 8), which was
introduced in the United Stated in 1971. In Italy, it
was introduced in 1985.

Between January to August 2019, 16 rubella cases

were reported in Italy. These cases were found to be
in adults (median age of 27 years), not in children.
The reason, as with the other viruses, is lack of
vaccination of these patients. Figure 8: number of rubella and CRS cases in USA (1966-2011)

Pathogenesis
The virus is transmitted via the respiratory route. As with VZV and measles, it replicates in the nasopharynx and
then reaches the regional lymph nodes. Viremia occurs 5 to 7 days after exposure with spread throughout the
body. There can also be a transplacental infection of the fetus during viremia, which may cause congenital
rubella syndrome (CRS).

Postnatal Rubella Surveillance

In Italy, rubella is a disease subject to mandatory Class II notification (relevant disease because of its high
frequency and/or subject to control interventions). In other words, it is mandatory to report a case of rubella.
Furthermore, integrated measles-rubella surveillance was introduced in 2013, as an evolution of the special
measles surveillance system started in 2007 (circular 20 February 2013 - establishment of an integrated
surveillance system for measles and rubella), which has permission to strengthen the surveillance of this
disease, in terms of timeliness of the notification and completeness of the collected data.
Given that measles and rubella affect the same age groups, have similar symptoms and can be difficult to
distinguish on a clinical basis, integrated surveillance also provides that cases of suspected measles that are

21
A child having otitis media due to measles should be given antibiotics immediately.
10
negative for confirmatory tests are tested for rubella and that vice versa, cases of suspected rubella that are
negative for results of confirmatory tests are tested for measles.

Clinical Manifestations
The incubation period is around 14 days (range 12-23 days).
A prodrome period is rare in children (in contrast to varicella and measles). In the
case of adults, the prodrome period is characterized by a low-grade fever.
A maculopapular rash (fig. 9) appears 2 weeks after exposure. The rash is not so
confluent as measles, but it is very similar to it. The rash usually appears first in the
trunk (in contrast to measles that starts in the face and upper neck).
Lymphadenopathy occurs before the rash and lasts for several weeks. The
lymphadenopathy is typical in children, specifically in the occipital region.
Therefore, in case one sees a child with a rash and an occipital lymphadenopathy,
he/she needs to think about rubella.

Complications Figure 9: rubella rash

Complications are rare, but can be any of the following:
• Arthralgia or arthritis (up to 70% in case of an adult female). Arthralgia or arthritis are rare in children.
• Encephalitis (1/6,000 cases).
• Hemorraghic manifestations (e.g., thrombocytopenic purpura) occurs in 1/3000 cases.
• Orchitis22, neuritis, progressive panencephalitis are rare.

Congenital Rubella Syndrome (CRS)

In the case of CRS, the infection may
affect all organs.
It may lead to fetal death or premature
delivery.
The severity of damage to the fetus
depends on the gestational age – up to
85% of infants are affected if infected
during the first trimester.

Clinical Manifestations (fig. 10)

• Deafness
• Eye defects
• Cardiac defects
• Microcephaly
• Mental retardation
• Bone alterations Figure 10: clinical manifestations of CRS
• Liver and spleen damage
Rubella can damage many organs. In particular, one needs to remember patent ductus arteriosus (PDA) as a
congenital heart defect, microcephaly and mental retardation, cataract, deafness, hepatosplenomegaly, and
low birth weight.

Diagnosis
• Isolation of rubella virus from clinical specimen (e.g., nasopharynx, urine)
• Serologic tests available vary among laboratories
• Positive serologic test for rubella IgM antibody
• Significant rise in rubella IgG by any standard serologic assay (e.g., enzyme immunoassay).

Treatment
Treatment consists of supportive care. No specific therapy for rubella infection is available.

22
Remember that in case of rubella infection in a male adolescent, it is important to check for the presence of orchitis.
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Prevention
• Vaccination: the goal of rubella vaccination is to prevent congenitally-acquired rubella. Immunization
of all young children and of all adults are recommended who did not get vaccinated in the past to reduce
the rates of CRS.
• Control measures: control measures for postnatal rubella include droplet precautions and exclusion
from school or childcare for 7 days after the onset of the rash.

Mumps
Mumps is an acute viral illness, characterized by parotitis and orchitis. The disease was first described by
Hippocrates in the 5th century BCE, whereas the viral etiology was described by Johnson and Goodpasture in
1934. Mumps was a frequent cause of outbreaks among military personnel in the pre-vaccine era.

The mumps virus is a paramyxovirus, an RNA virus, which is rapidly inactivated by chemical agents, heat, and
ultraviolet light.

Transmission of the virus occurs via the respiratory route – there is an airborne transmission of the virus by
direct contact with respiratory droplets or saliva.
Replication starts in the nasopharynx and continues in the regional lymph nodes. Viremia occurs 12 to 25 days
after exposure with spread to tissues. Multiple tissues are infected during the viremia.

Humans are the reservoir for the virus, and asymptomatic infections may transmit it.
There is a temporal pattern – peak in late winter and spring.
Communicability: several days before and after the onset of parotitis.
Fig. 11 shows the number of cases of mumps in Italy from 1996 to
2009. As can be seen, the number of cases has significantly
decreased thanks to the introduction of the mandatory vaccine.

Clinical Manifestations
The incubation period is 12 to 25 days. There are non-specific
prodromic symptoms that include myalgia, malaise, headache, and
low-grade fever. Parotitis (fig. 12) is seen in 94% of cases.
Asymptomatic infection is also a possibility. 15-27% of infections
were asymptomatic in the pre-vaccine era.

Complications
• Orchitis: a not so uncommon complication in males,
Figure 11: mumps cases in Italy (1996-2009)
occurring in up to 66% in post-pubertal males in the pre-
vaccine era, whereas only 3-10% occur in the post-vaccine era.
• Pancreatitis: occurred in 3.5% in the pre-vaccine era.
• Unilateral Deafness: occurred in 1 out of 20,000 in the
pre-vaccine era
• Death: occurred in 2 out of 10,000 from 1966-1971.
No deaths in recent U.S. outbreaks have been
reported.

CNS Complications
• Symptomatic aseptic meningitis: in the pre-vaccine
era, mumps accounted for approximately 10% of
cases of symptomatic aseptic meningitis
(inflammatory cells in cerebrospinal fluid resulting in
headache or stiff neck). Men were afflicted three Figure 12: parotitis in mumps
times as often as women. Aseptic meningitis resolves
without sequelae in 3 to 10 days
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 • Mumps encephalitis: accounted for 36% of all reported encephalitis cases in the United States in 1967.
The incidence of mumps encephalitis is reported to range from 1 in 6,000 mumps cases (0.02%) to 1 in
300 mumps cases (0.3%).

In the post-vaccine era, among all persons infected with mumps, reported rates of meningitis, encephalitis,
pancreatitis, and deafness have all been less than 1%.
Permanent sequelae such as deafness, paralysis, seizures, cranial nerve palsies, and hydrocephalus occurred
very rarely, even in the pre-vaccine era.

Laboratory Diagnosis
In case a child arrives to the hospital with parotitis and the doctor suspects of mumps, the next step to do is to
measure amylase and lipase in the blood, in order to detect a potential damage of the pancreas. The total
amylase and the pancreatic amylase are measured, and by comparing these values it is possible to understand
the amount of salivary amylase. Usually, there is a high amount of salivary amylase in the blood (due to the
parotitis) and a normal level of pancreatic amylase. However, in the case of a complication in the form of
pancreatitis, pancreatic amylase will be increased as well.

Diagnostic tools:
• rRT-PCR (commonly done)
• Culture (slow)
• Serology (IgM)

Diagnosis of mumps is usually clinical however, it is possible to perform laboratory diagnosis with PCR, culture
and serology. The problem with these methods is that the results take time to arrive.

Serology is the simplest method for confirming mumps virus infection and enzyme immunoassay (EIA) is the
most commonly used test. EIA is widely available and is more sensitive than other serologic tests. It is available
for both IgM and IgG.
In unvaccinated persons, IgM antibodies usually become detectable during the first 5 days of illness, reach a
peak about a week after onset, and remain elevated for several weeks or months. However, as with measles
and rubella, mumps IgM may be transient or missing in persons who have had any doses of mumps-containing
vaccine.

Differential diagnosis of a child presenting with parotitis can include the following: infectious mononucleosis
(though it is usually a bilateral swelling), a tumor (though not so common in children), and mainly sialoadenitis
– inflammation of the salivary glands that may occur due to a bacterial infection involving the parotid gland. In
the case of sialoadenitis from a bacterial infection, there is high fever, high levels of CRP and neutrophils,
whereas in the case of mumps there is no increase in the neutrophils count and there is a low-grade fever.
Another examination that can be done to differentiate a bacterial infection and mumps is ultrasound – there is
a typical pattern in the case of mumps, which is different from the pattern seen in bacterial infection. Moreover,
in the case of a bacterial infection, one can see a dilation and inflammation of the parotid duct in the buccal
mucosa. Another symptom of a bacterial infection is sialorrhea.

Treatment
Treatment is done by supportive care with the use of analgesic agents and/or antipyretic agents, such as
acetaminophen/paracetamol. In the case of mumps, ibuprofen is usually prescribed because of the very
inflamed parotid gland.

Prevention
Prevention is done with a live attenuated vaccine. The effectiveness is >90% (range is 66%-95%) in the case of
2 doses. The duration of immunity is lifelong.
Schedule: at least 1 dose should be administered in the form of measles, mumps and rubella (MMR) vaccine,
or measles, mumps rubella and varicella (MMRV) vaccine.

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MMR(V) vaccination
There is a tetravalent vaccine (mumps, measles, rubella and varicella, called MMRV) and a "trivalent (MMR)
plus varicella" vaccine. In the latter case, varicella vaccine is given separately.
It is recommended to have the first dose of the vaccine at 13 months of age, and the second dose in 5-6 years
of age and in all those subjects who were never vaccinated.

The MMRV Vaccine

The tetravalent vaccine has been available since 1995, consisting of a live attenuated23 virus. The vaccination
efficacy has been estimated to be 95%, in the prevention of moderate or severe forms; of 70-85% in the
prevention of mild forms. The vaccine is safe and well-tolerated, and the protection appears to be long lasting.
The vaccination must be carried out with two doses.

To expand our knowledge, the professor explained that the vaccine is considered efficacious if the coverage in
the general population is more than 90%. For example, for measles, rubella and mumps there is an almost
complete coverage in Italy. In contrast, there is not such a high coverage in Italy for varicella (it is below 90%).
This is because the tetravalent vaccine and the varicella vaccine were not mandatory in Italy until 2 years ago
when a new law was approved. Trentino-Alto Adige has a regional autonomy and has less coverage compared
to the rest of Italy.

People at high risk of severe varicella (some newborns, immunocompromised subjects) must receive
immunoglobulins intramuscularly (passive immunoprophylaxis) if exposed to people with chickenpox. These
should be administered as soon as possible and up to 96 hours after exposure.

Vaccination of susceptible children within 72 hours and no more than 120 hours after exposure may prevent
and significantly modify the disease. Oral acyclovir is not recommended as a prophylaxis.

Contraindications and Precautions to Vaccination

• Severe allergic reaction to vaccine component24 or following a prior dose
• Immunosuppression
• Pregnancy
• Moderate or severe acute illness
• Recent blood product (varicella, MMRV)
• Personal or family (i.e., sibling or parent) history of seizures of any etiology (MMRV only)
• If a child has fever from some reason, the vaccination should be postponed because the temporary
immunodepression from another infection may cause complication after the vaccination.

In case a child has a severe allergic reaction to a vaccine, it is needed to perform an allergic evaluation of the
child before doing another vaccination (e.g., prick test), in order to detect the specific component of the vaccine
that caused the allergic reaction.

For example, some children have an egg allergy, and some vaccines are cultivated in cultures that contain egg
components. Vaccines that contain egg components are the MMRV vaccine (but not the MMR vaccine), the
influenza vaccine, and the yellow fever vaccine. These children will get vaccinated in the ward because the risk
of adverse reactions is higher. In the professor's experience so far, none of those children had adverse reactions.

Adverse Reactions
• Local reactions (pain, erythema in site of injection): 19% (children); 24% (adolescents and adults)
• Generalized rash25 (3%); may be maculopapular rather than vesicular; average of 5 lesions
• Systemic reactions are not common.

23
This vaccine is therefore not recommended for immunocompromised children.
24
Some vaccines contain gelatin (stabilizer) or neomycin and if there is a child that is allergic to one of these components,
the vaccination should be done in the hospital settings and not in the ambulatory service.
25
Mainly occurs due to the live attenuated measles virus, which may cause mild form of measles, "morbillino" in Italian.
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26
In case the child has a local pain and some redness in the area of vaccination, it is not considered as an allergic
reaction, i.e. it is just an adverse effect of the vaccination. In contrast, an allergic reaction is an IgE immune-
mediated reaction causing urticaria, angioedema, anaphylaxis, or anaphylactic shock.
In case the child had an allergic reaction to a vaccine, it is needed to perform a skin prick test with the vaccine,
or an intradermal test with the vaccine. If the test is positive – no recommendation for the vaccine, but if the
test is negative – vaccination should be done in the hospital. Usually allergies are to some components of the
vaccine (e.g., gelatin and neomycin).
After the vaccination floppy infant syndrome, an exaggerated reaction to pain (not an allergic reaction), can be
observed.

Zoster Following Vaccination

Most cases occur in children. Not all cases are caused by the vaccine virus.
Risk from vaccine virus is less than from wild-type virus.
Zoster following vaccination is usually a mild illness without complications as postherpetic neuralgia.

26
An answer to a student’s question: “should I send my child to the hospital in case he/she has pain and redness in the
vaccine area?”
15