PEDIATRICS II​ L​ ecturer: Dr Elizabeth go-tan 

S1-05a: viral infections part 1​ Date: 10-06-2020

REQUIREMENTS BEFORE GIVING ANTIVIRALS ​ 📣

● Obtain appropriate diagnostic specimen
OUTLINE ● Clinical condition
● Intercurrent condition or comorbidities (e.g., DM)
I. Principles of Antiviral therapy ● Close monitoring for any adverse effects
a. Requirements Before Giving Antivirals ○ Potency of antiviral drugs: ​50% (remaining
b. Genotype Analysis 50% is ​inhibitory dose​) → “double-sword
c. Use of Antivirals effect” (affects sensitivity testing, unclear
d. MOA of Antivirals therapeutic outcomes)
e. Examples of Antivirals
II. Measles
●
○ 📣
Status of ​cell-mediated immunity ​is important
If patient is immunocompromised, this will
affect the function of the antiviral drug being
a. Etiology
b. Epidemiology administered
c. Transmission ○ CMV patients:
d. Pathology/Pathogenesis ■ Immunocompetent​: ​not needed
e. CM ■ Immunocompromised​: l​ ife-saving
f. Modified Measles infection
g. Labs, Diagnosis, Ddx GENOTYPE ANALYSIS ​ 📣
h. Complications ● Helps identify ​mutations in the molecular level
i. Treatment associated with ​antiviral resistance
j. Prognosis ● Understudied
k. Prevention
III. SSPE USE OF ANTIVIRALS ​ 📣
IV. Post Quiz ● Treatment​ of active end-organ disease
● Prophylaxis to prevent viral infection; ​no evidence
References: Nelson’s Pediatrics, 21st Edition, lecture of viral replication or shedding​; seropositive patient
recording, and Powerpoint presentation ● Preemptive therapy​: with ​active viral replication
but ​without symptoms

📖
Legend: ​(Please use these instead of changing fonts)
📣
📣 Reference textbook MOA OF ANTIVIRALS ​

💡 Audio from lecture recording

Nice-to-Know
⭐ TG Notes
●

●
Selective to each virus function because each virus
uses the host cell to replicate
Most possess significant toxicities to host cell
● Analogs of deoxy nucleosides, and subsequently
I. PRINCIPLES OF ANTIVIRAL THERAPY ​ 📣 ●
inhibit viral DNA polymerase
Nucleoside analogs which inhibit viral DNA
● Drugs used to treat viral infections act by ​targeting polymerase
● Sample targeted sites
📣
critical steps in viral replication without altering
host cellular functions ( N.B.: viruses thrive
inside cellular hosts)
○ Viral entry
○ Absorption
● Viruses need ​cellular function​ to ​live​ and r​ eplicate ○ Penetration
○ Viruses only replicate and propagate upon ○ Uncoating (Amantadine, Rimantadine)
entry into host cell or body ○ Transcription or replication (Acyclovir)
○ If maintained outside host cell or body (e.g., on ○ Viral protein synthesis
fomites or environment) → eventually die ○ Viral assembly
● The limitation that has hindered antiviral drug ○ Viral release
development: it ​exerts significant host cellular ○ Deaggregation (Oseltamivir)

●
toxicity
Antiviral drugs licensed for use: for ​herpesviruses​, EXAMPLES OF ANTIVIRALS ​ 📣
resp viruses​, ​hepatitis viruses ● Herpesviruses
○ Acyclovir, Valacyclovir, Penciclovir,
Ganciclovir, Foscarnet, Cidofovir, Trifluridine,
Vodarabine, ​Fomovirsen (for ​CMV retinitis​; via
direct injection to vitreous space)
○ New agents​: Cidofovir CMX001, Letermovir
(AIC246)

7RANS FORMERS 1
 S1-05A: viral infections part 1
● Respiratory Viruses
○ Ribavirin, Amantadine, Rimantadine, ●
PATHOLOGY ​ 📖
Necrosis of the respiratory tract epithelium
Oseltamivir, Zanamivir, Peramivir, Baloxavir
(Baloxavir added to Nelson’s 21st Ed.; >12
years old)
●
● 📣
Lymphocytic infiltrate
Warthin-Finkeldey
pathognomonic
giant cells are

■ Oseltamivir​: for treatment

prophylaxis; ​children >2 years old​: ​12
mg/kg/dose​; ​13 years old​: ​600 mg IV
and
(adult dose)
● Hepatitis Viruses (for Hepatitis B infections)
○ Interferon (IFN-α2b and peginterferon-α2a)
○ Nucleoside or nucleotide analog
○ Lamivudine​: FIRST LINE
○ Adefovir​: ADOLESCENT PATIENTS
PATHOGENESIS ​ 📖
● Prodromal illness - after the primary viremia
ensues and secondary viremia; associated with
epithelial necrosis and giant cell formation in body
tissues
● Cells are killed by cell-to-cell plasma membrane
fusion associated with viral replication that occurs
in many body tissues, includes the CNS

○ Entecavir, Tenofovir, Telbivudine
● Antiviral Immune Globulins
○ Useful ​adjuncts in management of viral
disease
○ Most valuable when administered as
📣
● Viral shedding occurs
● Primary target are alveolar macrophages,
dendritic cells, and lymphocytes
● Receptor used appears to be the signaling
lymphocyte activating molecules or CD150

📖
prophylaxis against infection and disease in

📣
high-risk patients CLINICAL MANIFESTATION ​
○ As therapeutic agents: is less clear ● Serious infection characterized by high fever,
○ All given as IV ​except Palivizumab an enanthem, cough, coryza, conjunctivitis, and a
○ Examples: prominent exanthem
■ Varicella-zoster immune globulin ● Koplik spots are the pathognomonic sign of
(human)​: for ​prophylaxis against VZV in measles appearing 1-4 days prior to the onset of
high-risk children the rash
■ Cytomegalovirus immune globulin for ● Appears as discrete red lesions with bluish white
pregnant​ patients spots in the center on the inner aspects of the

■ Palivizumab​: monoclonal [tablet / capsule]
given to high-risk, ​premature infants; ​has
replaced​ ​RSV immune globulin
■ Hepatitis B immune globulin ​indicated in
infants born to ​hepatitis B surface
antigen-positive mothers
II. MEASLES
●
● 📖
Highly contagious
Vaccines have interrupted the endemic
📣
cheeks at the level of the premolars
● Rash begins on the forehead (hairline), behind
the ears and on the upper neck as a red
maculopapular eruption
● In severe cases, generalized lymphadenopathy
may be present, cervical and occipital lymph
nodes especially prominent
📖
📣
MODIFIED MEASLES INFECTION ​
●
● 📣 In individuals with passively acquired antibody
infants, and recipients of blood products, a

● 📣
transmission in the US
Still a serious threat to children ●
subclinical form of measles may occur
Rash may be indistinct, brief, or rarely even

ETIOLOGY ​📣 ●
absent
Individuals who have received vaccine may have
a rash but few other symptoms
● Single-stranded, lipid-enveloped RNA
● Family Paramyxoviridae, genus Morbillivirus ● Patients with subclinical measles do not shed
● Induction of immunity: hemagglutinin protein and measles virus and do not transmit infection to
fusion protein household contacts

📣 📖
📖
EPIDEMIOLOGY ​ LABORATORY FINDINGS ​
● Measles vaccine has changed the ● Laboratory findings in the acute phase include
epidemiology of measles reduction of the total white blood cell count, with
● Endemic in the Philippines lymphocyte decreased more than neutrophils
● Increase in number of cases due to the decline in ● Absolute neutropenia have been known to occur
parents having their children vaccinated ● In measles not complicated by bacterial infection

TRANSMISSION ​ 📖 the erythrocyte sedimentation rate and C-reactive

protein level are normal
● Large droplets or small droplets aerosols
📖
📣
● Aerosolized virus: reported in airplanes, DIAGNOSIS ​
physicians’ office, and hospital ● In the absence of a recognized measles
outbreak a clinical diagnosis is often
recommended

7RANS FORMERS 2

● Serologic confirmation is done by identification of
immunoglobulins IgM
● If serum specimen is collected less than 72 hours
and is negative for measles antibody a second
specimen must be obtained can also be made by
●
demonstration of a fourfold-rise in the IgG
📣
antibodies, 2 weeks apart
Viral isolation from blood, urine, respiratory
secretions can be cultured
● Molecular detection by polymerase chain reaction
is available
DIFFERENTIAL DIAGNOSIS ​ 📖 ●
● Confused with a number of other exanthematous
immune-mediated illness and infections
● Including the rubella, adenovirus infection,
enterovirus infection, and Ebstein-barr virus
infection, Exanthem subitum and erythema
infectiosum may also be confused with measles
● Mycoplasma pneumoniae and group A 3% of liveborn infants
●
streptococcus may also produce a similar rash
Kawasaki syndrome may also cause many of the
same findings but lack discrete intraoral lesions
such as the koplik spot and a severe prodromal
cough and typically has increased neutrophils and
acute-phase reactants
● Drug eruptions may occasionally be mistaken for
measles
COMPLICATIONS ​ 📖 ●
● Complications are largely attributable to the
pathogenic effects of the virus on the respiratory
tract and immune system and several factors
📣
make the complications more likely
● Patients younger than 5 years of age and
📣
older than 20 years of age are greatly burdened
● In developing countries higher fatality rates
have been seen in crowding
● Severe malnutrition in children can result in
📣
suboptimal immune system
● Hyporetinolemia makes the measles infection
📣
symptomatic
● Pneumonia is the most common cause of
death and may be due to direct viral infection or
as superimposed bacterial infection, can have a
giant cell pneumonia
● S. pneumoniae, H. influenzae, and S. aureus
most common
● Development of bronchiolitis obliterans may
ensue in a final common pathway of severe
measles pneumonia
● Croup, tracheitis, and bronchiolitis whose severity
frequently requires intubation and ventilatory
support until the infection resolves
● Acute otitis media has particularly high incidence
during the epidemic in the 1980s and is the most
common complication of measles
● Diarrhea and vomiting are common symptoms
●
associated with acute measles and diffuse giant
📣
cell formation is found in the epithelium
Appendicitis or abdominal pain may occur due
to the obstruction of the appendiceal lumen
7RANS FORMERS
S1-05A: viral infections part 1
● Febrile seizures occur in <3% of cases, with
Encephalitis following measles being a
long-associated complication and it is a
postinfectious immunologically mediated process
● Clinical onset of Encephalitis: during the
● 📣
exanthems and manifests as seizures
Measles encephalitis in immunocompromised
patients result from direct damage to the brain by
the virus
● Hemorrhagic measles or the black measles
manifests as hemorrhagic skin eruptions
●
Keratitis appearing as multiple punctate epithelial
foci
Thrombocytopenia sometimes occur after
measles
●
● 📣
Myocarditis is a rare complication
Measles during pregnancy is associated with
high rates of maternal morbidity, fetal wastage
and stillbirths with and congenital malformation in
TREATMENT ​ 📖
● Supportive
● Goals of therapy: ​Maintenance of hydration,
oxygenation, and comfort​.
● Antipyretics​ - for comfort and fever control.
● Respiratory tract involvement - ​airway
humidification​ and s ​ upplemental oxygen​.
●
Respiratory failure from croup or pneumonia - may
require ​ventilatory support​.
Oral rehydration - effective in most cases;
however if severe dehydration - ​IV therapy
● Prophylactic antimicrobial therapy - not indicated
● Immunocompromised patients - HIGHLY
LETHAL; ​Ribavirin - active in vitro against
measles virus.
● Vitamin A
○ Vit. A deficiency in children - associated with
increased mortality from a variety of infectious
disease
○ Vitamin A Therapy - indicated for all patients
with measles
○ administered once daily for 2 days at doses of:
■ 200,000 IU - children ​>​12mos
■ 100,000 IU - infants 6-11mos
■ 50,000 IU - infants <6mos
■ If w/ s/sx of Vit. A deficiency, 3rd
age-appropriate dose is recommended 2
through 4 wks after 2nd dose.
PROGNOSIS ​ 📖
● With improvements in healthcare and antimicrobial
therapy, better nutrition, and decreased crowding,
the death:case ratio fell to 1 per 1000 cases.
● Complications in most fatal cases:
○ Pneumonia
○ Encephalitis
○ Immunodeficiency
PREVENTION ​ 📖
● Px shed virus from 7 days after exposure to 4-6
days after onset of rash.
3

○ Exposure of susceptible individuals should be
avoided in this period.
● In hospitals, standard and airborne precautions
should be observed during this period.
● Immunocompromised px with measles will shed
the virus throughout the duration of the illness →
isolation is maintained throughout the disease.
● VACCINE​:
○ Available as a monovalent preparation or
combined with the measles-rubella or
measles-mumps-rubella (MMR) vaccine.
📖
○ MMR is recommended in most.
○ Current recommendation:
■ 1st dose at 12-15mos of age, followed by
2nd dose at 4-6 yrs old.
■ Children who have not received 2 doses by
11-12yrs old → provide 2nd dose
■ Infant received dose before 12mos - give 2
additional doses: at 12-15mos and at 4-6
○ 📣 years old.
When there is an epidemic, Measles
vaccine can be given as early as 6mos old.
■ Not given earlier because seroconversion
is lower because of the persisting maternal
antibody. (Immune system is not yet
developed so no antibody production yet)
○ ⭐ Based on the DOH’s Expanded Program on
Immunization, Measles vaccine
recommended at 9-12 mos of age, followed by
a dose of MMR at 12-15mos of age, and a final
dose at 2-6yrs of age.
○ ADVERSE EVENTS:
■ Fever (6-12 days following vaccination)
■ Rash
■ Transient thrombocytopenia (rarely)
■ Children prone to febrile seizures may
experience an event following vaccination
(risks and benefits should be discussed
with parents)
○ Vaccination protects against ​Subacute
sclerosing panencephalitis and does not
accelerate its course nor trigger the disease in
those already infected with wild measles virus.
○ Passive administered immune globulin -
may inhibit the immune response to live
measles vaccine. Administration should be
delayed for variable amounts of time based on
the dose of immune globin.
○ Live vaccines - should not be administered to
pregnant women or to immunodeficient px.
■ HIV px who are not severely
immunocompromised should
immunized.
● Post Exposure Prophylaxis
○ Susceptible individuals exposed to measles
may be protected from infection by either
vaccine administration or ​immunization with
immune globulin​.
○ Vaccine is effective in prevention or
modification of measles if given within 72hrs of
exposure.
○ Immune globulin can be given up to 6 days
after exposure.
7RANS FORMERS
S1-05A: viral infections part 1
■ Indicated for susceptible household
contacts of measles patients, especially
infants younger than 6 mo. of age,
pregnant women, and
immunocompromised persons.
■ Immunocompetent children: 0.25 mL/kg
intramuscularly
■ Immunocompromised children: 0.5 mL/kg
■ Maximum dose of 15 mL/kg may be given
📖
III. SUBACUTE SCLEROSING PANENCEPHALITIS​
● Chronic complication of measles.
● Delayed onset
○ Harbored intracellularly in the central nervous
system.
○ After 7-10 years of measles infection, the virus
regains virulence.
○ Attacks the CNS cells that offered it protection.
●
●
Outcome is nearly always fatal.
“Slow virus infection” - inflammation and cell death
leads to ​inexorable neurodegenerative process​.
EPIDEMIOLOGY ​ 📖
● Rare disease
● Generally follows the prevalence of measles in a
population.
is
● Age of onset: ​<1yr to <30yrs old - Illness is
primarily one of children and adolescents
● Measles at an early age ​favors development of
SSPE​:
○ 50% of px with SSPE had primary measles
before 2yrs old.
○ 75% had measles before the age of 4.
● Males 2x > females
● Rural cases > Urban cases
● Higher prevalence among Hispanic children.
PATHOGENESIS ​ 📖
● Enigmatic
● Factors:
○ Defective measles virus
○ Interaction with an immature immune system
■ Further supported by the fact that most
SSPE ox were exposed at a young age.
● Virus isolated from the brain tissue of patients is
missing 1 out of 6 structural proteins: ​Matrix or ​M
protein
○ Responsible for assembly, orientation, and
alignment of the virus in preparation for
budding during the virus replication.
be
● Immature virus resides and propagates within
neuronal cells for long periods.
● Intracellular location of the virus sequesters it from
the immune system - ​Humoral Immunity​.
CLINICAL MANIFESTATIONS ​ 📖
● Appears insidiously 7-13 years after primary
measles infection.
● Subtle changes in behavior or school performance
○ Irritability, reduced attention span, temper
outbursts
4

● Stages of SSPE:
1. Initial phase (stage1)
■ Sometimes missed because of the
mildness of the symptoms
■ Absent fever, headache and other signs of
encephalitis
2. 2nd stage
■ Hallmark: ​Massive myoclonus
➢ Coincides with extension of
inflammatory process site deeper into
the structure of the brain - ​Basal
ganglia
■ Involuntary movements and repetitive
myoclonic jerks
➢ Begin in single muscle groups →
massive spasms and jerks → Axial
and appendicular muscles.
3. 3rd stage
■ Involuntary movements disappear
■ Choreoathetosis, immobility, dystonia, and
lead pipe rigidity (d/t destruction of deeper
parts of the Basal ganglia)
■ Sensorium deteriorates - dementia →
stupor → coma
4. 4th stage
■ Loss of critical centers that support
breathing, heart rate, and blood pressure.
■ Death soon ensues.
● Progression is characterized as acute, subacute,
or chronic progressive.
S1-05A: viral infections part 1
● Px with SSPE but no history of measles infection
but with exposure to vaccine → “Wild-type” virus
was found in brain tissue, not vaccine virus →
suggest previous subclinical measles.
VI. POST QUIZ
1. Which type of viral therapy must be used to
prevent viral infection if there is no viral replication?
a. Empiric therapy
b. Preemptive therapy
c. Prophylaxis
d. All of the above
2. This is the most common cause of death in
measles and can be due to direct viral infection or by
superimposed bacterial infection.
a. Diarrhea and vomiting
b. Measles encephalitis
c. Acute otitis media
d. Pneumonia
3. These when found during physical examination of
the patient are pathognomonic for measles.
a. Forchheimer’s spot
b. Koplik spots
c. Maculopapular rash
d. Prominent exanthema

DIAGNOSIS ​ 📖 4. Based on the Expanded Program on Immunization,

at what age is the recommended first dose of the
● Documentation of clinical course and at least one MMR vaccine?
of the following supporting findings: a. 6 months old
1) Measles antibody detected in the CSF. b. 9-12 months old
2) Characteristic electroencephalogram findings. c. 12-15 months old
3) Typical histologic findings in and/or isolation d. 4-6 years old
of virus or viral antigen from brain tissue
obtained by biopsy or postmortem 5. In what stage of ​Subacute sclerosing
examination. panencephalitis do you observe choreoathetosis,
● CSF analysis - normal cells but elevated IgG and immobility, dystonia, and lead pipe rigidity?
IgM antibody titers in dilutions >1:8. a. Initial phase
● EEG b. Stage 2
○ Normal in stage 1 c. Stage 3
○ Myoclonic phase - suppression-burst d. Massive myoclonus
episodes (Not pathognomonic for SSPE) e. Stage 4
● Brain biopsy - not routine anymore.

MANAGEMENT ​ 📖 Answers: c,d,b,d,b,c

● Primarily supportive, similar to care for px with
**********End of Transcription**********
neurodegenerative disease.
● Isoprinosine w/ or w/o interferon - significant
benefit
● Carbamazepine - significant benefit; control
myoclonic jerks in early stages
● Virtually all px eventually succumb to SSPE - most
die within 1-3 years of onset or loss of autonomic
control mechanisms.

PREVENTION ​ 📖
● Dependent on the prevention of primary measles
infection → VACCINATION.

7RANS FORMERS 5