Viral Exanthems

and
Other Cutaneous
Viral Infections
 Learning objectives
At the end of the session, the students will be able to
understand:

▰ General properties and classification of herpes viruses.

▰ Pathogenesis, clinical manifestations, complications, lab

diagnosis, treatment and prevention of herpes simplex
virus, VZV, Parvo virus, HPV, Pox virus, measles, rubella,
hand-foot-and-mouthEssentials
disease. of Medical Microbiology
3
INTRODUCTION
▰ Exanthem is an eruption or rash on the skin – may be
associated with fever or other systemic symptoms.

▰ Majority of exanthems - infectious etiology – most

commonly by viruses.

▰ Exanthems - also due to drug reactions.

4
Essentials of Medical Microbiology
Viral exanthems and other
cutaneous viral infections
Viruses Viral exanthems/other skin lesions
Herpesviruses
Herpes simplex virus Vesicular lesions

Varicella-zoster virus Chickenpox and zoster

Epstein-Barr virus Following ampicillin therapy

Human herpesvirus-6 Roseola infantum (exanthem subitum or

sixth disease)
Other DNA viruses
Poxviruses Smallpox, Molluscum contagiosum

Parvovirus Erythema infectiosum (fifth disease)

Papular-purpuric gloves and socks syndrome
Human papilloma virus (HPV) Warts: Common warts, flat warts, plantar
warts, anogenital warts (condyloma
5
acuminatum)
Essentials of Medical Microbiology
Viral exanthems and other
cutaneous viral infections (Cont..)
Viruses Viral exanthems/other skin lesions
RNA viruses
Measles virus Rashes, Koplik’s spots

Rubella virus Rashes

Coxsackie viruses Hand-foot-mouth disease

Agents of viral hemorrhagic fever
Dengue, Ebola and others

6
Essentials of Medical Microbiology
HERPESVIRUS
INFECTIONS
Essentials of Medical Microbiology
7
GENERAL PROPERTIES
▰ Herpesviridae comprises of a group of viruses that possess
a unique property of:

 Establishing latent or persistent infections in their hosts

 Undergo periodic reactivation.

8
Essentials of Medical Microbiology
Morphology
▰ Large (150–200 nm size),
spherical in shape -
icosahedral symmetry.

▰ Nucleocapsid: linear
dsDNA, surrounded by a
capsid comprising of
capsomeres 9
Essentials of Medical Microbiology
Morphology (Cont..)

▰ Envelope: Nucleocapsid - surrounded by a lipid envelope

into which glycoprotein spikes are inserted - help in viral
entry.

▰ Tegument: Between the capsid and envelope –

amorphous, asymmetric structure - tegument

10
Essentials of Medical Microbiology
Morphology (Cont..)

▰ Replication of herpes viruses - in the host cell nucleus -

similar to replication of other dsDNA virus.

▰ Only difference - linear dsDNA of herpesviruses becomes

circular inside the host cell - replicates by rolling circle
mechanism.

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Essentials of Medical Microbiology
Classification of human
herpesviruses (Family-
Herpesviridae)
Subfamily Duration of Site of Genus Species
(“- replication latency
herpesvirina and Official name Common name
e”) cytopatholog
y

Alpha Short (12–18 Neurons Simplexvirus Human Herpes simplex

hours) herpesvirus 1 virus type 1
Cytolytic Human Herpes simplex
herpesvirus 2 virus type 2
Varicelloviru Human Varicella-zoster
s herpesvirus 3 virus
Beta Long (>24 Glands, Cytomegalov Human Cytomegaloviru
hours) kidneys irus herpesvirus 5 s
Cytomegalic 12
Essentials of Medical Microbiology
Long (>24 Lymphoid Roseolovirus Human Human
Classification of human
herpesviruses (Family-
Herpesviridae) (Cont..)
Subfamily Duration of Site of Genus Species
(“- replication latency
Official name Common name
herpesvirina and
e”) cytopatholog
y

Gamma Variable Lymphoid Lymphocrypto Human Epstein-Barr virus

Lymphoprolifer tissues (B virus herpesvirus 4

ative cells) Rhadinovirus Human Kaposi’s

herpesvirus 8 sarcoma- 13
Essentials of Medical Microbiology
HERPES SIMPLEX
VIRUS
INFECTIONS
14
Essentials of Medical Microbiology
HERPES SIMPLEX VIRUS
INFECTIONS
▰ Belong to α-subfamily of Herpes viridae.

▰ Extremely widespread and exhibit a broad host range.

▰ However, the human herpes viruses infect exclusively man.

▰ Replicate fast (12-18 hours cycle), spread fast and are

cytolytic.

▰ Spectrum of diseases - skin, mucosa and various organs.

15
▰ Undergo latency in nerve cells; reactivate later causing
Essentials of Medical Microbiology
Differences between HSV-1
and HSV-2
Properties Herpes simplex Herpes simplex
virus 1 virus 2
Common modes of Direct contact with Sexual mode or
transmission mucosa or abraded vertical mode
skin
Latency in Trigeminal ganglia Sacral ganglia

Age affected Young children Young adults

Common  Oral-facial  Genital lesions

manifestations mucosal lesions  Skin lesions—
 Encephalitis below the waist
and meningitis  Neonatal
 Ocular lesions herpes
 Skin lesions—
above the waist
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Essentials of Medical Microbiology
Differences between HSV-1
and HSV-2 (Cont..)
Properties Herpes simplex Herpes simplex
virus 1 virus 2
Neurovirulence Less More

Drug resistance Less More

Antigenic homology HSV-1 and 2 show >80% antigenic

homology
DNA homology HSV-1 and 2 show >50% homology in the
genomic sequence

17
Essentials of Medical Microbiology
Pathogenesis - Primary
Infection
▰ Transmission - through abraded skin or mucosa, but more
commonly by:

 HSV-1: Oropharyngeal contact with infected saliva or

direct skin contact

 HSV-2: Sexual contact or rarely vertical mode (from

mother to fetus).
18
Essentials of Medical Microbiology
Pathogenesis - Primary
Infection (Cont..)
▰ Site of infection: HSV replicates at the local site of
infection and produces lesions commonly -

 HSV-1 lesions are confined to areas above the waist

(most common site-around mouth)

 HSV-2 produces lesions below the waist (most common

site-genital area)
19
Essentials of Medical Microbiology
Pathogenesis - Primary
Infection (Cont..)
▰ Spread via nerve- Virus then invades the local nerve
endings - transported by retrograde axonal flow to the
dorsal root ganglia - replicates further -undergoes latency.

▰ Primary HSV infections are usually mild (most are

asymptomatic).

▰ In immunocompromised hosts–Viremia occurs that leads to

widespread organ involvement and systemic
Essentials of Medical Microbiology
20
Pathogenesis - Latent
Infection
▰ HSV has a tendency to undergo latency in neurons

 HSV-1 - trigeminal ganglia

 HSV-2 - sacral ganglia

▰ HSV does not replicate in latent stage

21
Essentials of Medical Microbiology
Pathogenesis - Recurrent
Infections
▰ Reactivation of the latent virus: Following fever, axonal
injury, physical or emotional stress, and exposure to
ultraviolet light.

▰ Via the axonal spread, virus goes back to the peripheral

site and further replicates in skin or mucosa and produces
secondary lesions.
22
Essentials of Medical Microbiology
Pathogenesis - Recurrent
Infections (Cont..)
▰ Recurrent infections are less extensive and less severe
because of presence of pre-existing host immunity that
limits the local viral replication.

▰ Many recurrences are asymptomatic; but viruses are shed

in the secretions.

23
Essentials of Medical Microbiology
Clinical Manifestations
▰ Both HSV-1 and 2 - isolated from nearly all mucocutaneous
sites and viscera.

▰ In general - oral-facial infections - common with HSV-1.

▰ HSV-2 - causes genital infections and intrauterine infections.

▰ Incubation period - 1 to 26 days (median, 6–8 days).

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Essentials of Medical Microbiology
Oral-facial Mucosal Lesions
▰ Most common affected site - buccal mucosa

▰ Most frequent primary lesions - gingivostomatitis and

pharyngitis

▰ Most frequent recurrent lesion is herpes labialis (painful

vesicles near lips)

▰ Other lesions - ulcerative stomatitis and tonsillitis.

25
▰ Many cases are asymptomatic but can predispose to
Essentials of Medical Microbiology
Oral-facial Mucosal Lesions
(Cont..)

A. Vesicular lesions on lips and tongue due to

HSV-1 infection; B. Periocular vesicular lesions due to
HSV-1 infection.
26
Essentials of Medical Microbiology
Cutaneous Lesions
▰ Herpetic whitlow

▰ Febrile blisters

▰ Herpes gladiatorum

▰ Eczema herpeticum

▰ Erythema multiforme

27
Essentials of Medical Microbiology
Other Infective Syndromes
of HSV
▰ CNS infections

▰ Ocular manifestations

▰ Genital lesions

▰ Visceral and disseminated herpes

▰ Neonatal herpes

28
Essentials of Medical Microbiology
Epidemiology
▰ Herpes simplex viruses - worldwide in distribution.

▰ No animal reservoirs or vectors - involved with the human

viruses.

▰ HSV-1 and 2 differ in their epidemiological pattern

29
Essentials of Medical Microbiology
Epidemiological Pattern of
HSV-1
▰ Transmission: Contact with infected secretions (saliva).

▰ Primary infection - early in life .

▰ Age: Children are commonly affected

▰ Adults: Antibodies develop in 70–90% of adults - fail to

eliminate the virus from the body.

▰ Most adults - carriers throughout the life.

30
Essentials of Medical Microbiology
Epidemiological Pattern of
HSV-2
▰ Transmitted by sexual or vertical routes

▰ Primary infection - in adult life.

▰ Antibodies develop - in 20% of people.

▰ HSV-2 tends to recur more often than HSV-1, irrespective of

the site of infection.

31
Essentials of Medical Microbiology
Laboratory diagnosis of HSV
infections
▰ Cytopathology (Tzanck
preparation) by Wright’s or
Giemsa stain-detects
inclusion bodies (Lipschultz
A

body) and formation of Tzanck smear of a tissue scraping

showing
multinucleated giant cells
multinucleated giant cell (Tzanck c
in the center (arrow showing)
32
Essentials of Medical Microbiology
Laboratory diagnosis of HSV
infections (Cont..)
▰ Virus isolation by:

 Conventional cell lines—used to demonstrate diffuse

rounding and ballooning of cell lines

 Shell vial culture—detects antigens in cell line by IF.

33
Essentials of Medical Microbiology
Laboratory diagnosis of HSV
infections (Cont..)
▰ Viral antigen detection in specimen by direct IF

▰ HSV DNA detection by PCR and real-time PCR (detecting

glycoprotein B and UL 30 genes).

34
Essentials of Medical Microbiology
Laboratory diagnosis of HSV
infections (Cont..)
▰ Antibody detection by
ELISA or other formats-
detecting antibodies to
glycoprotein G.
B

Indirect IF for HSV1/2 antibody detec

35
Essentials of Medical Microbiology
Treatment of HSV infections
▰ Acyclovir - drug of choice - acts by inhibiting viral DNA
polymerase.

▰ For mucocutaneous infections: Acyclovir, famciclovir

and valacyclovir

▰ Ocular infection: Topical idoxuridine, trifluorothymidine,

topical vidarabine, and cidofovir .
36
▰ For HSV encephalitis and
Essentials neonatal
of Medical Microbiology herpes, acyclovir -
Treatment of HSV infections
(Cont..)

▰ Acyclovir resistance - reported among few HSV strains -

which have altered substrate specificity for phosphorylating
acyclovir.

▰ Resistance is more common - HSV-2 and among

immunocompromised patients.

▰ Foscarnet - drug of choice to treat such cases.

37
Essentials of Medical Microbiology
Prevention
▰ Use of condom to prevent genital herpes

▰ Neonatal herpes - prevented by prior administration of

acyclovir to mothers during third trimester of pregnancy or
delivery by elective caesarean section.

▰ No vaccine - currently licensed. Several vaccine trials -

going on - recombinant HSV-2 glycoprotein vaccine.
38
Essentials of Medical Microbiology
VARICELLA-ZOSTER
VIRUS INFECTIONS
39
Essentials of Medical Microbiology
VARICELLA-ZOSTER VIRUS
INFECTIONS
▰ Produces vesicular eruptions (rashes)on the skin and
mucous membranes in the form of two clinical entities-

 Chicken pox

 Zoster or Shingles

40
Essentials of Medical Microbiology
Chickenpox - Pathogenesis
▰ VZV enters through - upper respiratory mucosa or the
conjunctiva by aerosol (most common) and contact
transmission.

▰ From the local site, it spills over to blood - carried through

the infected mononuclear cells to target sites such as:
 Skin (produces rashes)
 Respiratory tract (shed in respiratory secretions)
41
Essentials of Medical Microbiology

Chickenpox - Clinical
Manifestations
▰ Incubation period - 10-21 days (2-3weeks).
▰ Typical description of chicken pox rashes-
 Rashes are vesicular
 Centripetal in distribution
 Bilateral and diffuse in distribution
 Rashes appear in multiple crops
 Fever appears with each crop of rashes
42
Essentials of Medical Microbiology
Chickenpox - Complications
▰ Most common infectious complication: secondary
bacterial infection of skin

▰ Most common extracutaneous complication - CNS

involvement (cerebellar ataxia, encephalitis and aseptic
meningitis)- usually occurs in children.

▰ Most serious complication is - Varicella pneumonia,

develops more commonly
Essentials ofin adults
Medical (up to 20% of cases)
Microbiology
43
Chickenpox – Complications
(Cont..)

▰ Reye’s syndrome

▰ Other complications are -myocarditis, nephritis, corneal

lesion and arthritis.

▰ Chickenpox in pregnancy: Affect both mother and the

fetus.

 Mothers - high-risk of developing varicella pneumonia

44
Essentials of Medical Microbiology

Chickenpox – Epidemiology
▰ Chicken pox - highly contagious disease.
▰ Period of infectivity - Child is infectious from 2 days before
the onset of rash to 5 days thereafter, until the vesicles are
crusted.
▰ One attack - lifelong immunity
▰ Reservoir- Humans - only known reservoir hosts.
▰ Source of infection- Patients - no carriers
▰ Secondary attack rate - 70–90%.
45
Essentials of Medical Microbiology
Zoster or Shingles or Zona

▰ Due to reactivation of latent VZV in old age (>60year age),

in immunocompromised individuals or occasionally in
healthy adults.

▰ Starts with severe pain in the area of skin or mucosa

supplied by one or more groups of sensory nerves and
ganglia.
46
▰ Rashes- are unilateral and segmental, confined to the area
Essentials of Medical Microbiology
Zoster or Shingles or Zona
(Cont..)

▰ Most common nerve involved- ophthalmic branch of

trigeminal nerve. Head, neck and trunk are the most
common affected sites.

Segmental distribution of rashes of Zos

47
Essentials of Medical Microbiology
Complications of Zoster
▰ Post-herpetic neuralgia

▰ Zoster ophthalmicus

▰ Ramsay Hunt syndrome

▰ Visceral disease

48
Essentials of Medical Microbiology
Laboratory Diagnosis (VZV)
▰ Specimen collection: Vesicular lesions, scabs and
maculopapular lesions

▰ Cytopathology: Giemsa staining of the scrapings from the

ulcer base (Tzanck smear) – cytopathological changes
similar to that of HSV infection - formation of multinucleated
giant cells.

▰ Virus isolation: In various cellMicrobiology

Essentials of Medical lines - produce HSV-like 49
Laboratory Diagnosis (VZV)
(Cont..)

VZV-specific methods:

▰ Specific antigen detection by direct immunofluorescence

staining

▰ Specific IgM and IgG antibody detection by ELISA

▰ PCR detecting VZV-specific genes

▰ BioFire Meningitis/Encephalitis (ME) Panel tests

50
simultaneously 14 microbial pathogens causing CNS
Essentials of Medical Microbiology
Treatment of VZV infections
▰ Acyclovir, famciclovir or valacyclovir - agents of choice.

▰ Can prevent the complications of chickenpox - also halt the

progression of zoster in adults, but cannot prevent post-
herpetic neuralgia.

51
Essentials of Medical Microbiology
Vaccine
▰ Live attenuated vaccine using Oka strain of VZV is
available.

▰ Given to children after 1 year of age; 2 doses, first dose is

given at 12-15months&second at 4-6yrs.

▰ Also given to seronegative adults;2 doses at 1-month gap.

52
Essentials of Medical Microbiology
Vaccine (Cont..)

▰ Transmission of the vaccine virus can occasionally cause

mild rashes in the recipient.

▰ Protectivity- Vaccine is >80%effective in preventing

chickenpox in children but less so in adults (70%). However,
it is 95% effective in preventing severe disease.

53
Essentials of Medical Microbiology
VZIG (Varicella-zoster
Immunoglobulin)
▰ Useful for post-exposure prophylaxis.

▰ Given within 96 hours (preferably within 72 hours) of

exposure.

▰ As adults are at higher risk of varicella-related deaths, VZIG

- recommended for adults - who are at greater risk for
complications—immunocompromised persons - HIV,
pregnancy, etc. Essentials of Medical Microbiology
54
VZIG (Varicella-zoster
Immunoglobulin) (Cont..)
▰ Also indicated for neonates born to mothers suffering
from chickenpox if the onset of chickenpox in mother is
between <5 days before delivery till 48 hours after delivery.

▰ Not indicated for the neonate if the mother has zoster.

55
Essentials of Medical Microbiology
Infection Control Measures
▰ Patients infected with VZV - kept in isolation.

▰ Airborne precautions (e.g. negative air-flow rooms) plus

contact precautions must be followed until lesions are dry
and crusted.

▰ For localized zoster - immunocompetent host, contact

precaution alone can be followed.
56
Essentials of Medical Microbiology
OTHER
HERPESVIRUS
INFECTIONS
57
Essentials of Medical Microbiology
OTHER HERPESVIRUS
INFECTIONS
▰ Epstein-Barr virus : Causes infectious mononucleosis and
various malignancies - can produce rashes following
ampicillin therapy

▰ Cytomegalovirus: Causes congenital infection - also

produces various infections in transplant recipients

58
Essentials of Medical Microbiology
OTHER HERPESVIRUS
INFECTIONS (Cont..)
▰ Human herpesvirus-6: Infects T cells by binding to CD46
receptor.

▰ It has two variants 6A and 6B

 Transmission - through infected oral secretions
 Sixth disease: In children - causes sixth disease –
exanthema subitum or roseola infantum - characterized
by high grade fever and skin rashes
 In older age groups - associated
Essentials with mononucleosis-like59
of Medical Microbiology
OTHER HERPESVIRUS
INFECTIONS (Cont..)
▰ Human herpesvirus 7: Shows tropism for T-cells,
transmitted by oral secretions, mainly in children.

▰ Associated with fever, seizures, respiratory or

gastrointestinal symptoms, and pityriasis rosea.

60
Essentials of Medical Microbiology
OTHER HERPESVIRUS
INFECTIONS (Cont..)
▰ Human herpesvirus 8: It causes a malignancy called
Kaposi sarcoma in HIV-infected individuals

61
Essentials of Medical Microbiology
OTHER DNA VIRUSES
CAUSING SKIN
INFECTIONS
62
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PARVOVIRUS
INFECTIONS
Essentials of Medical Microbiology
63
Morphology
▰ Simplest animal viruses infecting humans, responsible for -
childhood exanthema - erythema infectiosum (fifth
disease).

▰ Smallest viruses (18–26 nm size)

▰ Non-enveloped with icosahedral symmetry

▰ Only DNA viruses - possess single-stranded DNA

64
▰ Depend upon the host cell enzymes for replication.
Essentials of Medical Microbiology
Pathogenesis
▰ Transmission - Respiratory route, followed by blood
transfusion and transplacental route.

▰ Infects precursors of RBCs: Parvovirus B19 has a special

tropism for erythroid progenitor cells present in adult bone
marrow and fetal liver as it binds to blood group P antigen
as receptors; which are present on the RBC surface.

▰ This results in red cell destruction

Essentials and inhibition of
of Medical Microbiology
65
Clinical Manifestations
▰ Erythema infectiosum (or fifth disease)

▰ Transient aplastic crisis

▰ Pure red cell aplasia

▰ Non-immune hydrops fetalis

Fifth disease or rashes with
▰ Papular-purpuric gloves and socks slapped cheek appearance
syndrome

66
Essentials of Medical Microbiology
Laboratory Diagnosis

Molecular methods:

▰ PCR - detects viral DNA (e.g. genes coding for VP1 and VP2)
from serum, tissue or respiratory secretions.

▰ Real time PCR - used for quantification of viral load in blood,

during acute infections

67
Essentials of Medical Microbiology
Laboratory Diagnosis (Cont..)

▰ Antibody detection: ELISA – detecting antibodies against

VP1 and VP2 antigens. IgM appears early - recent infection
and remains elevated for 2–3 months

▰ Antigen detection: Immunohistochemistry - detect viral

antigens in fetal tissues and bone marrow.

68
Essentials of Medical Microbiology
Treatment of Parvovirus
infections
▰ No antiviral drug is available

▰ Symptomatic treatment is given

▰ Immunoglobulins containing neutralizing antibodies to

human parvovirus are available commercially

69
Essentials of Medical Microbiology
HUMAN
PAPILLOMAVIRUS
INFECTIONS
70
Essentials of Medical Microbiology
HUMAN PAPILLOMAVIRUS
INFECTIONS
▰ Selective tropism for epithelium of skin and mucous
membranes.

▰ Produces an array of infections ranging from benign warts,

to malignant neoplasia of cervix.

71
Essentials of Medical Microbiology
HUMAN PAPILLOMAVIRUS
INFECTIONS (Cont..)
▰ Benign warts: Small, hard, rough growth on the skin:
 Common skin warts (verruca vulgaris) and flat warts
(verruca plana) - common in children (seen with
serotypes 2, 4, 27, 57).
 Plantar warts (verruca plantaris)–benign lesion, widely
prevalent among adolescents (seen with serotype 1)
 Anogenital warts (condyloma acuminatum): Sexually
transmitted infection, seen among adults and is
associated with HPV serotypes 6 and 11 72
Essentials of Medical Microbiology
Plantar warts

73
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POXVIRUS
INFECTIONS
Essentials of Medical Microbiology
74
Morphology

▰ Largest (400 nm in length x 230 nm in diameter) among all

the viruses.

▰ Seen under light microscope.

▰ Most complex viruses; their structure does not fit into either
icosahedral or helical symmetry

▰ Brick-shaped or ellipsoid
75
Essentials of Medical Microbiology
Morphology (Cont..)

▰ Envelope: Externally, there is an

envelope, made up of two lipoprotein
membranes (outer and inner) with
ridges arising from the outer
membrane.

▰ The envelope encloses a core and two

structures of unknown function
Essentials called
of Medical Microbiology
76
Morphology (Cont..)

▰ Core or the nucleocapsid - biconcave dumbbell shaped

▰ Possess single linear dsDNA.

▰ Only DNA virus that replicates in the cytoplasm

77
Essentials of Medical Microbiology
POXVIRUS INFECTIONS

▰ The following are the poxviruses of human importance.

 Variola: Causative agent of smallpox.

 Vaccinia: Used as a vaccine for smallpox

 Molluscum contagiosum virus: Causes warty lesions -

molluscum contagiosum.

78
Essentials of Medical Microbiology
Smallpox

▰ First disease to be eradicated from the world.

▰ Characterized by highly contagious severe exanthema

(rashes).

79
Essentials of Medical Microbiology
Smallpox Time Line

▰ Last natural case of variola major- Bangladeshi women in

Assam in May 1975

▰ Last natural case of variola minor - Merca, Somalia, 26th

October1977

▰ Eradication was declared by WHO nearly after three years

of last case- i.e. on 8th May 1980
80
Essentials of Medical Microbiology
Smallpox Time Line (Cont..)

▰ Laboratory spread-There was a small outbreak in

Birmingham (1978), due to accidental spread of the virus
from the virus laboratory following which stocks from most
laboratories have been destroyed.

▰ Maintenance
 CDC Atlanta (USA)
 Center for Research on Virology and Biotechnology,
81
Koltsova (Russia).
Essentials of Medical Microbiology
Smallpox Time Line (Cont..)

▰ Agent of bioterrorism- As vaccination was stopped

following eradication people borne after 1980 are not
immunized. Hence can be a potential agent of bioterrorism.

82
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Reasons that Made
Eradication Successful
▰ Exclusively human pathogen, no animal reservoir

▰ Patients were the only source, there was no carrier state

▰ Case detection was easy-due to characteristic appearance

of rashes

▰ Subclinical disease were not transmitting the disease

83
Essentials of Medical Microbiology
Reasons that Made
Eradication Successful (Cont..)

▰ Global small pox eradication programme was launched in

1967 by WHO. With a strong international cooperation and
intense effort; disease was wiped out nearly after 10 years.

▰ Highly affective live vaccinia vaccine

84
Essentials of Medical Microbiology
Differences between smallpox
and chickenpox
Smallpox Chickenpox

Incubation period: Incubation period:

12 days (7–17 days) 15 days (10–21 days)
Site of rash: Palm, sole and Site of rash: Axilla and flexor
extensor surface surface
Rash: Deep seated and appear Rash: Superficial and
in single stage, evolution is pleomorphic (appear in crops)
slow, centrifugal distribution evolution is rapid, dew drop
rashes, centripetal distribution
Fever subsides with Fever rises with each crop of
appearance of rash rash

85
Essentials of Medical Microbiology
Clinical Manifestations
▰ Portal of entry - mucous membranes of the upper
respiratory tract.

▰ Incubation period- 12days (7-17days)

86
Essentials of Medical Microbiology
Clinical Manifestations (Cont..)

▰ Description of Rashes- Rashes were deep seated and all

rashes in an area appeared in one stage, evolution was
slow.

▰ Centrifugal distribution

▰ Fever subsided with appearance of rash.

87
Essentials of Medical Microbiology
Laboratory Diagnosis
▰ Direct detection in scrapings
from rashes:

 Intracytoplasmic inclusion
bodies (Paschen bodies)

 Electron microscopy: Brick- Smallpox virus (electron microgra

shaped appearance with

88
biconcave DNA core.
Essentials of Medical Microbiology
Laboratory Diagnosis (Cont..)

▰ Egg inoculation: Characteristic pock formation is seen on

the chorioallantoic membrane (CAM) of a chick embryo.

89
Essentials of Medical Microbiology
Treatment of Smallpox

Cases used to be treated in the past with:

▰ Vaccinia immunoglobulins

▰ Antiviral drugs - methisazone, cidofovir or tecovirimat.

90
Essentials of Medical Microbiology
Vaccination
▰ Live vaccinia vaccine was highly effective.
 Given as a single dose, at 1–2 years of age
 As un-attenuated live virus was used, adverse reactions
were common - mild vaccinia-induced rashes.

▰ Cowpox vaccine discovered by Edward Jenner (the father

of vaccination) was in use before vaccinia vaccine was
available
91
Essentials of Medical Microbiology
Vaccination (Cont..)

▰ Variolation - first attempt of providing artificial immunity

against smallpox.

▰ Was in use even before cowpox vaccine was available

(17th–18th century).

▰ Healthy people were inoculated with the skin scraping of a

smallpox patient.
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Essentials of Medical Microbiology
Vaccinia
▰ Vaccinia virus cross-reacts with variola and the antibodies
produced against vaccinia are protective for variola.

▰ Antigenic cross reactivity was so much that vaccinia was

able to eradicate variola globally.

93
Essentials of Medical Microbiology
Vaccinia (Cont..)

Vaccinia differs from variola in many ways:

▰ Non-pathogenic to humans or produces milder skin lesions

▰ Produces an inclusion body - Guarnieri body (variola

produces Paschen body)

▰ On CAM, vaccinia virus produces larger and hemorrhagic

and necrotic pock lesions than variola.
94
Essentials of Medical Microbiology
Molluscum Contagiosum
▰ Molluscum contagiosum virus is an obligate human poxvirus
that produces characteristic skin lesions.

95
Essentials of Medical Microbiology
Clinical Manifestations
▰ Lesions: Dome-shaped, pink pearly wartlike lesions (2–5
mm size), umbilicated, with a dimple at the center.

▰ Lesions are found singly or in clusters.

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Clinical Manifestations (Cont..)

Transmission:

▰ Children are commonly affected, acquire infection by direct

and indirect contact (e.g. by barbers, common use of
towels, swimming pools)

▰ Rarely sexual transmission - reported in young adults.

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Clinical Manifestations (Cont..)

▰ Self-limiting: Lesions disappear in 3–4 months - no

systemic complications

▰ In HIV-infected patients: Disease is more generalized,

severe and persistent.

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Laboratory Diagnosis
▰ Molluscum bodies -
intracytoplasmic eosinophilic
inclusions seen in skin
scrapings stained with
histopathological stains.

B
99
Essentials of Medical Microbiology
Laboratory Diagnosis (Cont..)

▰ Electron microscopy and PCR - used for confirmation

▰ Not cultivable: It cannot be propagated in tissue culture,

embryonated egg or in animals.

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Treatment of Molluscum
contagiosum
▰ Surgical removal of the lesions by ablation (by cryotherapy
or laser therapy) is the mainstay of treatment.

▰ Cidofovir has shown to have some efficacy.

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RNA VIRUSES
CAUSING SKIN
INFECTIONS
102
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MEASLES
103
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MEASLES
▰ Measles is an acute, highly contagious childhood disease
characterized by fever & respiratory symptoms, followed by
typical maculopapular rash.

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Pathogenesis
▰ Transmission

 Droplets inhalation over short distances and, less

commonly,

 Small-particle aerosols - remain suspended especially in

schools, hospitals, and enclosed public places in the air
for longer period.
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Pathogenesis (Cont..)

▰ Spread-The virus multiplies locally in the respiratory tract;

then spreads to the regional lymph nodes → enter into the
bloodstream in infected monocytes (primary
viremia)→further multiply in reticuloendothelial system →
spills over into blood (secondary viremia)→disseminateto
various sites.
106
Essentials of Medical Microbiology
Pathogenesis (Cont..)

▰ The virus is predominantly seeded in the epithelial surfaces

of the body, including the skin, respiratory tract, and
conjunctiva.

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Clinical Manifestations
▰ Incubation period -10days which may be shorter in infants
and longer (up to 3 weeks) in adults

▰ Disease can be divided into three stages:

 1. Prodromal Stage
 2. Eruptive Stage
 3. Post-measles Stage

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1. Prodromal Stage
▰ Lasts for four days (i.e. from 10th to 14th day of infection)

 Fever

 Koplik’s spots

 Non-specific symptoms

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Essentials of Medical Microbiology
1. Prodromal Stage
▰ Lasts for four days (i.e. from 10th to 14th day of infection)

 Fever

 Koplik’s spots

 Non-specific symptoms
A

Koplik spot in buccal mucosa (measl

(arrow showing)
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Essentials of Medical Microbiology
2. Eruptive Stage
▰ Maculopapular dusky red rashes

▰ Rashes typically appear first behind the ears → then

spread to face, arm, trunk and legs → then fade in the same
order after four days of onset

▰ Fever (10th day) → Koplik’s spot (12th day) → rash(14th day)

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3. Post-measles Stage
▰ Characterized by weight loss and weakness.

▰ There may be failure to recover and gradual deterioration

into chronic illness.

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Complications - Secondary
Bacterial Infections
▰ Otitis media and bronchopneumonia are most common

▰ Recurrence of fever or failure of fever to subside with the

rash

▰ Worsening of underlying tuberculosis with a false positive

Mantoux test

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Complications - Complications
Due to Measles Virus Itself
▰ Giant-cell pneumonitis in immunocompromised children,
and HIV infected people

▰ Acute laryngotracheobronchitis (croup)

▰ Diarrhoea, leads to malnutrition including vitamin A

deficiency

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Complications - Central Nervous
System Complications
▰ Post-measles encephalomyelitis

▰ Measles inclusion body encephalitis

▰ Subacute sclerosing panencephalitis (SSPE)

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Laboratory diagnosis of
Measles
▰ Specimen: Nasopharyngeal swab

▰ Antigen detection: By using anti-nucleoprotein antibodies

▰ Virus isolation: By inoculation of specimen into monkey or

human kidney cell line, produces CPE as multinucleated
giant cells (Warthin-Finkeldey cells)

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Essentials of Medical Microbiology
Laboratory diagnosis of
Measles (Cont..)

Multinucleated giant cell of measles

infected cell lines (arrow showing).
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Essentials of Medical Microbiology
Laboratory diagnosis of
Measles (Cont..)
▰ Antibody detection in serum: Against nucleoprotein
antigen by ELISA

▰ Reverse-transcription PCR: detects viral RNA.

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Treatment of Measles
▰ There is no specific antiviral therapy available for measles

▰ Treatment is symptomatic and consists of general

supportive measures

▰ Vitamin A - effective in reducing the morbidity and mortality

due to measles.

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Essentials of Medical Microbiology
General Preventive
Measures
▰ Airborne precaution - isolation in negative pressure room.

▰ Use of PPEs - N95 mask, etc. must be followed while

handling measles cases

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Measles Vaccine
▰ Live attenuated vaccine is available for measles.

▰ Strains: The following vaccine strains are used currently

 Schwartz strain
 Edmonston-Zagreb strain
 Moraten strain.

▰ Vaccine is prepared in chick embryo cell line

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Measles Vaccine (Cont..)

▰ Reconstitution - Available in lyophilized form - has to be

reconstituted with distilled water - used within 4 hours.

▰ Vaccine is thermolabile - stored at -200C.

▰ One dose (0.5ml) containing >1000 infective viral units is

administered subcutaneously.

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Measles Vaccine (Cont..)

▰ Combined vaccines: Measles vaccine combined form with

rubella (MR vaccine), with mumps and rubella vaccine (MMR
vaccine) and with varicella (MMR-V vaccine)

▰ Indication: Measles-rubella (MR) vaccine is given at 9

completed months to 12 months along with vitamin A
supplements and second dose of MR vaccine at 16–24
months Essentials of Medical Microbiology
123
Measles Vaccine (Cont..)

▰ Side effects include - Mild measles like illness, toxic

shock syndrome

▰ Contacts - Susceptible contacts over 9-12months may be

protected against measles if the measles vaccine is given
within 3 days of exposure.

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Measles Vaccine (Cont..)

▰ Side effects include - Mild measles like illness, toxic

shock syndrome

▰ Contacts - Susceptible contacts over 9-12 months -

protected against measles - given within 3 days of
exposure.

▰ Measles immunoglobulin - given within 3 days - 0.25mg/kg

of body weight. Essentials of Medical Microbiology
125
Epidemiology
▰ Source - Cases. Carriers - not known to occur. Inapparent
or sub-clinical infections - rare.

▰ Reservoir - Humans - no animal reservoir.

▰ Infective material - Virus - shed in the secretions of nose,

throat and respiratory tract of cases of measles - during the
prodromal stage and early stage of rash.
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Essentials of Medical Microbiology
Epidemiology (Cont..)

▰ Period of communicability - Patients are infectious from

four days before to four days after the onset of rash.
Isolation - recommended from the onset of prodromal stage
until third day of rash.

▰ Secondary attack rate is very high (>90%)

▰ Age - Measles is a childhood disease

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Essentials of Medical Microbiology
Epidemiology (Cont..)

▰ Immunity- No age is immune if there is no previous

immunity.

 There is single serotype hence one attack (vaccine or

infection) gives lifelong immunity.

 Infants are protected up to 6 months due to pre-existing

maternal antibodies.
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Essentials of Medical Microbiology
Measles elimination
▰ WHO has introduced ‘The Strategic Plan for achieving and
maintaining Measles and Rubella elimination in WHO
South- East Asia Region: 2020–2024

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Essentials of Medical Microbiology
Measles elimination (Cont..)

▰ The following objectives are set to achieve this target:

 (1) ≥ 95% coverage with two doses against measles and
rubella
 (2) Develop and sustain a case-based surveillance
system
 (3) Develop and maintain an accredited measles and
rubella laboratory network
 (4) Strengthen support and linkages to achieve the
above three strategic objectives.
Essentials of Medical Microbiology
130
RUBELLA
131
Essentials of Medical Microbiology
RUBELLA
▰ Rubella virus produces a childhood exanthema similar to
that of measles.

▰ Rubella - also known as German measles.

▰ Highly teratogenic - cause congenital rubella syndrome.

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Essentials of Medical Microbiology
RUBELLA (Cont..)

▰ Togaviridae family, and is the only member under genus

Rubivirus.

▰ Enveloped, single-stranded RNA virus , surrounded by

capsid (C) protein

▰ Envelope contains a lipid layer from which two types of

spike-like glycoproteins (E1 and E2) are projected
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Essentials of Medical Microbiology
TYPES OF RUBELLA
INFECTIONS
▰ Postnatal infection

▰ Congenital infection

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Postnatal Rubella
▰ Neonatal age, childhood, and adult life.

▰ Transmission- respiratory droplets via upper respiratory

mucosa.

▰ Spread - Rubella virus replicates locally in the nasopharynx

- spreads to the lymph nodes - viremia develops after 7–9
days - lasts until 14th day - both antibody and rashes
appear almost simultaneously suggesting an immunologic135
Essentials of Medical Microbiology
Clinical Manifestations
▰ Incubation period - 14 days (range, 12–23 days)

▰ Rashes - first manifestations in children, but in older

children and adults, 1 to 5-day prodrome - precedes the
rash - includes low-grade fever, malaise, and upper
respiratory symptoms

▰ Rashes - generalized and maculopapular in nature

▰ Forchheimer spots Essentials of Medical Microbiology

136
Child with rubella rash

137
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Complications
▰ Arthralgia and arthritis - common in adults - women.

▰ Thrombocytopenia and encephalitis - rarely encountered.

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Essentials of Medical Microbiology
Laboratory Diagnosis
▰ Isolation of virus: Nasopharyngeal or throat swabs taken
6 days before and after the onset of rash

 Ideal cell lines: Monkey or rabbit origin cell lines may be

used

 It can also be identified more rapidly in cell lines by shell

vial technique.
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Essentials of Medical Microbiology
Laboratory Diagnosis (Cont..)

Serology (Antibody detection):

▰ ELISA - detects both IgM and IgG separately.

▰ Various antigens - whole virus lysate or recombinant E1/ E2

antigens

▰ Results confirmed - IgG avidity test to differentiate active

infection from the past infection or vaccination.
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Essentials of Medical Microbiology
Laboratory Diagnosis (Cont..)

▰ Molecular test: RT-PCR - available for detecting rubella

specific RNA (nucleoprotein N gene) in clinical specimens.

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Congenital Rubella
Syndrome
▰ Most serious consequence of rubella virus infection

▰ Highly teratogenic - affects ear (deafness), eyes (cataract)

and heart (patent ductus arteriosus).

▰ Severity is maximum in first trimester.

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Essentials of Medical Microbiology
Epidemiology
▰ Source: Cases

▰ Duration of protection: Once infected, the person

acquires lifelong immunity.

▰ Period of communicability of rubella is about 1 week

before to 1 week after the appearance of rash.

▰ Transmission occurs via—airborne droplet, transplacental

and rarely via contact, and
Essentials sexual
of Medical modes
Microbiology
143
Treatment of Rubella
▰ Rubella is a mild, self-limited illness and no specific
treatment is available.

144
Essentials of Medical Microbiology
Rubella Vaccine
▰ RA 27/3 is a live attenuated vaccine for rubella, prepared
from human diploid fibroblast cell line.

▰ Schedule: Single dose (0.5 mL) of vaccine is administered

subcutaneously

▰ Indication: In India, rubella vaccine is indicated in all

women of reproductive age (first priority group) followed by
all children (1–14 years).
Essentials of Medical Microbiology
145
Rubella Vaccine (Cont..)

Precautions:

▰ Contraindicated in pregnancy

▰ As it is teratogenic, pregnancy should be avoided at least

for 4 weeks (28 days) following vaccination

▰ Infants below 1 year should not be vaccinated due to

possible interference from persisting maternal antibody.
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HAND-FOOT-AND-
MOUTH
(HFM) DISEASE
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HAND-FOOT-AND-MOUTH (HFM)
DISEASE
▰ Usually affects children.

▰ Characterized by ulcerations on oral and pharyngeal

mucosa and vesicular rashes on the palms and soles - heal
without crusting.

▰ Fever and sore throat with flu like symptoms are the other
manifestations.
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Essentials of Medical Microbiology
Vesicular eruptions in Hand-foot-
and-mouth (HFM) disease

A B C

A. Hand; B. Foot; C. Mouth

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Essentials of Medical Microbiology
HAND-FOOT-AND-MOUTH (HFM)
DISEASE (Cont..)
Agents:

▰ Coxsackievirus A16 - most common cause

▰ Coxsackievirus A6 can cause HFMD with more severe

manifestation

▰ Enterovirus 71 - associated with cases in East and

Southeast Asia.
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Essentials of Medical Microbiology
HAND-FOOT-AND-MOUTH (HFM)
DISEASE (Cont..)
Transmission:

▰ Infected person’s nose and throat secretions - saliva,

sputum, or nasal mucus, fluid from blisters or scabs and
also feces.

▰ Contact (direct or indirect) and droplets.

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Essentials of Medical Microbiology
Questions:
▰ Q1. All of the following are clinical manifestations of
Parvovirus B19 infection, except:

a. Erythema infectiosum

b. Transient aplastic crisis

c. Condyloma acuminate

d. Hydrops fetalis
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Essentials of Medical Microbiology
Questions:
▰ Q2. Subacute sclerosing panencephalitis (SSPE) is a
complication following which viral infection:

a. Mumps

b. Measles

c. Rubella

d. Influenza
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Essentials of Medical Microbiology
Questions:
▰ Q3. Which virus-vaccine strain combination is not correct:

a. Mumps—Jeryl-Lynn strain

b. Measles—Edmonston-Zagreb strain

c. Rubella—Schwarz strain

d. Chickenpox—Oka strain

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