CARDIOVASCULAR SYSTEM VIROLOGY

• Viral diseases of the heart, blood, and blood vessels along with the lymphatic
structures.
• Several other systems affected because the viral agents easily disseminate through
blood.
• Many viral diseases spread through the body via the lymphatic and cardiovascular
systems.
• EBV – Infectious mononucleosis
• CMV – Cytomegalovirus disease
• YFV –Yellow fever
• Coxsackie virus /Adenovirus/Coronavirus – Viral Induced Myocarditis
• Viral hemorrhagic fever (Ebola virus, Lassa virus, Maburg virus, RVFV, Dengue virus)

VIRAL HEMORRHAGIC FEVERS

• Arenaviridae
• Bunyaviridae
• Filoviridae
• Flaviviridae

EPSTEIN-BARR VIRUS (HHV-4)

• Human herpesvirus 4 (HHV-4) is also known as Epstein- Barr virus (EBV) after its
discoverers.
• EBV is a γ-herpesvirus
• The virus has an unusually large number of genes—more than 50 different proteins
are produced by complete expression of the DNA in EBV.
• EBV has tropism for both human B lymphocytes and epithelial cells.
• It is the etiologic agent of:
• Infectious mononucleosis (IM)
• African Burkitt’s Lymphoma AfBL
• Nasopharyngeal carcinoma (NPC)
• Hodgkin disease
EPIDEMIOLOGY

• Two main strains of EBV (types 1 and 2) and can co-infect a single individual
• Oral transmission - via saliva, often during the sharing of drinking glasses, while kissing,
or from a cough or sneeze. “Kissing Virus”
• Over 90% of the population is seropositive for EBV worldwide.
• There is causative association with African Burkitt lymphoma in malarial belt of Africa.
Immunocompromised people are at highest risk for life-threatening neoplastic
disease.
• It can become latent within cells, resulting in lifelong infection.
• Does not produce cytopathic effects or the characteristic intranuclear inclusions of
other herpesvirus infections.
PATHOGENESIS

• Initially infects epithelial cells of the throat and salivary glands

• EBV then enters the blood, where it invades B lymphocytes.
• It enters B lymphocytes by binding to a surface receptor CR2 or CD21.
• The viruses invade such sites as lungs, bone marrow, and lymphoid organs, where they
infect certain kinds of mature B lymphocytes.
• They penetrate B lymphocytes and replication begins within 6 hours after penetration.
• It establishes a persistent infection in which viruses are shed for months to years.
• EBV suppresses apoptosis (programmed cell death) of B lymphocytes, causing infected
cells to become immortal.
• Such infected B cells are one source of cancers.
 • The proliferation of EBV-infected lymphocytes is limited by cytotoxic T cells and
complement.
• Infectious mononucleosis is as a result of war between EBV infected cells and cytotoxic
T-cells
• The activated T cells appear as atypical lymphocytes (also called Downey cells)
• A large amount of energy is required to power the T-cell response, leading to great
fatigue.
• During infection, there is production of an IgM antibody to the Paul-Bunnell antigen,
termed the heterophile antibody.

Heterophile antibodies are IgM antibodies, which agglutinate erythrocytes from different species

CLINICAL MANIFESTATIONS
• Heterophile Antibody–Positive Infectious Mononucleosis (glandular fever/kissing
disease/mono)
• 4-to-7-week incubation
• Sore throat/pharyngitis(grey exudate), fever, rash
• Enlarged lymph nodes in the neck.
• Malaise, lethargy, extreme tiredness
• Liver (hepatitis) and spleen involvement and enlargement Hepatosplenomegaly
• Other: Ampicillin-induced rash
INFECTIOUS MONONUCLEOSIS
• These symptoms persist for days to weeks; they slowly resolve.
• Fatigue may last for months.
• Complications such as laryngeal obstruction, meningitis, encephalitis, hemolytic
anemia or splenic rupture may occur in 1% to 5% of patients.
• Whereas 90% of IM cases are due to EBV, 5-10% are due to CMV
 INFECTIOUS MONONUCLEOSIS

Tonsils are coated with a gray exudate (due to secondary infection by Strep group A)

DIAGNOSIS

• SEROLOGY- Screening for EBV IgM antibodies using Heterophile antibody

test/Mononuclear spot test
The Monospot test is the differential test between
EBV and CMV. CMV presents a negative
Monospot test
 • HEMATOLOGY-lymphocyte and monocyte count with more than 10% atypical
lymphocytes, called Downey cells
• Alterations in liver function tests may also occur, and enlargement of the liver and
spleen is a common finding.

TREATMENT

• There's no specific therapy available.

• Self-limiting
• Supportive care: bed rest, good nutrition and drinking plenty of fluids.
• Antibiotics can be used to treat secondary infections such as Strep throat and
tonsillitis.
 • Risk of rash with Amoxicillin and other penicillin derivatives hence these antibiotics
aren't recommended for people with mononucleosis.

CLINICAL MANIFESTATION

Oral hairy leukoplakia

• It’s a disease of the oral cavity
• Indicator of HIV infection also person's lessening or weakening immunity
• Pathogenesis of hairy leukoplakia is complex
• Symptoms include; a non-painful white plaque along the lateral tongue borders
• Mild pain, dysesthesia, alteration of taste
• Oral Hairy leukoplakia is often asymptomatic, and many patients are unaware of its
presence.
• Lesions may frequently appear and disappear spontaneously.
 DIAGNOSIS
• Most cases diagnosis is established on clinical basis.
• Oral thrush/candidiasis similar but thrush patches can be removed unlike ORL.
In cases where patches look unusual, biopsy and histologic examination are required
to exclude cancer.

TREATMENT
• Does not require specific treatment in every case.
• Antiviral therapy usually achieves resolution of the lesion within 1-2 weeks of therapy
• Oral therapy with acyclovir /Valacyclovir /Famciclovir

BURKITT’S LYMPHOMA
• Endemic (African) Burkitt lymphoma- Primarily affects children between ages 4-7
years in malaria endemic regions(e.g., equatorial Africa, Brazil, and Papua New
Guinea)
• Sporadic (non-African) Burkitt lymphoma occurs worldwide, it accounts for 1% to 2%
of adult lymphoma cases globally.
Immunodeficiency-associated Burkitt Lymphoma. This variant of Burkitt lymphoma is
most common in people with HIV/AIDS.

READ ARTICLE ON BURDEN OF BURKITTS LYMPHOMA IN AFRICA

AFRICAN BURKITT’S LYMPHOMA

• Malignant B-cell neoplasm
• Presents as a rapidly growing tumor of the jaw, face or eye
• Thought to occur from an early EBV infection that produces a large pool of infected
lymphocytes.
• Grows very quickly, and without treatment most children die within a few months.

DIAGNOSIS
• Prompt diagnosis is essential.
• Biopsy of an enlarged lymph node or suspicious disease site collected.
 • In a biopsy, a sample of tissue is examined under a microscope.
• Medium-sized lymphoid cells with high proliferative and apoptotic activity observed.
I think it should be high proliferative activity but low apoptotic activity

TREATMENT
• Although BL is a very rapidly growing tumour it responds well to treatment.
• Can be treated by surgery, radiotherapy and immunotherapy, chemotherapy is the
mainstay of treatment.
• Three pictures: before treatment, 3 days and 6 days after treatment

Will be very dominant in

B-CELL PROLIFERATIVE DISEASE AND LYMPHOMA immunocompromised
patients withCD4 count
<50
• In EBV infection, the virus is present in the B-cells, which are normally controlled by
T-lymphocytes.
• When T-cell deficiency exists, one clone of EBV-infected B-lymphocytes escapes
immune surveillance to become autonomously proliferating.
• EBV induced B cell lymphomas are most prevalent in immunocompromised patients.

NASOPHARYNGEAL CARCINOMA
• Another tumor associated with EBV, which also shows a distinct geographic
localization.
• Nasopharyngeal carcinoma (NPC), an epithelial derived tumor, is endemic in
southern China.
• It is responsible for approximately 25% of the mortality from cancer in China.
 • Genetic or environmental factors may also be important in the pathogenesis of the
disease.
NASOPHARYNGEAL CARCINOMA

Immunocompromised “War”
HIV patients
majorly from Malaria between CD8
cells and EBV
CYTOMEGALOVIRUS (HHV-5)
• A β-herpesvirus named for the cytopathic effect it produces in cell culture.
• Produce nuclear inclusions (“owl’s eye cells”)
• Produce cytoplasmic inclusions and enlargement of the cell (cytomegally)
• Typically infects humans early in their lives but remains in a latent state until the
immune system is compromised.

ds linear DNA
Enveloped

CMV NUCLEAR INCLUSIONS “OWL’S EYE CELLS”

The histologic hallmark of CMV infection is the cytomegalic cell, which is an enlarged cell
(25 to 35 mm in diameter) that contains a dense, central, “owl’s eye,” basophilic intra-
nuclear inclusion body.
EPIDEMIOLOGY

• Transmission involves bodily secretions (saliva, mucus, milk, urine, feces, semen, and
cervical secretions).
• Individual viruses are not highly contagious.
• Transmission usually occurs via sexual intercourse, vaginal birth, blood transfusions,
and organ transplants.
• CMV prevalent viral infection in neonates. Congenital CMV
PATHOGENESIS
• Primary infection site is T and B cells, monocytes, and lymphocytes.
• CMV becomes latent in various cells, and infection by CMV typically lasts for life. e.g.,
Monocytes, neutrophils, and vascular endothelial cells
• CMV can cause disease by direct tissue damage and immunologic damage.

CLINICAL MANIFESTATIONS
• Most people infected with CMV are asymptomatic.
• Primary infections are usually involve Heterophile negative mononucleosis
syndrome Negative Monospot test

• Congenital disease - may cause birth defects - mental retardation, hearing or visual
damage, death.
• About 10% of congenitally infected newborns develop enlarged liver and spleen,
jaundice, and anemia.
• Postpartum infections in infants are mostly asymptomatic.
• Immunosuppressed adults, such as transplant recipients, may develop.
• Pneumonia
• Retinitis/ Blindness (if the virus targets the retina)
Chorioretinitis*

Cytomegalovirus mononucleosis (symptoms similar to those of IM caused by EBV).

DIAGNOSIS
• Antigen detection using ELISA tests – biopsy, blood, urine , bronchoalveolar lavage
• Antibody detection using ELISA -presence of IgM antibody specific for CMV are best
indicators of primary infection
• DNA detection by PCR or antigen detection useful to find Viremia in blood samples
TREATMENT

• Treatment unnecessary for healthy children and adults.

• Newborns and Immunocompromised adults need treatment with signs and
symptoms of CMV infection.
• Antiviral medications can slow reproduction of the virus, but can't eliminate it
Ganciclovir, valganciclovir, cidofovir and foscarnet. “Fast car, Garbage, Violent garbage”

PREVENTION
• Screening - CMV-seronegative donors for seronegative recipients decreases risk of
post transplant complications
• Safe sexual practices including condom usage may reduce transmission.
• There is currently no vaccine available.
PARVOVIRUS B19

• Single-stranded DNA virus of the family Parvoviridae

• 50% adults acquire of immunity during childhood.
Erythroid cells
• The parvovirus B19 destroys the stem cells that give rise to red blood cells.
• A primary site of replication- nucleus of an immature cell in the erythrocyte lineage
that is mitotically active.
EPIDEMIOLOGY
• The virus is primarily transmitted by the respiratory route.
• Can be transmitted through blood or blood products or mother to child.
• Incubation period of 4 to 12 days
• Found to cause fifth disease (erythema infectiosum) in normal children.
• It is also common in children of ages 5 to 14 and often goes unnoticed.
 • Often the infection is totally asymptomatic.
• The disease is self-limiting and confers lifetime immunity.

CLINICAL MANIFESTATION Aplastic crisis

• Can be fatal to those who have chronic hemolytic anemias e.g. sickle cell anaemia
• The virus can be transmitted across the placenta and cause the fetus to develop fatal
anemia. Fetal Hydrops
• Immunodeficient patients cannot control replication of the virus and may develop
chronic anemia
• B19 is a cause of aplastic crisis in sickle-cell anemia

FIFTH DISEASE

Fifth disease is known for a rash that makes a child's cheeks bright red. That's why it's
sometimes called a "slapped cheek" rash. A few days later, the rash spreads down to the
trunk, arms, and legs. It usually lasts 1 to 3 weeks.

DIAGNOSIS
• Parvovirus serology (anti–parvovirus B19 immunoglobulin M [IgM] and
immunoglobulin G [IgG] antibodies)
• PCR detects viral DNA present in the blood or other tissues/fluids
 TREATMENT
• Treatment is unnecessary for healthy people
• Patients in aplastic crisis require packed RBC transfusions
• In rare instances Intravenous Immunoglobulin (IVIG) can be administered in life
threatening cases

Adenovirus induced myocarditis

Adenovirus is ubiquitous and is the most common cause of myocarditis in children and adults
globally. The virus is spread through contact with viral loaded droplets from the nose and
throat of an infected person. Although majority of viral-induced myocarditis is attributed to
adenovirus, there is limited information on how viral-host immune response drive the
progress of the disease.

Adenovirus induced myocarditis

Adenoviruses are frequent causes of pediatric myocarditis. Little is known about the
pathogenesis of adenovirus myocarditis, and the species specificity of human adenoviruses
has limited the development of animal models, which is a significant barrier to strategies for
prevention or treatment.
The course of viral myocarditis is often more severe in neonates and infants than in older
patients, with up to 67% mortality in newborns and 55% in infants less than 1 year of age,
compared to 20 to 25% in older children and 38% in adults.
Associations between myocarditis and adenovirus infection are well established.
Persistent human adenovirus (HAdV) infections of the myocardium have been implicated in
the development of dilated cardiomyopathy and cardiac dysfunction
CLINICAL MANIFESTATION
o Generalized fatigue
o Respiratory distress/shortness of breath
o Malaise
o Chest pain
o Congestive heart failure (CHF)
o Cardiogenic shock
 o Arrhythmias
o Cardiac arrest.
DIAGNOSIS
The initial evaluation should include electrocardiography, echocardiography, and often
contrast-enhanced cardiac MRI.
PCR techniques may facilitate precise viral genomic diagnosis.

TREATMENT/MANAGEMENT

To date, no specific evidence-based treatment is available for virus-induced myocarditis. Since

the pathogenesis of cardiac damage in myocarditis is often attributed to
autoimmune/hyperimmune response to viral infection, immunomodulatory therapy has
been considered potentially useful.

Myocarditis can be managed by reducing inflammation with analgesics and thus limiting the
amount of heart damage that occurs.

COXSACKIE B VIRUS INDUCED MYOCARDITIS

• Non-enveloped, linear, positive-sense single-stranded RNA viruses, Picornaviridae and
the genus Enterovirus
• Among the leading causes of aseptic meningitis.
• Coxsackie B viruses have an affinity for the pericardium and myocardium.
• Infect the heart, pleura, pancreas, and liver, causing pleurodynia, myocarditis,
pericarditis, and hepatitis.
• Coxsackie B infection of the heart can lead to pericardial effusion

PATHOGENESIS

• The coxsackie B virus initially replicates in the gut and spleen and eventually spreads
to its target organ, the heart.
• Once in the heart, replication of the virus causes damage to the heart cells and induces
migration of white blood cells into the heart tissue.
 • The white blood cells subsequently activate an autoimmune process in which the
white blood cells kill the virus infected heart cells and normal heart cells which are not
infected.
• This autoimmune process persists long after viral particles are no longer detected.

• The destruction and damage to the heart cells results in myocarditis and heart failure.
•
• Several injurious stimuli, including infection, ischemia, trauma and pharmacotoxic
agents can promote cell death in differentiated cardiomyocytes.
• In fact, such persistent insults to heart tissue can lead to cardiac dysfunction and heart
failure.

MORE READING

CLINICAL MANIFESTATION

• Fatigue
• Malaise
• Failure to thrive or poor weight gain
• Fever
• Low urine output (a sign of decreasing kidney function)
• Pale
• Cool hands and feet (a sign of poor circulation)
• Rapid breathing
• Rapid heart rate
• Chest pain

DIAGNOSIS
RT-PCR ON SERUM, EXCRETA OR TISSUES – Detection of viral genome

TREATMENT /MANAGEMENT
• Myocarditis can be managed by reducing inflammation with analgesics and thus
limiting the amount of heart damage that occurs.
 • Because myocarditis impairs the functioning of the heart activity should be limited and
excessive dietary intake of salt should be avoided.
• Oxygen can also be given to reduce the workload on the heart and in cases of heart
failure, heart transplants can be performed.

PREVENTION

• While coxsackie virus infection cannot be prevented it can be controlled through

sanitary measures.
• As a fecal-orally transmitted virus, spread of the virus can be limited by improving
sanitation and thoroughly washing hands.

Coronavirus-induced myocarditis

The novel coronavirus has been primarily shown to cause respiratory tract infections. There is
emerging evidence however that the virus can also infected the heart and cause myocarditis.
The mechanisms of how coronavirus-induced myocarditis occurs is still unclear.
Chronic cardiovascular disease may become unstable in the setting of viral infection as a
consequence of imbalance between infection-induced increase in metabolic demand and
reduced cardiac reserve. Patients with coronary artery disease and heart failure may be at
particular risk as a result of coronary plaque rupture secondary to virally induced systemic
inflammation, and rigorous use of plaque stabilizing agents (aspirin, statins, beta-blockers, and
angiotensin-converting enzyme inhibitors) has been suggested as a possible therapeutic
strategy.
ACTIVITY

1. Based on this video what are the two main cardiac issues that can predispose a patient
to COVD-19 induced myocarditis
2. What advice would you give to a COVID-19 patient who is on ACE inhibitor?
3. Like COVD-19, CVB affects males more than females. Provide two biological reason as
to why this might be the case? Use these article 1, article 2 and this video as guides
4. Provide two non-biological reason CVB and coronavirus is common in males than
females