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Bordetella_ EBV_ CMV

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					Bordetella

CMV

EBV

WHOOPING COUGH

• Outbreaks of pertussis were first described in the 16th century
• In unimmunized populations in the world, pertussis remains a major health problem among children, with an estimated 300,000 deaths per year due to the disease.

• In United States, pertussis was one of the most common childhood diseases and a major cause of childhood mortality during the 20th century.
• With the widespread use of pertussis vaccine, the number of cases dropped

Whooping cough or pertusis is a severe disease of childhood. Causative agent: Bordetella pertussis

Properties: Gram-negative coccobacillary, encapsulated. It is confined to humans

Virulence factors: 1. Pertusis toxin: is a subunit toxin with Active (A) unit Binding (B) unit Unit A is a adenosine diphosphate (ADP) – ribosyl transferase. The functional consequence is to inhibit signal transduction by chemokine receptors, resulting in failure of lymphocytes to enter lymphoid tissue such as spleen & lymphnodes. Due to this there is an increase in their number in the blood. 2. Adenylate cyclase toxin: is a single peptide that can enter host cell & synthesize & export adenylate cyclase.

This enzyme when taken up by neutrophils, it results in inhibition of defense function like chemotaxis, phagocytosis, & bactericidal killing. 3. Tracheal cytotoxin: is a cell wall toxin which specifically kills tracheal epithelial cells. 4. Endotoxin: may play role in the pathogenesis of infection.

Pathogenesis:
Mode of transmission: by air borne droplets. The organism attaches & multiply to ciliated respiratory mucosa. It does not invade deeper. Incubation period: 1-3 wks. Clinical symptoms: Severe coughing spasms, inspiratory whoop, lymphocytosis

Transmission: • Pertussis bacteria live in the mouth, nose and throat of an infected person.

• Disease is spread through close contact when an infected person sneezes or coughs.
• It is most contagious during the first 2-3 weeks of infection, from the time the runny nose begins until 1-2 weeks after the onset of severe coughing spells.

• Recent outbreaks have shown that older children, adolescents, and adults including parents may carry the disease in milder form & is hard to recognize.

Pathogenesis

Stages of disease Catarrhal -> Paroxysmal -> Convalescent Catarrhal - is similar to upper respiratory tract infection. There is runny nose, sneezing, low grade fever, mild cough that worsens over a period of 1-2 weeks. Patient is highly infectious.

Paroxysmal - is characterized by a series of short coughs producing copious mucus, followed by a ‘whoop’. Sound produced by inspiratory gasp of air.
Infants and young children are especially vulnerable during this stage.

• During coughing attacks they may turn blue, and appear very ill or distressed. Vomiting and exhaustion commonly follow the episode.

• This stage usually lasts 1-6 weeks.
Convalescent – frequency & severity of coughing . Recovery is gradual as the cough disappears over 2-3 weeks • Many patients will continue to get cough attacks with later respiratory infections. • The disease is usually milder in adolescents and adults.

Complications: i) Subconjunctival haemorrhage due to pressure effects of violent coughing. ii) Bronchopneumonia & lung collapse. iii) Convulsions & coma.

Laboratory diagnosis: Specimen collected: Respiratory secretions, nasopharyngeal swabs taken during paroxysmal stage.

Culture: Media used: 1. Regan- Lowe medium
2. Bordet – Gengou medium which contains high % of blood (20-30%) to inactivate inhibitors. Plates are incubated at 35 – 360C for 3-5 days. Immunofluorescence is useful in identification of bacilli in smears.

• Some laboratories use the nasal passage swab to look for pertussis DNA fragments or antibodies to pertussis.

Serology Antibodies can be demonstrated in third week. Rise in titer of antibodies can be demonstrated in samples by Agglutination test Complement fixation test Immunofluorescent test Treatment: Tetracycline, chloramphenicol, erythromycin & ampicillin are sensitive. Erythromycin is drug of choice. It is useful in prevention in exposed, unimmunized individuals.

Prophylaxis:

Immunisation: there are two vaccines available • Acellular vaccine – it contains inactivated pertussis toxin & other bacterial components. • Inactivated B. pertussis organisms. Pertussis vaccine is generally administered in combination with diphtheria toxoid & tetanus toxoid ‘DPT’ or ‘triple vaccine’. Killed vaccine is no longer recommended in USA.

Adolescents:
• In 2005, two new pertussis booster vaccines, formulated for use in adolescents and adults, were approved by the FDA. • BOOSTRIX® is indicated for ages 10-18
• ADACEL® is indicated for ages 11-64. • Both vaccines contain tetanus, diphtheria, and acellular pertussis components (Tdap).

• Adolescents aged 11-18 years should receive a single dose of Tdap vaccine (BOOSTRIX® or ADACEL®) instead of Td (tetanus and diphtheria alone) as booster dose.

Adults Adult immunization with Tdap vaccine (ADACEL®) is intended to prevent spread to infants and other vulnerable populations

• Adults aged 19-64 should receive a dose of Tdap vaccine to replace their next tetanus (Td) booster.
• Adults who have or anticipate having close contact with an infant <12 months of age (e.g. parents, child care providers, health care providers) should receive a single dose of Tdap, ideally at least one month before beginning close contact with the infant. • Women should receive a dose of Tdap right after giving birth, if they have not previously received Tdap.

Side effects of vaccine are:  Fever, malaise & pain at the site of administration.

 Convulsion, thought to be associated with vaccine.
 Encephalopathy & permanent neurologic sequelae associated with vaccine. Rate is 1 in million doses administered.  Efforts are now concentrated on the production of subunit vaccines containing only the ‘protective ’ antigens.

Childhood Immunization Schedule
Birth 1m 2m 3m 4m 6m 12m 15m 18m 4-6y 11-12y

HBV2 HBV1
DTP DTP

HBV3
DTP Hib Polio MMR
Varicella MMR or MMR

DTP
Hib Hib Polio Polio Hib

INFECTIOUS MONONUCLEOSIS
It is caused by Epstein-Barr virus (EBV or Human Herpes Virus 4: HHV-4)

Infectious mononucleosis is named for the presence of large numbers of white blood cells (mononuclear cells) in the bloodstream. Infection occurs world wide among humans and occurs as a subclinical infection in early childhood.
About 70% of the people in US are infected by 30 years of age Infectious mononucleosis occurs in young adults 15-25 years of age. Incubation period is 1-2 months

• Most of these infections produce symptoms similar to those of a cold or other mild viral illness.
• Sometimes, teenagers and young adults develop different and more severe symptoms from EBV infection. • Teenagers and young adults usually catch infectious mononucleosis by kissing or having other intimate contact with someone infected with EBV.

• Rarely, EBV contributes to the development of several uncommon types of cancer, such as Burkitt's lymphoma and certain cancers of the nose and throat.

• A child with Burkitt's lymphoma

• It is thought that specific viral genes alter the growth cycle of infected cells and cause them to become

cancerous.
• EBV has been implicated in chronic fatigue syndrome.

Infectious mononucleosis, EBV is linked to causes cancers that kill 100,000 people around the world each year. The virus, which infects the immune system's B cells and causes them to grow - is directly responsible for Burkitt's lymphoma, an often-fatal malignancy affecting thousands of African children annually.

It is also associated with at least four other kinds of human cancers, includingHodgkin's lymphomas Lymphomas in AIDS patients Lymphomas in organ transplant recipients Nasopharyngeal carcinomas.

Transmission:

It is passed from person to person by saliva, hence the term kissing disease and can also be spread by the sharing food and utensils. It is also possible for it to spread through sexual contact however carriers of the virus can pass it on without developing it themselves.

By the age of 30, nearly 90% of all adults will have developed antibodies to EBV, indicating a full degree of immunity.

Once the virus enters the body it multiplies in lymphocytes, and affectsThe respiratory system

Lymphatic tissues
Glands in the neck, groin, armpit Bronchial tubes Spleen Liver

• All the viruses in the herpes group have the capacity to stay in the body after causing an initial infection, and produce lifelong latent infections.
• This latent infection is usually kept in check by the host’s immune system, however any compromise in immunity can lead to reactivation of the virus and a recurrent infection. • This infection can further disrupt immunity and lead to other diseases.

Pathogenesis: Disease is the result of viral replication and host immune responses to viral antigens. EBV infects the B cells in the oropharyngeal epithelium. The infected B cells spread the infection throughout the reticular endothelial system (RES), ie liver, spleen and peripheral lymphnodes. EBV infection of B- lymphocytes results in the humoral (Bcell mitogen) and cellular response to the virus.

• When a resting naive B cell in the follicle of a lymph node interacts with cognate antigen, it becomes activated and begins to proliferate as a B-cell blast. • Epstein-Barr virus (EBV) infection of B cells causes them to become proliferating B blasts due to expression of the viral growth transcription programme. • The antigen-activated B blast then enters the follicles, where it expands to form a germinal centre (GC). • Within the germinal centre, the survival of the cell depends on its ability to receive signals from antigen, carried on FOLLICULAR DENDRITIC CELLS, and antigen-specific T-helper (TH) cells. • These signals are mimicked through expression of the viral default transcription programme which can replace the TH and antigen signals. • Finally, the cells leave the follicle as resting memory B cells that enter the peripheral circulation.

B cell invasion: EBV invades B cells by means of their CD21 receptor, and 18-24 hrs later EBV antigens are detectable within the lymphocyte nucleus. During the acute phase, as many as 20% of the circulating B cells will show EBV antigens, while only 1% will show them during convalescence. B cell mitogen: The EBV infection initiates B cell proliferation and immortalization without the role of T helper cells. EBV can be thought of as a B cell mitogen.

Lymphocytosis: associated with infectious mononucleosis is caused by an increase in the number of circulating activated T cells; also called Downey cells because of their atypical presence in peripheral blood.

Manifestations: Usually a triad of symptoms: Fever, pharyngitis, and lympadenopathy. Acute disease: Fever Cervical lymphadenopathy Sore throat Diffuse pharyngeal inflammation Petechiae on hard and soft palates Splenomegaly Chronic disease: EBV can cause recurrent disease. These patient experience chronic tiredness, low grade fever, headaches and sore grades.

EBV-associated malignancies • The strongest evidence linking EBV and cancer formation is found in Burkitt's lymphoma and Nasopharyngeal carcinoma. • Burkitt's lymphoma is a type of Non-Hodgkin's lymphoma and is most common in equatorial Africa and is co-existent with the presence of malaria. • Malaria infection causes reduced immune surveillance of EBV immortalized B cells, so allowing their proliferation

• This proliferation increases the chance of a mutation to occur. • Repeated mutations can lead to the B cells escaping the body's cell-cycle control, so allowing the cells to proliferate unchecked, resulting in the formation of Burkitt's lymphoma. • Burkitt's lymphoma commonly affects the jaw bone, forming a huge tumor mass. It responds quickly to chemotherapy treatment, namely cyclophosphamide, but recurrence is common.

Diagnosis: The presence of atypical lymphocytes: During acute EBV disease, lymphocyte numbers elevate to 5060% of the total leukocyte in the peripheral blood. Of which 10% are atypical lymphocytes or Downey cells. Detection of heterophile antibodies: IgM that is produced recognize antigenic determinants on sheep, horse, and beef erythrocytes. Monospot test (Paul-Bunnell heterophile test)

EBV

Therapy: Most cases are mild. Acute illness lasts 2-3 weeks and patients recover in 4-6 weeks Systemic acyclovir stops EBV replication. Major complication occurs in 1-5% of cases. Most common complications are lymphocytic meningitis, encephalomyelitis, polyneuritis and mononeuritis. Guillian-Barre syndrome is a common condition that can lead to respiratory paralysis and death.

Cytomegalovirus (CMV)
CMV is a double-stranded, DNA herpesvirus that infects man and other species, producing unique large cells with inclusion bodies. Human CMV is also known as human herpesvirus-5 or HHV-5. In immunocompentent individuals, most CMV infections are mild and may produce a viral syndrome resembling infectious mononucleosis. CMV infections occur mainly early in life. Approximately 30 90% of immunocompetent adults >40 years old have antibodies (IgG) to CMV.

In healthy adults, CMV remains inactive or latent, but ready to be become active under favorable conditions. In immunocompromised or immunosuppressed patients, CMV reactivation can result in invasive CMV disease such as pneumonitis, esophagitis, encephalitis, hepatitis, pacreatitis, adrenalitis, esophagitis, gastritis, enteritis, colitis, and retinitis. Transmission: (1) Close contact (2) Blood transfusion

CMV

The replication cycle takes approximately 24 hours and consists of 3 phases: Immediate early phase (4 hrs) during which regulatory proteins are made Early phase ( 8 hrs) during which viral DNA polymerase is made Late phase ( 12 hrs) during which structural proteins are made and new viruses (virions) are assembled.

There are two clinical situations where infection with CMV may cause serious disease. (1)Congenital infection (2)Immunosuppressed individuals

Congenital infection If a mother becomes infected with CMV during pregnancy, the infant is at risk of congenital infection. Infection in immunosuppressed individuals Transplant patients and patients with AIDS, may develop life-threatening disease following either primary infection with CMV or reactivation.
Common syndromes include: Interstitial pneumonia, retinitis, enteritis, or disseminated infection

Clinical features
Most infected babies appear normal at birth. Affected infants may, however, later develop deafness or mental retardation. Rarely a severe generalized CMV infection of the neonate may occur (Cytomegalic inclusion disease). This condition is associated with jaundice, hepatosplenomegaly, thrombocytopenia, haemolytic anaemia and microcephaly. The histology of affected organs shows enlarged cells (‘cytomegalo’) with owls eye inclusions.

The prognosis for this condition is poor.

CMV usually infects epithelial cells. The infected cells are larger than uninfected, hyperplastic type II cells and have both nuclear (owl's eye) and cytoplasmic blue inclusions (arrow shows one infected cell).

H&E stained lung section showing typical owl-eye inclusions

CMV

Laboratory Diagnosis:

Direct detection :- CMV antigen in patient’s WBC’s
by immunofluorescence

Culture: -monolayers of human fibroblasts. Serology :- IgG and IgM antibodies
Treatment: Gancyclovir or Foscarnet These drugs are highly toxic and should only be used to treat life threatening infections

1. A 60 yr old woman had a adenocarcinoma of the colon that was surgically removed. Several blood transfusions were given, and she did well until 3 weeks after surgery when fever,omitting and diarrhea began. Blood and stool cultures were negative for bacteria, and the tests for Clostridium difficile and Hepatitis B surface antigen were negative. A liver biopsy revealed intranuclear inclusion bodies Which one of the following is the MOST likely cause? A B C D Cytomegalovirus Hepatitis A virus Rotavirus Dengue virus

2. A 19 yr old female college girl had fever,sore throat and lymphadenopathy accompanied by lymphocytosis with atypical cells and an increase in sheep cell agglutinins. The diagnosis is most likely

A Viral meningitis B Infectious mononucleosis C Chickenpox D German measles

References: Levinson : 7th edition- chapter – 19, 37,45 MIMS:2nd edition – chapter - 17. Jawetz- chapter 33,44


				
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