EPSTEIN-BARR VIRUS INFECTIONS, & INFECTIOUS MONONUCLEOSIS

1. EPSTEIN-BARR VIRUS INFECTIONS, & INFECTIOUS MONONUCLEOSIS Ar. Arun R Nair Dept. of PM

2. The virus, a member of the family Herpesviridae,EBV is a member of the herpes virus family. It infects B-lymphocytes. DEFINITION Epstein-Barr virus (EBV) is the cause of heterophile-positive infectious mononucleosis (IM), which is characterized by fever, sore throat, lymphadenopathy, and atypical lymphocytosis. EBV is also associated with several human tumors, including nasopharyngeal carcinoma, Burkitt’s lymphoma, Hodgkin’s disease, and (in patients with immunodeficiencies) B cell lymphoma Dr. Arun R.Nair, S.K.H.M.C

3. EPIDEMIOLOGY: EBV infections occur worldwide. These infections are most common in early childhood, with a second peak during late adolescence. By adulthood, more than 90% of individuals have been infected and have antibodies to the virus. IM is usually a disease of young adults. In lower socioeconomic groups and in areas of the world with lower standards of hygiene (e.g., developing countries), EBVtends to infect children at an early age, and symptomatic IM is uncommon. Dr. Arun R.Nair, S.K.H.M.C

4. Pathogenesis The virus infects epithelial cells primarily and replicates in them, leading to lysis of the cells. In EB virus induced pharyngitis, the saliva contains infective virus. Other sites of invasion are the cervical epithelium and B-lymphocytes. Immunosuppressant therapy predisposes to, and augments the development of EBvirus induced lymphoproliferative syndromes. One of the modes of spread of infection is through saliva and kissing is attributed to play a role. Dr. Arun R.Nair, S.K.H.M.C

5. Only B lymphocytes have receptors for EB virus, and therefore, EB virus attacks B lymphocytes initially. These cells begin to proliferate and are altered antigenically. Though T lymphocytes are not affected by EB virus they also proliferate enormously. The T cells destroy EB virus infected B cells resulting in the liberation of antigenic materials which stimulate the formation of autoantibodies. Both cellular and humoral responses occur, the former is more effective in conferring immunity. The virus develops strategies to elude the immune system and the infection tends to persist. Dr. Arun R.Nair, S.K.H.M.C

6. Symptoms • Sore throat • Malaise • Headache • Abdominal pain, nausea, or vomiting • Chills • Signs • Lymphadenopathy • Fever • Pharyngitis or tonsillitis • Splenomegaly • Hepatomegaly • Rash • Periorbital edema • Palatal enanthem • Jaundice • CLINICAL FEATURES Dr. Arun R.Nair, S.K.H.M.C

7. CLINICAL FEATURES The incubation period may range from 1 to 10 weeks, usually 2 weeks. The clinical spectrum may vary from that of a mild benign illness to that of a more severe and prolonged one. A prodrome of fatigue, malaise, and myalgia may last for 1 to 2 weeks before the onset of fever, sore throat, and lymphadenopathy. Fever is usually low-grade and is most common in the first 2 weeks of the illness; however, it may persist for 1 month. Lymphadenopathy and pharyngitis are most prominent during the first 2 weeks of the illness, while splenomegaly is more prominent during the second and third weeks. Dr. Arun R.Nair, S.K.H.M.C

8. C. F (con’t) • Lymphadenopathy most often affects the posterior cervical nodes but may be generalized. Enlarged lymph nodes are frequently tender and symmetric but are not fixed in place. • Pharyngitis, often the most prominent sign, can be accompanied by enlargement of the tonsils with an exudate resembling that of streptococcal pharyngitis. • A morbilliform or papular rash, usually on the arms or trunk, develops in 5% of cases. Erythema nodosum and erythema multiforme have also been develops • Most patients have symptoms for 2 to 4 weeks, but malaise and difficulty concentrating can persist for months. Dr. Arun R.Nair, S.K.H.M.C

9. C. F (con’t) • Symptomatic IM is uncommon in infants and young children. IM in the elderly presents relatively often as nonspecific symptoms, including prolonged fever, fatigue, myalgia, and malaise; in contrast, pharyngitis, lymphadenopathy, splenomegaly, and atypical lymphocytes are relatively rare in elderly patients Laboratory Findings Initially there is leukopenia due to decrease in neutrophils, but this is followed by leukocytosis in which the leukocyte count may go upto 15-20,000/cmm. The characteristic finding is the presence of atypical lymphocytes which may form 60-80% of the total. Low-grade neutropenia and thrombocytopenia are common during the first month. Dr. Arun R.Nair, S.K.H.M.C

10. Laboratory Findings(con’t) Liver function is abnormal in more than 90% of cases. Serum levels of aminotransferases and alkaline phosphatase are usually mildly elevated; the serum concentration of bilirubin is elevated in 40% of cases. Diagnosis should be strongly suspected if the proportion of atypical lymphocytes exceeds 50%. Presence of heterophile antibodies demonstrable by the Paul-Bunnell test (sheep-cell agglutination) strongly suggests the diagnosis of infectious mononucleosis. The titre of antibodies increases with the passage of time. They are detectable for 4 to 6 weeks. Recently a rapid slide test called monotesthas become available for quick diagnosis. Specific antibody to EB virus can be demonstrated by immunofluorescence, complementfixation, and gel diffusion methods Dr. Arun R.Nair, S.K.H.M.C

11. Chronic active EBV infection is diagnosed by the following features: • 1. Severe illness more than six months duration. • 2. Histological evidence of organ involvement such as pneumonitis, hepatitis, bone marrow hypoplasia and uveitis and • 3. Demonstration of EBV antigens or EBV DNA in tissues. • Complications. • These include haemolytic anemia, thrombocytopenia, aplastic anemia, myocarditis, hepatitis, genital ulcers, splenic rupture and Guillain-Barré syndrome. Some cases go into chronicity. Dr. Arun R.Nair, S.K.H.M.C

12. The Differential Diagnosis includes Rubella, Measles, Viral Hepatitis, Secondary Syphilis, Follicular Tonsillitis, Diphtheria and Herpetic Pharyngitis. The prolonged fever and constitutional symptoms may suggest Enteric Fever, Influenza, or even Acute Rheumatic Fever. The cases which present with neurological manifestations may have to be distinguished from encephalitis or lymphocytic choriomeningitis. Dr. Arun R.Nair, S.K.H.M.C

13. Burkitt lymphoma Dr. Arun R.Nair, S.K.H.M.C

14. Burkitt lymphoma The classic form of this B-cell tumour, first described by Burkitt in 1958, is found in certain parts of Africa and Papua New Guinea where the temperature does not fall below 16°C or the annual rainfall below 55 cm. Endemic Burkitt lymphoma is distinct from the 'Burkitt-like' tumours that occur sporadically everywhere in the world (sometimes called 'American' Burkitt lymphoma) and that have a different age incidence, anatomical distribution, and response to therapy, and arise from B cells with different phenotypic characteristics. The association between EBV and endemic Burkitt lymphoma is so close that it is generally accepted that the virus is an essential link along with cofactors in a complicated chain of events which leads to the malignancy. Hyperendemic malaria has been identified as the important cofactor, and its spread by anopheline mosquitoes requiring warmth and moisture explains the climate dependence of Burkitt lymphoma. Dr. Arun R.Nair, S.K.H.M.C

15. Burkitt lymphoma is a disease of childhood, is extremely rare over the age of 14 years, and in the endemic areas it is more common than all other childhood tumours added together. • Symptoms • The tumour is usually multifocal and the symptoms depend entirely on the anatomical location. Jaw tumours are present in 70 per cent of patients, are the usual presenting feature, may be multiple in up to all four quadrants, and are almost always accompanied by tumours elsewhere. They give a rapidly growing mass with loosening of teeth and exophthalmos from orbital spread. Abdominal tumours involve retroperitoneal nodes, liver, ovaries, intestines, and kidneys. Burkitt lymphoma sometimes presents in thyroid, the adolescent female breast, testicles, and salivary glands; extradural tumours in the spine cause rapid paraplegia, and skeletal tumours also occur. Characteristically Burkitt lymphoma does not involve the spleen or peripheral lymph nodes. Dr. Arun R.Nair, S.K.H.M.C

16. Signs The tumours are firm, very rapidly growing, painless, and cause minimal constitutional disturbance. Their sites determine the clinical signs. Clinical course Tumour growth is relentless and death ensues within a few months in the absence of treatment. Laboratory diagnosis Histological examination of a biopsy sample gives ready confirmation. Antibodies to EBV antigens show a unique pattern and titres rise or fall with disease progression or response to therapy. IgG anti-VCA(virus capsid antigen) titres are around 10 times higher than in controls and antibodies to EBV-restricted early antigens (EA-R) and membrane antigens (MA) are also detectable Dr. Arun R.Nair, S.K.H.M.C

17. Influenza Dr. Arun R.Nair, S.K.H.M.C

18. Influenza is a common viral disease which presents as an acute febrile illness. • caused by groups of myxoviruses • viruses contain a segmented RNA genome ( v. group in which genome consist of more than one RNA molecule, segments packaged within a single virion particles) • Types A, B, and C are antigenically distinct; of these, types A and B are important in human disease. • The viral envelope contains two glycoproteins, the Haemagglutinin(H) and Neuraminidase (N), which are critical in host immunity. • Influenza viruses are designated by the virus type, place of isolation, strain designation, year of isolation, and the H and N antigen subtype, for example A/Sydney/5/95 (H3N2). Dr. Arun R.Nair, S.K.H.M.C

19. Epidemiology The H and N genes of influenza types A, B, and C undergo mutational change resulting in the emergence of antigenic variants ('antigenic drift'). Every few years, a variant successful in evading the prior immunity of the human population emerges, to cause a global epidemic. 15 H and 9 N subtypes of influenza A are found in aquatic birds, the natural reservoir of the virus. Human influenza A viruses in the first half of this century carried H1N1 surface antigens. In 1957, this virus acquired the genes for different H and N antigens (H2N2) by reassortment of its segmented genome with an avian virus ('antigenic shift'). The human population had no immunity to these new antigens and the virus caused the 'Asian flu' pandemic. A similar reassortmentevent gave rise to the H3N2 virus and the 'Hong Kong influenza' pandemic of 1968. While all three influenza pandemics this century resulted in significant morbidity and mortality, the toll exacted by the 'Spanish flu' of 1918 was horrendous—over 20 million deaths, greater than that of both World Wars combined. Since influenza B and C have no significant zoonotic reservoirs, antigenic shift and pandemics do not occur. Dr. Arun R.Nair, S.K.H.M.C

20. Pathogenesis Viral replication occurs in the columnar epithelial cells leading to its desquamation down to the basal cell layer. The pathology involves the entire respiratory tract. Infection results in decreased ciliary clearance, impaired phagocyte function, and increased adherence of bacteria to viral infected cells, all of which promote the occurrence of secondary bacterial infection. Virus dissemination outside the respiratory tract is uncommon in humans, though it has been occasionally detected in the brain, heart, and fetus. Immunity Infection by an influenza virus results in long-lived immunity to homologous reinfection. However, the continued antigenic change in the virus allows it to keep ahead of the host immune response. Cross-immunity to 'drifted' strains within the same H or N subtype may provide partial protection, but there is little cross protection between different subtypes. Local and systemic antibody responses and cytotoxic T cells contribute to host protection. Dr. Arun R.Nair, S.K.H.M.C

21. Pathology Virus spreads by the respiratory route. Viral multiplication reaches its peak in 24-72 hours after the onset of the clinical illness. The virus multiplies in cells lining the respiratory tract including the ciliated epithelium, alveolar cells, mucous gland cells and macrophages. The infected cells show degenerative changes like cytoplasmic granulation, vacuolation and swelling. Ultimately the cells undergo necrosis and they slough away. The mucosa is hyperemicand edematous. Focal hemorrhagesare common in these sites. Pneumonia may occur primarily due to viral infection, though it is more common to get secondary bacterial pneumonia. In viral pneumonia intraalveolar hemorrhagemay occur. Secondary bacterial infection occurs in about 25% of cases and it gives rise to suppurative inflammation. Dr. Arun R.Nair, S.K.H.M.C

22. Clinical features Influenza ranges from asymptomatic infection, through the typical influenza syndrome, to the complications of influenza. While it cannot always be distinguished from other viral infections on clinical grounds, the typical influenza syndrome is relatively characteristic. It is associated with fever, chills, headache, sore throat, coryza, non-productive cough, myalgia, and sometimes prostration. The onset of illness is abrupt and the fever lasts 1 to 5 days. The pharynx is hyperaemic but does not have an exudate. Cervical lymphadenopathy is often present and crackles or wheezing are heard in around 10 per cent of patients. While the acute illness usually resolves in 4 to 5 days, the cough and fatigue may persist for weeks thereafter. Dr. Arun R.Nair, S.K.H.M.C

23. Clinical features • Common (>10 per cent of symptomatic patients) complications of influenza include otitis media (in children) and exacerbation of asthma, chronic obstructive airways disease, and cystic fibrosis. • Less common complications are acute bronchitis, primary (viral) and secondary (bacterial) pneumonia, myocarditis, febrile convulsions, encephalopathy, encephalitis, and myositis (especially in patients with influenza B infection). Age, prior immunity, virus strain, the presence of underlying diseases, pregnancy, and smoking all influence morbidity and severity. Mortality is higher in the age groups below 2 years and above 65 years. Dr. Arun R.Nair, S.K.H.M.C

24. Complications Pulmonary Complications These include primary influenza virus pneumonia, influenzalpneumonia with secondary bacterial infections, and bacterial pneumonia with multiple organisms. 1. Primary influenza virus pneumonia: This is a serious condition associated with high mortality. These subjects present with high fever, cough with blood stained expectoration, dyspnea and cyanosis. Examination of the chest may reveal bilateral rhonchi and crepitations. Pulmonary involvement is diffuse. Fever and respiratory signs persist despite antibiotic therapy and other symptomatic measures. The course is more acute and serious in those cases with rheumatic heart disease, myocardial infarction, or chronic obstructive airway disease. 2. Influenzal pneumonia with secondary bacterial infection: In addition to viral pneumonia, localized consolidation may also develop. 3. Bacterial pneumonia: The condition is caused by multiple organisms such as staphylococci, Hinfluenzae, group A streptococci, and pneumococci. This type of pneumonia carries a grave prognosis. Dr. Arun R.Nair, S.K.H.M.C

25. Cardiac Complications Toxic myocarditis may occur. This gives rise to tachycardia and cardiac failure. The ECG may be abnormal. Neurological Complications These include febrile convulsions, meningitis, meningoencephalitis and encephalitis. A rare complication is the development of Reye’s syndrome, which is more frequently seen in children. It presents as hepatic failure with encephalopathy and rise in intracranial tension. Reye’s syndrome is associated with ingestion of aspirin. Apart from influenza A and B other viruses may also lead to this syndrome, e.g. varicella. Reye’s syndrome develops as a result of serious derangement of mitochondrial function Dr. Arun R.Nair, S.K.H.M.C

26. LABORATORY FINDINGS AND DIAGNOSIS Influenza virus may be isolated during acute influenza from throat swabs, nasopharyngeal washes, or sputum. Virus is usually detected by use of tissue culture or, less commonly, chick embryos within 48 to 72 h after inoculation. Most commonly, the diagnosis is established by the use of rapid viral tests that detect viral nucleoprotein or neuraminidase with high sensitivity and a specificity of 60 to 90% compared with that of tissue culture. Viral nucleic acids can be detected in clinical samples by reverse transcriptase polymerase chain reaction. Dr. Arun R.Nair, S.K.H.M.C