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PART TWO PART TWO SYSTEMIC VIROLOGY SYSTEMIC VIROLOGY Prepared by Professor Dr Hassan J Hasony Prepared by Professor Dr Hassan J Hasony Dept Med Microbiology,

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Presentation on theme: "PART TWO PART TWO SYSTEMIC VIROLOGY SYSTEMIC VIROLOGY Prepared by Professor Dr Hassan J Hasony Prepared by Professor Dr Hassan J Hasony Dept Med Microbiology,"— Presentation transcript:

1 PART TWO PART TWO SYSTEMIC VIROLOGY SYSTEMIC VIROLOGY Prepared by Professor Dr Hassan J Hasony Prepared by Professor Dr Hassan J Hasony Dept Med Microbiology, Basrah Medical College Dept Med Microbiology, Basrah Medical College

2 OBJECTIVES: Viral infections attributed to each system will be discussed concentrating on : Viral infections attributed to each system will be discussed concentrating on : - properties of viral aetiologic agent - properties of viral aetiologic agent - clinical finding and case presentation - clinical finding and case presentation - Epidemiology of viral infections - Epidemiology of viral infections - prevention and control measures - prevention and control measures - Laboratory diagnosis and interpretation of lab. Test results - Laboratory diagnosis and interpretation of lab. Test results

3 LEARNING OBJECTIVES student should be able to answer the questions attached to each lecture concerning the target system and having a skil to identify and interprept the results of any related investigations for linking the presented case to the viral aetioloigic agent(s) student should be able to answer the questions attached to each lecture concerning the target system and having a skil to identify and interprept the results of any related investigations for linking the presented case to the viral aetioloigic agent(s)

4 THE FAMILY OF VIRUSES RNA VIRUSES A.Orthomyxoviridae B.Paramyxoviridae C.Rhabdoviridae D.Filoviridae E.Flaviviridae F.Picornaviridae G.Reoviridae H.Togaviridae I.Retroviridae


6 Replication Sites and Clinical Manifestations

7 Why so many? Constant exposure: 21,000 L of air/day Constant exposure: 21,000 L of air/day RT is a favorable environment for viruses: RT is a favorable environment for viruses: Warm, moist, and dark Warm, moist, and dark Plenty of cell types (25), which are good tissue culture media Plenty of cell types (25), which are good tissue culture media Optimal temperature Optimal temperature Easy transmission via: Easy transmission via: Sneezing – aerosol m particles at 100 ft/sec Sneezing – aerosol m particles at 100 ft/sec Cough – disperses nasopharyngeal content at 850 ft/sec Cough – disperses nasopharyngeal content at 850 ft/sec Intimate and non-intimate contact Intimate and non-intimate contact

8 Determinants of Viral Respiratory Disease Viral Factors Viral Factors Tissue tropism Tissue tropism Route of infection Route of infection Stability of the virus Stability of the virus Replication and release of viruses into aerosols Replication and release of viruses into aerosols Host Factors Host Factors Age Age Immune status Immune status Underlying disease Underlying disease adaptationadaptation Environmental Factors Dosage Exposure Occupation Life Style: Occupation Day care setting Public transport


10 RNA VIRUSES Enveloped, Single-stranded RNA Viruses Orthomyxoviruses: Influenza - spherical particles with an average diameter of nm - contains 7 structural proteins : PB1, PB2, PA – bound to viral RNA ; responsible for RNA transcription and replication Nucleoprotein ( NP ) – associates with viral RNA to form a structure 9 nm in diameter that assumes a helical configuration Matrix ( M ) protein – forms a shell underneath the viral lipid envelope; important in particle morphogenesis HA ( hemagglutinin ) } determines antigenic variation NA ( neuraminidase ) } of influenza viruses

11 11 ORTHOMYXOVIRUSES M1 protein helical nucleocapsid (RNA plus NP protein) HA - hemagglutinin polymerase complex lipid bilayer membrane NA - neuraminidase type A, B, C : NP, M1 protein sub-types: HA or NA protein

12 Influenza virus genome: - divided into eight separate segments reassorting during viral assembly antigenic nature of proteins change - antigenic drift : changes in a single amino acid - antigenic shift : the accumulation of enough changes to create a new subtype different from the original strain - 16 H and 9 N ( H= 2 to the power 16,N=2 to power 9

13 Classification and nomenclature : - antigenic differences between NP and M proteins divides influenza viruses into : type A : highly variable antigenically ; responsible for most cases of epidemic influenza type B : may exhibit antigenic changes and sometimes causes epidemics type C : antigenically stable ; causes only mild illness

14 Properties : - relatively stable; may be stored at 4 degrees C for a week - infectivity destroyed by heating at 56 degrees C for a few minutes, treatment with ether, formaldehyde, phenol and other protein denaturants - initial isolation best accomplished by amniotic inoculation of embryonated chicken eggs and monkey cell cultures

15 EPIDEMIOLOGY: Influenza A - acute, highly contagious, respiratory illness afflicting people of all ages marked by seasonal regularity and pandemics at predictable intervals - five pandemics in recorded history : the worst was in 1918 where there were at least 50 million deaths - the most virulent among the three types of influenza viruses


17 ( cont. epidemiology ) - influenza A strains are also known for pigs, horses,ducks and chicken - antigenic changes in group A > B; group C appears to be antigenically stable - interpersonal spread due to formation of virus-laden aerosol droplets when an infected patient sneezes or coughs if virus is not neutralized ( e.g. local IgA specific anti- hemagglutinin Ab ), initial replication occurs

18 Mode of influenza transmission: - inhalation of aerosol and droplets major route of infection - transmission greatly facilitated by crowding and poor ventilation usually in late fall and winter in temperate countries throughout the year in the tropics - occupational contact with ducks, other poultry,and swine constitutes a special high-risk category for disease - OVERALL MORTALITY FOR INFLUENZA A : 0.1 % of cases with deaths occurring among the elderly and small children Pathogenesis: Virus binds to ciliated columnar cells (respiratory mucosa) rapid shedding of mucosal cells together with a load of viruses trachea and bronchial epithelia are stripped to the basal layer leading to severe inflammation and irritation viruses remain in respiratory tract (viremia is rare); ciliated columnar epithelium restored w/in 1-2 wks

19 FACTORS AFFECTING EFFICIENCY OF AEROSOL SPREAD: 1. direct proportion to the number of particles generated 2. density of susceptibles 3. physical and temporal contiguity to aerosols 4. degree of stagnation of ambient atmosphere - high attack rates : nursing homes, classrooms, ships, barracks, aircraft - smokers : increased susceptibility to infection - young children ( pre-school or grade school ) : most effective disseminators of the disease - periodicity of influenza epidemics/pandemics: determined by the surface antigens of the virus and the antibodies induced within a population

20 Recovery from infection depends on: a. general health b. immunity from previous exposure c. vaccination d. age

21 DIAGNOSIS: 1.Virus isolation /detection of viral antigen in respiratory secretions ( nasal/throat swabs; nasal washes ; combined nose-and-throat swab ; sputum ) which are inoculated into : a. rhesus monkey kidney or Madin-Darby canine kidney cell cultures CPE or hemadsorption b. embryonated hens eggs ( allantoic or amniotic cavity )

22 2. Rapid diagnosis a. samples centrifuged directly onto cells in shell vials detection of viral antigens by IF or ELISA * sensitivity higher in nasophrayngeal washes and swabs b. PCR

23 3. serologic testing - compares acute and convalescent sera ( days apart ): 4 fold rise in titer a. CF b. HAI 4. epidemiologic diagnosis - when infection is confirmed within a region by the local health department

24 PREVENTION: - primary means of prevention : vaccines - vaccines not used much because: a. offers only a short duration of protection b. possibility of sensitization or severe allergic reactions in persons hypersensitive to eggs ( vaccine viurs grown in chick embryo ) c. possibility of toxic reactions to the high concentration of virus material administered parenterally d. uncertainty of protection because of the changing antigenicity of the circulating influenza strains - vaccination recommended for high-risk groups: a. the chronically ill b. the elderly ( > 65 years old ) c.persons with high degree of exposure to the public

25 -standard vaccines containing viruses grown in embryonated eggs have an overall effectiveness of 70 % ( accompanied by side effects of chills and fever) - newer subunit vaccines made by disrupting virus with detergents or solvents have fewer side reactions but are more limited in scope of protection - recent tests being done on influenza vaccine administered intra-nasally ( greater potential for immunogenicity)

26 CONCEPT QUESTIONS - -Mention the major groups of viruses causes RTI. - - What are the determinants of viral respiratory diseases ? - -What are the properties of orthomyxoviruses ? - - What is the major characters of influenza virus genome ? - - On what basis influenza viruse can be classified ? - - What is the possible mechanism for influenza virus antigenic changes? - - What is the mode of influenza virus trasmission ? - - Illustrate the pathogenesis of influenza virus ? - - What are the factors affecting efficiency of aerosole spread ? - - Recovery from influenza virus infection depends on: - - What are the diagnostic methods for influenza infections? - - What are the strategies for influenza prevention ? - - Who are the target for influenza virus vaccinatio ? - -What are the types of influenza vaccines, giving the advantages of each ?

27 ENVELOPED, RNA VIRUSES PARAMYXOVIRUSES The important human paramyxoviruses: a. Paramyxovirus ( parainfluenza and mumps ) b. Morbillivirus ( measles virus ) c. Pneumovirus ( respiratory syncytial virus ) - resembles the influenza virus but are larger - all are transmitted thru respiratory droplets - envelope has HN spikes and F glycoprotein spikes that allow the virus to infect neighboring cells : HN ( hemaglutinin and neuraminidase ) : responsible for host cell attachment F glycoprotein : mediates membrane fusion and hemolysin activity

28 Paramyxoviridae Properties of the Paramyxoviridae 2. Morphology & structural proteins

29 Paramyxoviridae Properties of the Paramyxoviridae 2. Morphology & structural proteins

30 PARAMYXOVIRUSES: Mechanism of infection: cell membrane of infected cell modified by insertion of spikes HN spikes immediately bind an uninfected neighboring cell in the presence of F spikes two cells permanently fuse chain reaction of multiple cell fusions produce a syncytium or a multinucleate giant cell (with cytoplasmic inclusion bodies)

31 I. PARAINFLUENZA 4 major serotypes : 1. Parainfluenza virus types 1 and 2 - usually infects infants and children 2. Parainfluenza virus type 3 - infects infants < 2 years - year round infections - more severe than types 1 and 2 3. Parainfluenza virus type 4 - mild disease

32 Epidemiology and Pathology - primary infection with virus occurs throughout the year ( seasonal peaks in late fall and winter ) - droplets and respiratory secretions disseminate the virus into the air and onto fomites - usual route of transmission: inhalation or inoculation of mucous membranes by contaminated hands - usually seen most frequently in children - NO transplacental immunity ; babies in first year are particularly susceptible ( more severe symptoms )

33 Characteristic symptoms of parainfluenza: a. minor upper respiratory tract disease (a cold)- caused by all types b. bronchitis – usually caused by type 3 c. bronchopneumonia – usually caused by type 3 d. laryngotracheobronchitis ( croup)- afflicts larynx of infants and young children causing labored,noisy breathing with hoarse cough; usually asso. with types 1& 2 * second only to RSV as a cause of lower respiratory tract infection * commonly cause croup

34 LABORATORY DIAGNOSIS : 1. Isolation and identification of the virus * specimens : throat and nasal swabs and nasal washes * inoculated on primary human and monkey kidney cells -> isolates typed by IF or hemadsorption inhibition or HI 2. Serology : uses paired sera

35 CONCEPT QUESTIONS - Mention the important human paramyxoviruses. - What is the mechanism of infections with paramyxoviruses ? - Four serotypes of parainfluenza, mention the host range and disease caused by each type. disease caused by each type. - What are the epidemiologic feature and pathology of parainfuenza virus infections? parainfuenza virus infections? - What are the characteristic symptoms of parainfluenza ? - Mention the main laboratory diagnostic methods for parainfluenza. parainfluenza.



38 Adenovirus Penton Fiber What might be its function ?? What are these components?









47 CONCEPT QUESTIONS: - Mention the main characteristic of adenoviruses. - - Describe the pathogenesis of adenovirus infections. - - What are the epidemiological feature of adenovirus infection? - - What are the clinical significane of addenovirus infections? - - What are the main clinical finding associated with acute - febrile pharyngitis? - - In what ways adenovirus can evade host immune response?

48 II. MUMPS ( EPIDEMIC PAROTITIS ) : - self-limited, mildly epidemic illness associated with painful at the angle of the jaw with occasional swelling of the testes - virus bears morphologic and antigenic characteristics similar to the parainfluenza virus - has only one serological type - grows readily in embryonated eggs esp. in the amniotic sac - can be grown in cell culture to produce large multinucleated giant cells ( syncytia ) and a hemagglutinin - infectivity of virus destroyed by heating at 56 degrees C for 20 mins.

49 Mumps Inflammation, parotitis in a child with mumps

50 Mumps Parotid gland

51 Epidemiology and Pathology of Mumps: - humans are the exclusive natural hosts - occurs worldwide, epidemics occur in the late winter and early spring - high rate of infection among crowded populations - most cases occur in children under 15 years ( 40 % subclinical) - lasting immunity follows any form of mumps infection - communicated thru salivary and respiratory secretions ( less contagious than measles or varicella )

52 ( cont. epidemiology and pathology of mumps ) - incubation period : 2-3 weeks followed by symptoms of fever, nasal discharge, muscle pain, and malaise - inflammation of salivary glands ( esp. the parotids) produce the classic gopher-like swelling of the cheeks on one or both sides - viral multiplication in salivary glands viremia and invasion of other organs ( e.g. testes, overies, thyroid gland, pancreas, meninges, heart, kidney) -PROGNOSIS: most will have complete, uncomplicated recovery

53 Complications of Mumps: 1.Orchitis and epididymitis : occurs in 20-30% of young adult males : painful but no permanent damage occurs 2. Pancreatitis : virus replicates in beta cells and pancreatic epithelial cells 3. Viral meningitis : fever, headache, nausea, vomiting, and stiff neck : common in mumps : appears 2-10 days after onset of parotitis : lasts 3-5 days, dissipates with few or no adverse side effects 4. Hearing loss : a rare occurrence : affects only one side : virus replicates in the organ of Corti causing permanent deafness

54 ( cont. mumps ) Diagnosis: 1. history ( exposure ) and PE ( parotid swelling ) 2. serologic studies * IgM antibodies by ELISA or 4 fold increase between acute and convalescent sera 3. viral isolation * virus present in saliva for about 1 week aftre onset of parotitis Treatment : Symptomatic treatment usually adequate Prevention : a live, attenuated mumps vaccine given routinely as part of the MMR vaccine at 15 months of age ( powerful and effective control agent ) : protection often lasts a decade

55 CONCEPT QUESTIONS - -What are the characteristic of mumps disease ? - - What are the epidemiologic feature and pathology of mumps? - - What are the major complication of mumps ? - - What are the diagnostic methods for mumps? - - What are the main method s for prevention & control of mumps ? mumps ?

56 III. MEASLES ( Morbillivirus Infection ) - also known as red measles and rubeola - entirely unrelated to rubella ( German MEASLES ) - characterized by maculopapular eruption, URTI,conjunctivitis Epidemiology: - one of the most contagious infectious diseases - rare under 6 months of age: transplacental IgG - transmitted principally by direct contact with respiratory aerosols - epidemic spread favored by crowding, a prevalence of nonimmune children, malnutrition measles epidemic linked to lack of immunization in children or the failure of a single dose of vaccine in many children - no reservoir other than humans - person considered infectious during period of incubation, prodrome, and skin rash - single attack confers lifelong immunity

57 Measles (measles or rubeola) maculopapular rash

58 Maculopapular rash on buttocks of boy during 3 rd day of the rash

59 Conjunctivitis Eyes of child with measles

60 CPE typical of measles virus infection of Hela cells (Hematoxylin & Eosin staining) ( The large syncytia, or multinucleated giant cells, result from fusion of cell membranes bearing viral glycoproteins e syncytia, or multinucleated giant cells, result from fusion of cell membranes bearing viral glycoproteins.)

61 ( cont. Measles ) Infection and Disease: * incubation period : 2weeks : invasion of mucosal lining of respiratory tract, followed by viremia Symptoms : sore throat, dry cough, headache, conjunctivitis, lymphadenitis, and fever Signs : Kopliks spots( on lateral buccal mucosa ) appear as a prelude to the red maculopapular exanthem that erupts on the head which progresses to the trunk and extremities : rash gradually coalesce into red patches that fade to brown

62 Kopliks spot Patient who presented with Kopliks spots on palate due to pre-eruptive measles on day 3 of the illness

63 Complications : in most instances, a self-limited infection : may be severe enough to cause death in about 1 in 500 children : laryngitis, bronchopneumonia, bronchitis, pneumonitis, bacterial secondary infections, otitis media and sinusitis : children with leukemia predisposed to pneumonia due to lack of natural T-cell defense : SSPE ( subacute sclerosing panencephalitis ) ( manifests 5-7 years after initial infection)

64 Diagnosis : 1. Clinical - age, history of recent exposure to measles, ( useful clues to diagnosis) - cough, coryza, conjunctivitis, Kopliks spots, a maculopapular rash beginning on the face 2. Laboratory a. virus isolation b. identification of measles antigen in infected tissues ( IF from nasal exudates/urine sedi- ments and RT-PCR ) c. demonstration of specific serologic response ( ELISA, HI on paired serum samples )

65 Treatment : symptomatic treatment for most cases : antibiotics may be given for bacterial complications : large doses of immune globulin may be therapeutic Prevention : vaccination is the most practical, economical, and enduring strategy to combat measles

66 Measles vaccine : - attenuated virus given subcutaneously - immunity persists for about 20 years - may cause atypical infection - recommended for all healthy children at the age of 15 months ( MMR vaccine, with mumps and rubella ) and a booster prior to entering school - any person who received the vaccine prior to 1980 or whose immunization history is in doubt should be revaccinated

67 CONCEPT QUESTIONS - Define measles. - - What are the epidemiologic picture of measles. - - What are the major sign and symptoms of measles. - - What are the complications of measles ? - - What are the basis for the diagnosis of measles clinically or laboratory? clinically or laboratory? - What are the major preventive measures of measles? - What is the schedule of measles vaccination and what type of vaccine ? what type of vaccine ?

68 Rubella Electron micrograph of rubella virus

69 Rubella Epidemiology of Rubella Virus Disease / Viral Factors - Rubella infects only humans. - Virus can cause asymptomatic disease. - There is one serotype.

70 Rubella Epidemiology of Rubella Virus Transmission - Respiratory route Who Is at Risk? - Children: mild exanthematous disease. - Adults: more severe disease with arthritis / arthragia - Neonates younger than 20 weeks: congenital

71 Rubella Rash of rubella on skin of child's back.Distribution is similar to that of measles but the lesions are less intensely red.

72 Rubella Prenatal or congenital rubella The risk to a fetus is highest in the first few weeks of pregnancy and then declines in term of both frequency and severity, although there is still some risk in 2 nd trimester. The virus infects the placenta and then spreads to the fetus. If non-immune mothers are infected in the 1 st trimester, up to 80% of neonates may have sequelae.

73 Rubella The sequelae of congenital rubellar syndrome are: Hearing loss: This is the most common sequella of congenital rubella infection especially when the latter occurs after 4 months of pregnancy. Congenital heart defects Neurologic problems: psychomotor retardation : mental retardation Ophthamic problems: cataract, glaucoma, retinopathy

74 Rubella Prominent Clinical Findings in congenital rubella Syndrome Cataracts & other ocular defects Heart defects Deafness Intrauterine growth retardation Failure to thrive

75 Rubella Prominent Clinical Findings in congenital rubella Syndrome Mortality within the first year Microcephaly Mental retardation

76 Rubella This infant has the rash of congenital rubella (German measles).These infants are at great risk for severe mental retardation, deafness, blindness (atrophic eyes, cataracts and chorioretinitis) as well as congenital heart disease and other abnormalities..

77 Rubella Baby born with rubella: Thickening of the lens of the eye that causes blindness (cataracts)

78 Rubella Immune response - Specific IgM antibody appears within a few days of the rash, and is followed soon after by IgG. - The titer of IgM increases rapidly, reaching a peak about 10 days after onset and thereafter declining to undetectable amounts over several weeks or months. * Humoral Immunity

79 Rubella Immune response - The rapid appearance of specific IgM antibody is invaluable for diagnostic purposes. - IgG antibody peaks at about the same time as IgM, and persists for many years, as does IgA antibody, which appears in the serum and nasopharyngeal secretion. * Humoral Immunity

80 Rubella Immune response - The cell-mediated response precedes the appearance of antibody by a few days, reaches a peak at about the same time, and is also detectable for many years. * Cellular Immunity

81 Rubella Diagnosis of rubella - Many (~ 50%) infections are apparently subclinical and many infections go unrecognized, even if symptoms develop (rash is not always present). - Infections with many other agents give similar symptoms to rubella (e.g. infection with human parvovirus, certain arboviruses, many of the enterovirus group of piconaviruses, some adenoviruses, EBV, scarlet fever, toxic drug reactions).

82 Rubella Diagnosis of rubella - Serological tests or isolation of virus (immunofluorescence) are needed to confirm infection of individual Cord blood rubella- IgM

83 Rubella Epidemiology - Human is the only host and rubella occurs world wide. - Periodic epidemics occur in an unvaccinated population. - Natural infection protects for life (there is a single serotype).

84 Rubella Prevention - The best means of preventing rubella is vaccination with the live cold-adapted RA27/3 vaccine strain of virus. - The live rubella vaccine is usually administered with the measles & mumps vaccines (MMR vaccine) at 24 months of age.

85 Rubella Prevention - A live vaccine (attenuated strain) is available. The vaccine virus is grown in human diploid fibroblasts. Since there is only 1 serotype, a univalent attenuated vaccine can provide lifelong immunity.

86 Rubella Prevention - It is important that women are vaccinated prior to their 1 st pregnancy. - United States recommendations are for childhood vaccination to prevent epidemics, combined with vaccination of susceptible, non-pregnant adolescent and adult females.

87 Rubella Prevention - The vaccine is contraindicated for pregnant women, but when unwittingly used, no problems have been seen. - If the patient is pregnant and seronegative, the pregnancy should be monitored carefully and the patient vaccinated postpartum.

88 Rubella Treatment There is no specific treatment. Supportive care should be used.

89 CONCEPT QUESTIONS - What is the epidemiologic feature of rubella ? - - Who is at risk of rubella infections? - - What are the differences between measles and rubella ? - - What is CRS ? - - Describe the consequences of congenital rubella ? - - What are the sequellae of congenital rubella syndrome ? - - What are the prominant clinical findings in CRS ? - - Describe the humoral responses to rubella virus infection? - - Describe the cellular responses to rubella virus infection? - -Is the diagnosis of rubella virus infection always feasible ? - - What are the diagnostic methods for rubella and CRS ? - - What are the epidemiologic feature of rubella? - - Mention the main methods for rubella prevention? - - In what situations rubella vaccine can be contraindicated ?

90 IV. RESPIRATORY SYNCYTIAL VIRUS - Also called Pneumovirus - infects the respiratory tract and produces giant multinucleate cells - peak incidence in the winter and early spring - children 6 months or younger are especially susceptible to serious disease RSV Infection : - incidence of RSV in children < one year old is 5/1000 live births ( most prevalent cause of respiratory infection in this age group) - mortality highest for children with complications ( e.g., prematurity, congenital disease, and immunodeficiency ) - immunity is partial or transient, hence, infection could be recurrent - manifests itself as a common cold in older children and adults

91 ( cont. RSV infections ) Pathogenesis - transmission : respiratory route - portal of entry : epithelia of the nose and eye - main site of replication: nasopharynx - symptoms : ( 1 o infection) fever that lasts for three days : rhinitis, pharyngitis, and otitis : infection of the bronchial tree and lung parenchyma gives rise to croup ( acute bouts of coughing, wheezing, dyspnea and rales )

92 Clinical Disease : - major cause of respiratory illness in young children - < 24 months : devastating disease -> 4 months : no protective maternal antibody 1.Lower respiratory tract infections - pneumonia, bronchiolitis, tracheobronchitis 2. Upper respiratory tract infections - presents as common cold 3. Complications - otitis media: common

93 Diagnosis - critical in babies than in older children - positive identification of RSV must be made as rapidly as possible 1.Viral isolation on nasal wash / naspharyngeal and throat swab ( done ASAP since virus is labile ) 2. Direct and indirect fluorescent staining from a fresh sample ( the virus is very fragile ) 3. ELISA testing and DNA probes

94 ( cont. RSV ) Treatment : Ribavirin (virazole) appears beneficial since it interferes with the replication of the virus in infected cells : Ribavirin is administered as an aerosol ( cannot be given to persons whose ventilation is compromised) : costly treatment with some adverse side effects : supportive measures Prevention : intranasal live vaccine presently being developed

95 CONCEPT QUESTIONS CONCEPT QUESTIONS - -In what age groups the incidence of RSV is highest ? - - Describe the pathogenesis of RSV. - - Mention the clinical diseases caused by RSV and their complications. their complications. - -What are the diagnostic methods of RSV infections? - - What are the treatment of RSV and the methods for prevention? for prevention?

96 HUMAN RHINOVIRUS (HRV ) - an extremely large group of picornaviruses ( > 110 serotypes ) - associated with the common cold - characteristics which distinguish the rhinovirus from the other picornaviruses: 1. Rhinoviruses are sensitive to acidic environments ( e.g. stomach ) 2. Optimum temperature for multiplication is not normal body temperature, but 33 o C, the average temperature in the human nose structure of the Rhinovirus: - the capsid units are of two types: a. protruberances (knobs), which are antigenically diverse among the rhinoviruses b. indentations (pockets) of which there are two types


98 Pathogenesis and Clinical Manifestations Portal of entry: nose, mouth, eyes Portal of entry: nose, mouth, eyes Replication: in the nose Replication: in the nose Primarily infects upper airway common cold Primarily infects upper airway common cold Binds to ICAM-1 as cellular receptors Binds to ICAM-1 as cellular receptors Causes lysis of cells Causes lysis of cells Infected cells release bradykinin and histamine rhinitis & rhinorrhea Infected cells release bradykinin and histamine rhinitis & rhinorrhea Sore throat, cough, headache, malaise Sore throat, cough, headache, malaise Immunity is serotype specific Immunity is serotype specific

99 Rhinoviruses -the surface antigens are the only ones accessible to the immune system ( i.e. a successful vaccine would have to contain hundreds of different antigens- not practical ) -the indented antigens are too deeply situated for either immune surveillance or antibody fit Epidemiology and Infection of Rhinoviruses : - infection occurs in all areas, and all age groups at all times of the year. - many strains circulate in the population at one time ( occasionally a single type may cause epidemics) - children are the most successful disseminators of colds, often introducing the virus to the whole family - virus is shed from infected respiratory tract for several days – weeks - transmission is linked very closely to inoculation by hands and fomites ( to a lesser extent to droplet nuclei )

100 Rhinovirus Control of infection: - combined antiviral-antimediator treatment: In a trial using interferon-alpha 2 + ipratropium (both instilled into the nose) + oral naproxen - > viral shedding and progression of illness were reduced in the treatment group -Other measures: a. hand washing b. avoiding finger-eye and finger-nose contact c. covering coughs and sneezes with disposable nasal tissues

101 Rhinovirus Symptomatic therapy: -Combination of a 1 st generation antihistamine and a non-steroidal anti-inflammatory compound effective treatment -Treatment started a early as symptoms are recognized and continued every 12 hours for 4-5 days -Antibiotics have no place in therapy Antiviral therapy: - the most promising results have been obtained with recombinant interferon-alpha 2 applied topically in the nose - interferon-alpha 2 is given prophylactically on doses of approximately 5 million units or greater per day highly effective in prevcnting experimental infection or illness - side effects of chronic topical interferon-alpha 2 include : nasal irritation, stuffiness, pinpoint mucosal ulcerations

102 CONCEPT QUESTION - -What are the characteristics of Rhinoviruses ? - - What are the pathogenesis and clinical manifestation of rhinoviruses? of rhinoviruses? - - what are the epidemiologic feature of Rhinoviruses? - - How can we control rhinovirus infections? - - mention the strategies for rhinovirus infection therapy : symptomatic therapy : symptomatic therapy : antiviral therapy : antiviral therapy

103 Single-stranded RNA, + strand, enveloped Coronavirus Upper respiratory infections

104 SARS Cause: SARS-associated corona (RNA) virus Cause: SARS-associated corona (RNA) virus Respiratory illness with onset Respiratory illness with onset T > 100.5°F (>38° C) T > 100.5°F (>38° C) Cough, shortness of breath, difficulty breathing, hypoxia, or radiographic findings of either pneumonia or acute respiratory distress syndrome Cough, shortness of breath, difficulty breathing, hypoxia, or radiographic findings of either pneumonia or acute respiratory distress syndrome Travel within 10 days of onset of symptoms to an area with documented or suspected community transmission of SARS Travel within 10 days of onset of symptoms to an area with documented or suspected community transmission of SARS Close contact with a person with SARS within 10 days of onset Close contact with a person with SARS within 10 days of onset

105 Define: Coronaviruses Define: SARS - Mention the main clinical feature of SARS - Mention the main routes of transmission.

106 RHABDOVIRUSES Rabies virus ( Lyssavirus ): - have a distinctive bullet –like appearance ( round on one end and flat on the other end ) - helical nucleocapsid with spikes that protrude thru the envelope - family contains approximately 60 different viruses - only the rabies virus affect humans ( rarely, other mammalian lyssaviruses ) - killed by UV irradiation or sunlight


108 Epidemiology - slow, progressive zoonotic disease characterized by a fatal meningitis - worldwide distribution in various mammals ( skunks, foxes, raccoons, wolves, mongooses, and badger ) - humans become accidental hosts thru dog bites, cat scratches and contact with sylvan animal reservoirs 1.Sylvatic rabies - rabies in wild animals ( bats, skunks, racoons, foxes ) - fruit and herbivorous bats are known to transmit rabies 2. Urban rabies - rabies in domestic animals ( dogs, cats, horses, cattle) - vampire bats in S. America ( source of rabies in cattle)

109 TRANSMISSION - primarily affects wild animals - humans and animals : accidentally infected 1.animal bite – majority 2. via a scratch 3. inhalation of contaminated aerosolized animal material 4. transplantation of infected tissue ( cornea ) 5.inoculation through intact mucous membrane * virus found in saliva of infected animal few days before clinical signs * bat infection : latent ( bats excrete virus in saliva for months )

110 110 Murray et al., Medical Microbiology Note: no viremia

111 Infection and Disease - begins when an infected animals saliva enters a puncture site ( it may also be inhaled or inoculated orally) - virus multiplies at the trauma site, up to a week upon transmission - virus gradually enters sensory nerve endings or neuromuscular junction and advances toward the sensory ganglia, spinal cord and brain - virus multiplies throughout the brain with migration to other sites ( eye, heart, skin, and oral cavity ) - viral replicates in the salivary glands and is shed into the saliva - considered a slow, progressive infection

112 Clinical phases of Rabies: Average incubation period: 1-2 months ( extremes of 1 week to more than a year ) Incubation period : depends on wound site, its severity, virus concentration in inoculum, hosts age, hosts immune status : shorter in facial, neck and scalp wounds due to their proximity to the brain : prodrome begins with fever, anorexia, nausea, vomiting, headache, fatigue, some may have pain, burning, pricking or tingling sensation at the site of the wound

113 Forms of Rabies: 1.Furious form – agitation, disorientation, seizures, and twitching - spasms in the neck and pharyngeal muscles lead to severe pain on swallowing ( even the sight of liquids can bring about hydrophobia ) - the patient is fully coherent and alert 2.Dumb form – patient is paralyzed, disoriented and stuporous *Both forms eventually lead to coma and death from cardiac or respiratory arrest. *Only 3 patients have recovered from rabies with minimal residua

114 Diagnosis - when symptoms appear after a rabid animal attack the diagnosis is readily made - often the diagnosis is made at autopsy - the laboratory criteria most diagnostic of rabies are : 1. intracelllular inclusions ( Negri bodies ) 2. identification, isolation of rabies virus in saliva or brain tissue 3. demonstration of rabies virus antigens in brain, serum, CSF

115 Section of brain showing rabies viruses Bullet-shaped Rabies virus

116 Rabies virus infected - Negri body - note dark blue basophilic granules (Sellers stain)

117 Rabies Prevention and Control: Measures that effectively prevent and limit rabies are: 1. Postexposure vaccination 2. Animal control - 3 IM injections of HDCV ( human diploid cell vaccine) are recommended for high risk groups ( veterinarians, animal handlers, lab personnel, and travelers to endemic areas ) - other control measures such as vaccination of domestic animals elimination of strays, strict animal quarantine have reduced the virus reservoir A new genetically engineered vaccine made with a vaccinia virus that carries the gene for rabies virus surface antigen have been incorporated into bait placed in habitats of wild reservoir species. It is hoped eating this bait will render animals immune to rabies.

118 Postexposure Prophylaxis: 1. A wild animal especially a skunk, raccoon, fox, or coyote that bites without provocation is considered to be rabid and treatment is commenced 2.If the animal is captured, brain samples, and other tissues are examined for verification of rabies 3.In an apparently healthy dog or cat they are quarantined for 10 days for observation 4.Following an animal bite the wound should be scrupulously washed with soap or detergent and water, followed by debridement and application of an antiseptic that inactivates the virus ( alcohol or peroxide ) 5.Combination of passive and active postexposure immunization is very effective: wound is infused with ( HRIG) human rabies immunoglobulin to impede spread of virus, also injected IM -a full course of (HDCV) is given simultaneously

119 CONCEPT QUESTIONS - Is the rabies virus morphology distinctive ? - -Define: rabies - - Mention the epidemiologic feature of rabies virus. - - What is sylvanic rabies, and whatis urban rabies ? - - What are the of rabies virus transmission ? - -Describe infection and disease development of rabies. - - Mention the cliniocal phases of rabies. - - Enumerate the forms of rabies. - -Mention the lab. Criteria most diagnostic to rabies. - - Define negri bodies. - - What are the measures that effectively prevent rabies? - - What are thew postexposure prophylaxis ?

120 OTHER ENVELOPED RNA VIRUSES Arboviruses: viruses spread by arthropod vectors : includes members of several virus families ( see table) : named according to place of discovery * rubella virus : only member of the genus Rubiviridae that is also a member of the Togaviridae family : not an arbovirus because it is transmitted from person to person

121 FAMILY FAMILY STRUCTURAL STRUCTURAL CHARACTERIS- CHARACTERIS- TICS TICS GENUS GENUS EXAMPLES EXAMPLES ( virus ) ( virus ) Togviridae Togviridae + RNA + RNA enveloped enveloped Alphaviruses Alphaviruses Eastern equine encephalitis; Western equineencephalitis; California equine encepha- litis; Venezeluan equine encephalitis Flaviviridae Flaviviridae + RNA + RNA enveloped enveloped Flaviviruses Flaviviruses Yellowfever ; Dengue; St. Louis encephalitis; Japanese B encephalitis; Central European ence- Phalitis Bunyaviridae Bunyaviridae - RNA - RNA enveloped enveloped Bunyaviruses Bunyaviruses Phleboviruses Phleboviruses Nairoviruses Nairoviruses California encephalitis; Lacross encephalitis; Sandfly fever Sandfly fever Crimean-Congo hemorrhagic fever Reoviridae Reoviridae Segmented, double Stranded RNA, naked Orbiviruses Orbiviruses Colorado tick fever

122 Arboviruses These viruses multiply inside the vertebrate host as well as the vector. These viruses multiply inside the vertebrate host as well as the vector. The vector transmits the disease to human and other mammals, through the bite. The vector transmits the disease to human and other mammals, through the bite. Man generally plays no role in the natural history of arboviruses. Man generally plays no role in the natural history of arboviruses. Humans are not the natural reservoir for the virus. Humans are not the natural reservoir for the virus.

123 Arboviruses associated with hemorrhagic fever. Arboviruses associated with hemorrhagic fever. 1- Dengue virus. Family: Flaviviridae. Family: Flaviviridae. 2- Yellow fever virus. family : Flaviviridae. family : Flaviviridae. 3- Rift valley fever virus. Family : Bunyaviridae. Family : Bunyaviridae. 4- Crimean congo hemorrhagic fever virus. Family : Bunyaviridae. Family : Bunyaviridae.

124 Arboviruses with hemorrhagic fever 2- yellow fever : 2- yellow fever : Geographical distribution : Africa and South America. Geographical distribution : Africa and South America. Vector : Mosquitoes. Vector : Mosquitoes. Vertebrate host : Human, monkeys. Vertebrate host : Human, monkeys. Symptoms: Most cases are mild or asymptomatic. Symptoms: Most cases are mild or asymptomatic. The severe form of the disease is characterized by fever, myalgia, arthralgia, nausea, vomiting, jaundice, mucosal bleeding, bleeding under the skin, vomiting blood, seizures and coma. The severe form of the disease is characterized by fever, myalgia, arthralgia, nausea, vomiting, jaundice, mucosal bleeding, bleeding under the skin, vomiting blood, seizures and coma.

125 Yellow fever cycle. Yellow fever cycle. 1- Jungle yellow fever : Involves transmission between mosquitoes and non-human primate, with human as accidental host. 2- Urban yellow fever : Involves transmission between mosquitoes and human

126 2- Arboviruses associated with encephalitis. 1- West Nile Encephalitis (WNE ). 1- West Nile Encephalitis (WNE ). Family : Flaviviridae. Family : Flaviviridae. 2- Eastern Equine Encephalitis ( EEE ). 2- Eastern Equine Encephalitis ( EEE ). Family : Togaviridae. Family : Togaviridae. 3-Western Equine Encephalitis (WEE ).. 3-Western Equine Encephalitis (WEE ).. Family : Togaviridae. Family : Togaviridae. 4-Venezuelan Equine Encephalitis (VEE ).. 4-Venezuelan Equine Encephalitis (VEE ).. Family : Togaviridae. Family : Togaviridae.

127 Rift valley fever. Rift valley fever. 3- Meningoencephalitis : fever, severe headache, stiffness of neck, back pain, hallucination. Mental confusion, lack of coordination, convulsions and coma. 3- Meningoencephalitis : fever, severe headache, stiffness of neck, back pain, hallucination. Mental confusion, lack of coordination, convulsions and coma. Transmission :By direct contact with infected animal blood or tissue. Transmission :By direct contact with infected animal blood or tissue. Through the bite of mosquitoes. Through the bite of mosquitoes. Human to human transmission has not been documented.. Human to human transmission has not been documented..

128 Arboviruses associated with hemorrhagic fever 4- Crimean Congo H F : 4- Crimean Congo H F : Geog. Dist. : Africa, Asia and middle east. Geog. Dist. : Africa, Asia and middle east. Vector : Ticks. Vector : Ticks. Vertebrate host : Sheep, goats, cattle and human. Vertebrate host : Sheep, goats, cattle and human. Symptoms : Most cases are mild or asymptomatic. In severe cases, the symptoms are : fever, headache, myalgia, artheralgia, nausea, vomiting, mucosal bleeding and bleeding under the skin. In severe cases, the symptoms are : fever, headache, myalgia, artheralgia, nausea, vomiting, mucosal bleeding and bleeding under the skin.

129 The major arboviruses pathogenic to man: 1. Togaviruses ( Alphavirus) 2. Flavivirus 3. Bunyaviruses ( Bunyavirus and Phlebovirus ) 4. Reoviruses ( Orbivirus ) The chief vectors ( bloodsucking arthropods ) : a. mosquitos b. ticks c. flies d. gnats

130 Most types of illness caused by the virus: a. mild undifferentiated fevers b. some would cause severe encephalitides c. some would cause life-threatening hemorrhagic fevers General characteristics of Arbovirus Infections : - sudden, unexpected epidemics, sometimes with previously unreported viruses are due to the uncertain nature of host and viral cycles - travelers entering endemic areas are at special risk because, unlike the natives of that region,they have no immunity to the viruses

131 Arboviruses ( cont ) The influence of the Vector: - activity and distribution of arboviruses closely tied to ecology of vectors - factors to consider: a. longevity of the arthropod b. availability of breeding sites c. climactic influence ( temp. & humidity ) Epidemiology of arbovirus disease: - worldwide distribution ( being arthropod-borne ) - vectors and viruses tend to be clustered in the tropics and subtropics - many temperate zones report periodic epidemics - vertebrate host : recovers vector: carries virus for life

132 PATHOGENESIS : * infected vector bites -> virus injected into capillary circulation -> viral replication in vascular endothelium -> viremia ( precedes onset of clinical symptoms ) -> circulating virus reaches the organ for which it has special tropism ex. liver ( yellow fever virus ) ; brain ( encephalitis virus ) 1. incubation period : short ( 1 week ) because viruses are introduced directly into the bloodstream 2. morbilliform rash – secondary to : a. endothelial cell damage * if severe and disseminated : rash becomes hemorrhagic and involves the mucous membranes, GIT mucosa and skin * may lead to disseminated intravascular coagulation ( DIC ) and thrombocytopenia b. increased vascular permeability

133 CLINICAL SYNDROMES: I. Febrile Illness : - of undifferentiated type with or without a maculopapular rash and usually benign A. infections typified by dengue fever and Colorado tick fever: ( 1 ) mild, and self-limited, with no sequelae ( 2 ) fever of up to 40 o C, prostration, headache, myalgia, orbital pain, muscle aches, and joint stiffness ( 3 ) midway thru the illness, a maculopapular or petechial rash may erupt over trunk and limbs

134 II. Encephalitis:( invasion of brain, meninges and spinal cord ) - caused by alphaviruses, flaviviruses, bunyaviruses a). exemplified by Western equine, eastern equine, St. Louis, and California encephalitis b). viruses cycle between wild animals ( primarily birds ) and mosquitos or ticks – humans are not the reservoir hosts c). begins with an arthropod bite release of virus into tissues replication in nearby lymphatics prolonged viremia establishes virus in brain -> swelling and inflammation causes damage to various nuclei and tracts including the meninges d). symptoms : ( variable ), may include coma, convulsions, paralysis, tremors, rigidity, loss of coordination, palsies, memory deficits, changes in speech and personality, and heart damage. e). survivors may have permanent brain damage ( young children and very old patients )

135 III. Hemorrhagic Fevers a. flu-like syndrome ( mild cases ) - fever, chills, headache, backache, nausea, vomiting b. extensive hemorrhage ( severe cases ) in mucous membranes of nose, GIT, bladder - melanemesis ( vomiting of digested blood ) - decrease in pulse pressure accompanied by a paradoxical decrease in pulse rate - jaundice/proteinuria - certain arboviruses can disrupt vascular bed which can cause sudden localized bleeding in the tissues leading to shock or death ( e.g. yellow fever and dengue fever viruses )

136 - exact mechanisms of pathology are obscure : the virus causes capillary fragility and disrupts the blood clotting mechanisms - these hemorrhagic syndromes are caused by a variety of viruses, carried by variety of vectors, and are distributed globally - reservoir animals: small mammals : yellow fever and dengue fever can be harbored in human population

137 Arenavirus Helical capsids contain RNA- containing granules Lymphocytic choriomeningitis VEE and Lassa Fever Rodent transmitted Single-stranded RNA, – strand, multiple RNA strands

138 Bunyavirus (CE virus) Hantavirus-cause hemorrhagic fevers & pulmonary syndrome assoc. with rodents. Single-stranded RNA, – strand, multiple RNA strands

139 Single-stranded RNA, + strand, enveloped Alphavirus Alphaviruses are transmitted by arthropods; include EEE, WEE Rubivirus (rubella virus)

140 Single-stranded RNA, – strand, one RNA strand Filovirus Enveloped, helical viruses Ebola and Marburg viruses

141 C. Dengue Fever ( DF) / Dengue Hemorrhagic Fever ( DHF ): C. Dengue Fever ( DF) / Dengue Hemorrhagic Fever ( DHF ): - four serotypes ( Types 1-4 ) of dengue ( in tropics ) - transmitted by mosquitoes ( Aedes aegypti ) * principal mosquito vector which are adapted to breed around human dwellings ( in man made water- holding receptacles, around human habitation, in tree holes or plants close to human dwelling ) ( intensification of dengue transmission in tropical cities) * epidemics start often during rainy season when Aedes aegypti is most abundant

142 ( cont. Dengue ) * viral replication in the mosquito takes about (1-2 weeks) then undergoes extrinsic incubation * extrinsic incubation period required before it can transmit the virus on subsequent feedings * feeding attempts may number several times a day depending on the availability of hosts * lifespan of mosquito is 1-4 weeks * mosquitoes sheltered indoors and bite during day at 1-2 hour intervals in the morning and late afternoon

143 PATHOGENESIS ( DF/ DHF ): - self-limited dengue is the usual outcome of infection - an immunopathologic response in some patients usually in the setting of a heterologous immunity produces the syndrome DHF-DSS Infectious mosquito bite viral replication in local lymph nodes disseminates via the blood to various tissues (w/in 2-3 days) virus circulates in blood in infected monocytes, B cells, an T cells (for 4-5 days) nearly all patients are viremic at the point of clinical presentation with fever virus cleared from blood within a day after defervescence local suppression of erythrocytic, myelocytic, and thrombocyticpoeisis ( within 4-5 days)

144 - shock in DHF-DSS follows sudden extravasation of plasma into extravascular sites including pleural and abdominal cavities usually with defervescence of fever - the increase vascular permeability may be due to: 1. Increased levels of soluble tumor necrosis factor 2. Interferon-gamma 3. Activation of the complement system - rapid, predictive reversibility of syndrome within 48 hours ( with paucity of histopathologic correlation) suggests an inflammatory response causing vasculopathies - the rise of levels of neutralizing antibodies correlates with clearance of viremia

145 CLINICAL FEATURES: 1. Dengue Fever: - acute febrile illness with headaches, musculoskeletal pain and rash - asymptomatic in 80 % of infants and children - cannot be distinguished from other common childhood infections - in adults more severe and acute incubation period ( 4-7 days) of fever, chills, severe frontal headache, retroorbital pain scarlatiniform rash develops within (3-4 days) - virtually all cases are uncomplicated - hepatitis frequently complicates dengue fever ( deaths are rare ) - vertical transmission of virus to neonates where mothers had an onset of 1 o or 2 o dengue fever ( 0-8 days before delivery) resulted in acute neonatal dengue fever

146 2. DHF-DSS: - may occur in individuals with heterologous dengue antibody ( possibly acquired as maternal antibody or endogenously produced ) - hemorrhagic phenomena and hypovolemic shock due to increased vascular permeability and plasma leakage - clinical signs similar to DF but with defervescence within 2-7 days condition worsens with associated : 1. hypoprotenemia 2. thrombocytopenia 3. prolonged bleeding time 4. elevated prothrombin time

147 may lead to Dengue Shock Syndrome - cyanosis, restlessness, diaphoresis, cool, clammy skin - with support, spontaneous resolution of vasculopathy and circulatory problem within 2-3 days with complete recovery

148 ( cont. Dengue ) Factors responsible for occurrence of DSS: poorly understood ( ? hypersensitivity reactions ) secondary Dengue infection formation of virus antibody complexes activation of complement system vascular dysfunction due to complement products * due to formation of large amounts of cross-reacting antibodies at the time of second dengue infection

149 Dengue Prevention: - relies on public health and community-based A. aegypti control programs to remove or destroy mosquito-breeding sites - insecticidal fogging is considered unhelpful - in sealed houses, indoor insecticide sprays should be effectual - vaccines: The most advanced is a tetravalent combination of attenuated dengue strains that is under phase II clinical evaluation - travelers can protect themselves by using repellents and insecticidal sprays indoors

150 DIAGNOSIS: 1. viral isolation ( most accurate ) - most sensitive is intracebrebral inoculation of suckling mice - successful recovery from blood only before an antibody response develops 2. PCR - identifies the presesnce of Dengue virus and serotypes ( used in specialized lanoratories ) 3. serum IgM in dengue infection ( within 60 days ) by a. antibody capture ELISA- preferred technique b. indirect immunofluorescence for IgM and IgG antibodies 4. Rapid immunochromatographic test - for dengue and JE IgM and IgG * high sensitivity and specificity

151 CONCEPT QUESTIONS -Define: Arboviruses - Name the major arboviruses pathoigenic to man. - The chief vectors of arboviruses include: - - Most types of illnesses caused by arboviruses include: - - What are the general characteristicsa of arboviruses? - - Activity and distribution of arboviruses closely tied to ecology of vectors, what factors to be considered? vectors, what factors to be considered? - - Mention the epidemiologic feature of arboviruses. - - Describe the pathogenesis of arboviruse with an example to each. - - What are the clinical syndrome associated with arboviral infections? - - Mention the characters, members and mode of transmission of arbov. - - Which viruses causing hemorrhagic and pulmonary syndrome associated with rodents? with rodents?

152 - What are the members of Togaviridae? - - What are the characteristic of filoviruses? mention the diseases caused. - -Define : Lassa fever, Ebola virus, Marburg HF, Dengue fever - - What are the main epidemiologic characteristics of DHF ? - - Describe the pathogenesis of DF/DHF. - - In DF/DHF, what are the causes for increased vascular permeability? - - What are the clinical feature of DF? - -Dengue shock syndrome(DSS), how its caused ? - - What are the factors responsible for occurrence of DSS? - - What are the conditions that worsens DSS if associated? - - What are the preventive measures of DF? - - Mention the methods for diagnosis of DF/ DHF.

153 NONENVELOPED SINGLE-STRANDED RNA VIRUSES: PICORNAVIRUSES AND CALICIVIRUSES PICORNA viruses are named for their small ( pico )size and their RNA core. Important representatives include: 1. Enterovirus 2. Rhinovirus 3. Cardiovirus ( infects the brain and heart in humans and other mammals)

154 Selected Characteristics of the human picornaviruses Genus GenusRepresentative 1 o Disease EnterovirusPolioviruspoliomyeitis Coxsackievirus A Focal necrosis,myositis Coxsackievirus B Myocarditis of newborn Echovirus Aseptic meningitis,enteritis Enterovirus 72 Hepatitis A RhinovirusRhinovirus Common Cold CardiovirusCardiovirus Encephalomyocar ditis AphthovirusAphthovirus Foot and Mouth Disease

155 POLIOVIRUS: - an acute enteroviral infection of the spinal cord that may cause neuromuscular paralysis - also called infantile paralysis ( often affects small children) Properties : - inactivated when heated at 55 degrees C for 30 minutes - purified poliovirus is inactivated by chlorine concentration of 0.1 ppm - requires primate-specific membrane receptor for infection - undergoes replication after attaching to viral receptors : serves both as its own messenger RNA and as the source of genetic information


157 (poliomyelitis)

158 Poliomyelitis: - transmission via mechanical vectors such as flies may occur - respiratory droplets are only rarely involved - has been virtually eliminated in North and South America - prevalence varies in Asia, Africa, and European countries Infection and Disease: Ingestion of an infectious dose ( approx virions) polioviruses adsorb to receptors of mucosal cells in oropharynx and intestine viral multiplication ( precise location unknown but may be mucosal epithelia or lymphoid tissue) large numbers of viruses are shed into the throat and feces and some leak into the blood

159 Polio Incubation period: 1-2 weeks 4 types of infections: a. subclinical infection ( inapparent without symptoms) b. minor disease c. aseptic, nonparalytic meningitis d. paralytic disease - Most infections ( 95% ) are contained as a short-term asymptomatic viremia - a small number of persons will develop minor disease (with nonspecific symptoms of fever, headache, nausea, sore throat, and myalgia ) - being neurotropic, it may gain access to the CNS via the blood-brain barrier -> infiltrate the motor neurons of the spinal cord -> invasion of nervous tissue without destruction causes nonparalytic meningitis

160 Paralytic Disease: - highly virulent virus + / or highly susceptible host = destruction of nervous tissue ( various degrees of flaccid paralysis ) - flaccid paralysis ensue over a period of a few hours to several days - depending on the level of damage to the motor neurons of the anterior horn of the spinal cord ( occasionally, the spinal ganglia, cranial nerves,and motor nuclei) paralysis of the muscles of the legs abdomen, back, intercostals, diaphragm, pectoral girdle, and bladder may occur. - bulbar poliomyelitis : less frequent : disintegration of the brain stem, medulla, cranial nerves : autonomic cardiorespiratory regulatory centers, palate, pharynx, and vocal cord are affected

161 Epidemiology - has 3 serotypes; Types 1 and 3 cause the most severe forms of disease - protective capsid and lack of an envelope confer chemical stability and resistance to acid and bile detergents SIGNIFICANCE: the virus is capable of passing thru the gastric environment undamaged - incidence is more pronounced during the summer and fall in temperate - virus is passed within the population thru food, water, hands, and objects contaminated with feces

162 Paralytic Disease (cont) - antibodies to poliovirus: occur locally in the intestine and tonsils ( secretory antibodies), and in the serum One exposure confers lifelong immunity DIAGNOSIS: * suspected when epidemics of neuromuscular disease occurs in the summer in temperate climates * must be differentiated from Guillain-Barre syndrome, infant botulism, and encephalomyelitis caused by other enteroviruses 1.CSF : increased leucocytes and proteins; glucose normal 2. virus can be isolated by inoculating cell cultures with stool or throat washings in the early part of the disease 3. stage of infection demonstrated by testing serum samples for the type and amount of antibody


164 Immune response - Infection induces antibodies with complement-fixing and neutralizing activities and they may be used retrospectively for laboratory confirmation at polio infection. - There is the usually early specific IgM response, rapidly followed by a much longer-lasting production of specific IgG. - Neutralizing antibodiesIgG in the blood and IgA at mucous surfacesare important in protecting against reinfection. - However, antibody against one of the 3 serotypes does not in general protect against the others, although there may be some cross-protection between types 1 and 2.

165 Treatment and Control of Polio: - no specific therapy, treatment rests largely on alleviating pain and suffering -respiratory failure may require artificial ventilation -secondary pulmonary infection as a result of impairment of swallowing and coughing may require antibiotics - after the acute febrile phase, prompt physical therapy to diminish crippling deformities and to retrain muscles

166 Prevention : - vaccination is the mainstay of prevention. - 2 forms of vaccine currently in use: 1. Salk Vacine – inactivated poliovirus vaccine ( IPV ) 2. Sabin Vaccine – oral poliovirus vaccine ( OPV ) - both vaccines are prepared from animal cell cultures and are trivalent ( combinations of 3 serotypes ) - both vaccines are effective - in tropical countries where exposure of infants to wild virus is common, both vaccines may be given - polio immunization must be instituted as early in life as possible, usually four doses starting at about two months of age -adult candidates are travelers and members of the armed forces.

167 NONPOLIO ENTEROVIRUSES - commonly cause transient neonatal infections - Coxsackieviruses A and B, echoviruses, and nonpolio enteroviruses are like polioviruses in many epidemio- logic and infectious characteristics - spread thru fecal contamination - incidence is highest from late spring to early summer in temperate climates - 50 % to 80 % of enteroviral infections are subclinical, and the remainder fall into the category of undifferentiated febrile illness - initial phase of infection is intestinal after which the virus enters the lymph, blood and disseminates to other organs


169 Coxsackievirus & Echovirus Infection Coxsackie A virus : - Herpangina is caused by several types of Coxsackie A virus & is not related to a herpesvirus infection. Fever, sore throat, pain on swallowing, anorexia, & vomiting. The classic finding is vesicular ulcerated lesions around the soft palate & uvula

170 Herpangina

171 Coxsackievirus & Echovirus Infection Coxsackie A virus : - Hand-foot-and-mouth disease: a vesicular exanthem usually caused by coxsackievirus A16.

172 Hand-foot-and-mouth disease caused by Coxsackie A virus.

173 Coxsackievirus & Echovirus Infection Coxsackie B virus : - Myocardial & pericardial infections (The symptoms resemble those of myocardial infarction with fever.)

174 Acute Hemorrhagic Conjunctivitis Acute Hemorrhagic Conjunctivitis: - caused by Enterovirus 70 ( responsible for tens of millions of cases since 1969 ) - a variant of coxsackie A24 causes a similar, but geographi- cally more restricted disease - AHC first recognized in Ghana and Indonesia in 1969 and has spread rapidly in different parts of the world ( in Africa, some parts of Europe and Asia.) - regions of Asia where it has caused epidemics include: Vietnam, Bangladesh, Thailand, Sri Lanka, Taiwan, The Philippines, The Philippines, Samoa, and Japan - large-scale epidemics have occurred predominantly in crowded costal areas of tropical countries during the hot, rainy season

175 AHC: - unlike most other enterovirus infections, transmission is primarily from fingers or fomites directly to the eye - both enterovirus 70 and coxsackie A24 can be isolated from the conjunctiva early in the illness - highly contagious and spreads rapidly - contagion is favored by crowding and unsanitary living conditions - reuse of water for bathing and sharing of towels are implicated as factors contributing to spread of infection - begins abruptly, reaches its peak within 1 day - main symptoms: burning, foreign body sensation, ocular pain, photophobia, swelling of eyelids, and watery discharge - subconjunctival hemorrhage is the most distinctive feature of enterovirus infection ( much less with coxsackie)

176 AHC : - conjunctival edema more common in the elderly; hemorrhage more profuse in the young - recovery is noticeable on the 2 nd or 3 rd day and is complete by 10 days Complications: 1. Keratitis occasionally persists but no permanent scarring occurs 2. Motor paralysis similar to polio occurs in persons who have recently recovered from AHC ( a rare occurrence consi- dering the number of AHC cases) * Bulbar paralysis can occur in half of the cases * CSF abnormalities are that of aseptic meningitis

177 AHC: Diagnosis : - Diagnosed easily in major epidemics but may be confused with adenovirus infection causing epidemic keratoconjunctivitis in sporadic cases - AHC has shorter incubation period ( 1 day) compared to 5-7 days with epidemic keratoconjunctivitis - Bacterial and chlamydial conjunctivitis do not cause extensive outbreaks Lab: - Virus can be recovered from conjunctival swabs or scrapings of patients with AHC - Rising antibody titers in paired sera Treatment: Symptomatic Prevention : hand washing, use separate towels, sterilization of oph- thalmologic instruments

178 CONCEPT QUESTIONS - -Show the main characteristics of human picornaviruses. - - Mention the properties of polioviruses. - - Define: poliomyelitis - - Describe infection and disease of polioviruses. - - Mention the 4 types of poliovirus infections. - -What is the paralytic poliomyelitis ? - -Mention the characters of bulbar poliomyelitis. - - Show the epidemiologic feature of poliovirus. - - The diagnosis of poliomyelitis include: - - What are the clinical feature of poliomyelitis? - - Describe the immune responses to poliovirus ionfection. - - What are the steps for the treatment of poliomyelitis? - -What are the prevention measures of poliomyelitis ?

179 NON-POLIO ENEROVIRUSES - -What are the general properties of Coxsackie & Echo viruses? - - Mention the types of infections associated with coxsackievirus A & B. - - What is acute hemorrhagic conjunctivitis(AHC) ? - - What are the complications associated with AHC ? - Coxsackieviruses incriminated as a cause of: - - What are the diagnostic methods and preventive measures of AHC?

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