1. TASHKENT MEDICAL ACADEMY
Infectious and children infectious diseases department
Theme: Early and Comparative diagnosis of diseases with the respiratory syndrome
Lecturer:

2. Viruses Associated with Respiratory Infections

3. Influenza Virus RNA virus, genome consists of 8 segments
enveloped virus, with haemagglutinin and neuraminidase spikes
3 types: A, B, and C
Type A undergoes antigenic shift and drift.
Type B undergoes antigenic drift only and type C is relatively stable
(Courtesy of Linda Stannard, University of Cape Town, S.A.)

4. Influenza A Virus
Undergoes antigenic shifts and antigenic drifts with the haemagglutinin and neuraminidase proteins.
Antigenic shifts of the haemagglutinin results in pandemics. Antigenic drifts in the H and N proteins result in epidemics.
Usually causes a mild febrile illness.
Death may result from complications such as viral/bacterial pneumonia.

5. Epidemiology
Pandemics - influenza A pandemics arise when a virus with a new haemagglutinin subtype emerges as a result of antigenic shift. As a result, the population has no immunity against the new strain. Antigenic shifts had occurred 3 times in the 20th century.
Epidemics - epidemics of influenza A and B arise through more minor antigenic drifts as a result of mutation.

6. Past Antigenic Shifts
1918 H1N1 “Spanish Influenza” million deaths
1957 H2N2 “Asian Flu” 1-2 million deaths
1968 H3N2 “Hong Kong Flu” 700,000 deaths
1977 H1N1 Re-emergence No pandemic
2009 H1N1 “Swine Flu Mild Pandemic
At least 15 HA subtypes and 9 NA subtypes occur in nature. Up until 1997, only viruses of H1, H2, and H3 are known to infect and cause disease in humans.

7. Avian Influenza
H5N1
An outbreak of Avian Influenza H5N1 occurred in Hong Kong in 1997 where 18 persons were infected of which 6 died.
The source of the virus was probably from infected chickens and the outbreak was eventually controlled by a mass slaughter of chickens in the territory.
All strains of the infecting virus were totally avian in origin and there was no evidence of reassortment.
However, the strains involved were highly virulent for their natural avian hosts.
H9N2
Several cases of human infection with avian H9N2 virus occurred in Hong Kong and Southern China in 1999.
The disease was mild and all patients made a complete recovery
Again, there was no evidence of reassortment

8. Theories Behind Antigenic Shift
1. Reassortment - Reassortment of the H and N genes between human and avian influenza viruses through a third host. There is good evidence that this occurred in the 1957 H2N2 and the 1968 H3N2 pandemics. The 2009 pandemic virus was thought to be novel virus that was a triple re-assortant involving human, bird, N. American pig and Eurasian pig viruses.
2. Recycling of pre-existing strains – this probably occurred in 1977 when H1N1 re-surfaced.
3. Gradual adaptation of avian influenza viruses to human transmission. There is some evidence that this occurred in the 1918 H1N1 pandemic.

9. Reassortment

10. Laboratory Diagnosis
Rapid Diagnosis – nasopharyngeal aspirates, throat and nasal swabs are normally used.
Antigen Detection – can be done by IFT or EIA
RNA Detction – RT-PCR assays give the best sensitivity and specificity. It is the only method that can differentiate the 2009 pandemic H1N1 strain from the seasonal H1N1 strain. However, it is expensive and technically demanding.
Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates and throat swabs.
Serology - a retrospective diagnosis may be made by serology. CFT most widely used. HAI and EIA may be used to give a type-specific diagnosis

11. Management
Neuraminidase inhibitors - are now the drugs. They are highly effective and have fewer side effects than amantidine. Oseltamivir (Tamiflu) is the most commonly used agent as it can be given orally unlike Zanamivir (Relenza). The resistance to different types varies enormously year to year. H3N2 strains were mainly sensitive whereas seasonal H1N1 were almost totally resistant. More than 98% of the 2009 pandemic influenza H1N1 tested were sensitive.
Amantidine is effective against influenza A if given early in the illness. However, resistance to amantidine emerges rapidly. Rimantidine is similar to amantidine but but fewer neurological side effects.
Ribavirin is thought to be effective against both influenza A and B.

12. Prevention
Inactivated split/subunit vaccines are available against influenza A and B.
The vaccine is normally trivalent, consisting of one A H3N2 strain, one A H1N1 strain, and one B strain.
The strains used are reviewed by the WHO each year.
The vaccine should be given to debilitated and elderly individuals who are at risk of severe influenza infection.
Amantidine can be used as an prophylaxis for those who are allergic to the vaccine or during the period before the vaccine takes effect.

13. Parainfluenza Virus ssRNA virus enveloped, pleomorphic morphology
5 serotypes: 1, 2, 3, 4a and 4b
No common group antigen
Closely related to Mumps virus
(Linda Stannard, University of Cape Town, S.A.)

14. Clinical Manifestations
Croup (laryngotraheobroncitis) - most common manifestation of parainfluenza virus infection. However other viruses may induce croup e.g. influenza and RSV.
Other conditions that may be caused by parainfluenza viruses include Bronchiolitis, Pneumonia, Flu-like tracheobronchitis, and Corza-like illnesses.

15. Laboratory Diagnosis
Detection of Antigen - a rapid diagnosis can be made by the detection of parainfluenza antigen from nasopharyngeal aspirates and throat washings.
Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates and throat swabs.
Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

16. Management No specific antiviral chemotherapy available.
Severe cases of croup should be admitted to hospital and placed in oxygen tents.
No vaccine is available.

17. Respiratory Syncytial Virus (RSV)
ssRNA eveloped virus.
belong to the genus Pneumovirus of the Paramyxovirus family.
Considerable strain variation exists, may be classified into subgroups A and B by monoclonal sera.
Both subgroups circulate in the community at any one time.
Causes a sizable epidemic each year.

18. Clinical Manifestations
Most common cause of severe lower respiratory tract disease in infants, responsible for 50-90% of Bronchiolitis and 5-40% of Bronchopneumonia
Other manifestations include croup (10% of all cases).
In older children and adults, the symptoms are much milder: it may cause a corza-like illness or bronchitis.

19. Infants at Risk of Severe Infection
1. Infants with congenital heart disease - infants who were hospitalized within the first few days of life with congenital disease are particularly at risk.
2. Infants with underlying pulmonary disease - infants with underlying pulmonary disease, especially bronchopulmonary dysplasia, are at risk of developing prolonged infection with RSV.
3. Immunocompromized infants - children who are immunosuppressed or have a congenital immunodeficiency disease may develop lower respiratory tract disease at any age.

20. Laboratory Diagnosis
Detection of Antigen - a rapid diagnosis can be made by the detection of RSV antigen from nasopharyngeal aspirates. A rapid diagnosis is important because of the availability of therapy
Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates. However, this will take several days.
Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

21. Treatment and Prevention
Aerosolised ribavirin can be used for infants with severe infection, and for those at risk of severe disease.
There is no vaccine available.
RSV immunoglobulin can be used to protect infants at risk of severe RSV disease.

22. Adenovirus ds DNA virus non-enveloped At least 47 serotypes are known
classified into 6 subgenera: A to F
(Linda Stannard, University of Cape Town, S.A.)

23. Clinical Syndromes
1. Pharyngitis 1, 2, 3, 5, Pharyngoconjunctival fever 3, Acute respiratory disease of recruits  4, 7, 14, Pneumonia 1, 2, 3, Follicular conjunctivitis 3, 4, Epidemic keratoconjunctivitis 8, 19, Pertussis-like syndrome Acute haemorrhaghic cystitis 11, Acute infantile gastroenteritis 40, Intussusception 1, 2, 5
11. Severe disease in AIDS and other immunocompromized patients 5, 34, 35
12. Meningitis 3, 7

24. Laboratory Diagnosis
Detection of Antigen - a rapid diagnosis can be made by the detection of adenovirus antigen from nasopharyngeal aspirates and throat washings.
Virus Isolation - virus may be readily isolated from nasopharyngeal aspirates, throat swabs, and faeces.
Serology - a retrospective diagnosis may be made by serology. CFT most widely used.

25. Treatment and Prevention
There is no specific antiviral therapy.
A vaccine is available against Adult Respiratory Distress Syndrome. It consists live adenovirus 4, 7, and 21 in enterically coated capsules. It is given to new recruits into various arm forces around the world.

26. Common Cold Viruses
Common colds account for one-third to one-half of all acute respiratory infections in humans.
Rhinoviruses are responsible for 30-50% of common colds, coronaviruses 10-30%.
The rest are due to adenoviruses, enteroviruses, RSV, influenza, and parainfluenza viruses, which may cause symptoms indistinguishable to those of rhinoviruses and coronaviruses.

27. Rhinovirus ssRNA virus Belong to the picornavirus family acid-labile
at least 100 serotypes are known
Reconstructed Image of rhinovirus particle (Institute for Molecular Virology)

28. Coronavirus ssRNA Virus Enveloped, pleomorphic morphology
2 serogroups: OC43 and 229E

29. Measles Highly contagious viral illness First described in 7th century
Near universal infection of childhood in prevaccination era
Frequent and often fatal in developing areas

30. Measles Virus Paramyxovirus (RNA) One antigenic type
Hemagglutinin important surface antigen
Rapidly inactivated by heat and light

31. Measles Pathogenesis Respiratory transmission of virus
Replication in nasopharynx and regional lymph nodes
Primary viremia 2-3 days after exposure
Secondary viremia 5-7 days after exposure with spread to tissues

32. Measles Clinical Features
Incubation period days
Stepwise increase in fever to 103 F or higher
Cough, coryza, conjunctivitis
Koplik spots
Prodrome

33. Measles Clinical Features
Rash
2-4 days after prodrome, 14 days after exposure
Maculopapular, becomes confluent
Begins on face and head
Persists 5-6 days
Fades in order of appearance

34. Measles Complications
Condition
Diarrhea
Otitis media
Pneumonia
Encephalitis
Death
Hospitalization
Percent reported 8 7 6
0.1
0.2 18
Based on surveillance data

35. Measles Complications by Age Group

36. Measles Laboratory Diagnosis
Isolation of measles virus from a clinical specimen (e.g., nasopharynx, urine)
Significant rise in measles IgG by any standard serologic assay (e.g., EIA, HA)
Positive serologic test for measles IgM antibody

37. Measles Epidemiology Reservoir Human Transmission Respiratory Airborne
Temporal pattern Peak in late winter and spring
Communicability 4 days before to 4 days after
rash onset

38. Measles – United States, 1950-2001*
Vaccine Licensed
*2001 provisional data

39. Measles – United States, 1980-2001*
*2001 provisional data

40. Age Distribution of Reported Measles, 1975-2000

41. Measles Resurgence – United States, 1989-1991
Cases ,622
Age group affected Children <5 yrs
Hospitalizations >11,000
Deaths
Direct medical costs >$150 million

42. Measles 1993-2001 Endemic transmission interrupted
Record low annual total in 2000 (86 total cases)
Many cases among adults
Many cases due to importation
86 cases reported for provisional total in Endemic transmission believed to have been interrupted in 1996 or earlier.

43. Measles Clinical Case Definition
Generalized rash lasting >3 days, and
Temperature >38.3 C (101 F), and
Cough, coryza, or conjunctivitis

44. Measles Vaccines 1963 Live attenuated and killed vaccines
1965 Live further attenuated vaccine
1967 Killed vaccine withdrawn
1968 Live further attenuated vaccine
(Edmonston-Enders strain)
1971 Licensure of combined measles-
mumps-rubella vaccine
1989 Two dose schedule

45. Measles Vaccine Composition Live virus Efficacy 95% (range, 90%-98%)
Duration of Immunity Lifelong
Schedule 2 doses
Should be administered with mumps and rubella as MMR

46. MMR Vaccine Failure
Measles, mumps, or rubella disease (or lack of immunity) in a previously vaccinated person
2%-5% of recipients do not respond to the first dose
Caused by antibody, damaged vaccine, record errors
Most persons with vaccine failure will respond to second dose

47. Measles (MMR) Vaccine Indications
All infants >12 months of age
Susceptible adolescents and adults without documented evidence of immunity

48. Measles Mumps Rubella Vaccine
12 months is the recommended and minimum age
MMR given before 12 months should not be counted as a valid dose
Revaccinate at >12 months of age

49. Second Dose of Measles Vaccine
Intended to produce measles immunity in persons who failed to respond to the first dose (primary vaccine failure)
May boost antibody titers in some persons

50. Second Dose Recommendation
First dose of MMR at months
Second dose of MMR at 4-6 years
Second dose may be given any time >4 weeks after the first dose

51. ACIP Recommendations
All states ensure that 2 doses of MMR required for school entry
All children in kindergarten through grade 12 have 2 doses of MMR by 2001

52. Adults at Increased Risk of Measles
College students
International travelers
Health-care personnel

53. Measles Immunity in Health Care Personnel
All persons who work in medical facilities should be immune to measles

54. Measles Immunity Born before 1957
Documentation of physician-diagnosed measles
Serologic evidence of immunity
Documentation of receipt of measles-containing vaccine

55. Measles Vaccine Indications for Revaccination
Vaccinated before the first birthday
Vaccinated with killed measles vaccine
Vaccinated prior to 1968 with an unknown type of vaccine
Vaccinated with IG in addition to a further attenuated strain or vaccine of unknown type

56. MMR Adverse Reactions Fever 5%-15% Rash 5% Joint symptoms 25%
Thrombocytopenia <1/30,000 doses
Parotitis rare
Deafness rare
Encephalopathy <1/1,000,000 doses

57. MMR Vaccine and Autism
Measles vaccine connection first suggested by British gastroenterologist
Diagnosis of autism often made in second year of life
Multiple studies have shown no association

58. MMR Vaccine and Autism
“The evidence favors a rejection of a causal relationship at the population level between MMR vaccine and autism spectrum disorders (ASD).”
- Institute of Medicine, April 2001

59. MMR Vaccine Contraindications and Precautions
Severe allergic reaction to prior dose or vaccine component
Pregnancy
Immunosuppression
Moderate or severe acute illness
Recent blood product

60. Measles and Mumps Vaccines and Egg Allergy
Measles and mumps viruses grown in chick embryo fibroblast culture
Studies have demonstrated safety of MMR in egg allergic children
Vaccinate without testing

61. Measles Vaccine and HIV Infection
MMR recommended for persons with asymptomatic and mildly symptomatic HIV infection
NOT recommended for those with evidence of severe immuno- suppression
Prevaccination HIV testing not recommended

62. PPD and Measles Vaccine
Apply PPD at same visit as MMR
Delay PPD >4 weeks if MMR given first
Apply PPD first - give MMR when skin test read