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Epidemiology of Airborne Diseases Dr. Yeşim YASİN Fall-2013.

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1 Epidemiology of Airborne Diseases Dr. Yeşim YASİN Fall-2013

2 Outline Basics of epidemiology Basics of airborne infections Epidemiology of “tuberculosis” Epidemiology of “measles” Epidemiology of “influenza”

3 Introduction “Epidemiology: The study of the distribution and determinants of a health- related events and application of this study to control of health problems” (John Last, 1988). Epidemiology of air-borne diseases provides an overview of airborne disease burden and its likely future evolution.

4 Basics of Epidemiology INFECTIVITY: The ability of an agent to invade and multiply (produce infection) in a susceptible host. How to measure (Infectivity); ease & spread of infection? Secondary Attack Rate The proportion of exposed susceptible persons who become infected. Measles has high infectivity whereas leprosy has low infectivity.

5 Basics of Epidemiology (cont.) PATHOGENICITY: It is the ability of the organisms to produce specific clinical reaction after infection. It refers to the proportion of infected persons who develop clinical disease. How to measure pathogenicity? By the ratio of clinical to sub-clinical cases. Measles has high pathogenicity whereas TB has low pathogenicity.

6 Basics of Epidemiology (cont.) VIRAL SHEDDING Multiplication of a virus in an infected person with subsequent release of the virus from that infected person, such that others who come into contact with the person may become infected. A state of being contagious. VIRULENCE The degree of pathogenicity of an infectious agent. i.e. the ability of the agent to invade and damage tissues of the host causing severe manifestations or death.

7 Modes of transmission

8 Airborne transmission

9 Transmission medium

10 Airborne transmission Airborne transmission occurs by particles that are suspended in air. There are two types of these particles: - dust - droplet nuclei 1.Dust particles: -result from re-suspension of particles that have settled on floor or bedding, -infectious particles blown from the soil by the wind. Example: Fungal spores.

11 Airborne transmission (cont.) 2.Droplet nuclei They represent the dried residue of droplets that have been coughed or sneezed into the air. They are very tiny particles less than 5 µ (microns) in size and may remain suspended in the air for long periods. Examples: Tuberculosis is transmitted more often indirectly, through droplet nuclei, than directly, through direct droplet spread. Legionnaires’ disease and histoplasmosis also spread through airborne transmission.

12 Airborne infection requirements Pathogen must be dispersed as fine particles (1-5 μm size) Respiratory tract-cough aerosol TB wound Remain suspended in air Reach the alveolar level (TB) Resistant upper respiratory tract Minute infectious dose (droplet nucleus)

13 Particle size and suspension in air Particle size & deposition site 100 μ 20 μ 10 μ-upper airway 1-5 μ-alveolar deposition Time to fall the height of a room 10 sec 4 min 17 min Suspended indefinitely by room air currents

14 Droplet vs. airborne spread Transmission within a meter of the source Relatively large numbers of organisms in inoculum (small inoculum may be tolerated) Access to vulnerable site (mucosal membranes of eye, nose, mouth, trachea, etc.) Hand washing may be effective Transmission beyond a meter-shared breathing volume Relatively small numbers of organisms in inoculum-virulence required Access to vulnerable site (alveoli in the case of TB) Hand washing not effective.

15 Mycobacterium tuberculosis? More than 1m!


17 Model airborne infections Focus on TB (MDR, XDR-TB) and measles but implications for other infections that are partially, opportunistically, or conditionally airborne. Rhinovirus, influenza, adenovirus, SARS, Bioterrorist agents (smallpox, anthrax), environmental agents (M. bovis, coccidiomycosis, Q-fever, Hanta – not necessarily person to person)


19 Agent and transmission Agent: A virus of the paramyxovirus (RNA) family causes measles. The measles virus normally grows in the cells that line the back of the throat and lungs. Modes of transmission: Direct: Droplet Indirect: Airborne The virus spreads by the respiratory route via aerosol droplets and respiratory secretions which can remain infectious for several hours. The infection is acquired through the upper respiratory tract or conjunctiva.

20 Reservoir Reservoir: Humans in the form of: Carriers (sub-clinical, during the incubation period) Cases (through-out the course of the clinical syndrome) In contrast to the influenza virus, measles does not have an animal reservoir, which makes it candidate for “elimination” if we manage to successfully prevent infection among human reservoirs.

21 Time and portals Temporal pattern: Peak in late winter- spring Portals of exit/entry Respiratory system Exit: exhalation Entry: inhalation

22 Incubation and clinical features The incubation period: 7 to 21 days with an average of 14 days. After incubation period, the patient enters the prodromal stage with fever, coryza, malaise, sneezing, rhinitis, congestion, conjunctivitis and cough followed by a maculopapular rash that usually appears first on the face and then spreads distally. A case of measles is infectious for a period of 4 days prior to the onset of rash until 4 days after the onset of rash.

23 Clinical features Koplik's spots, which are pathognomonic for measles, appear on the buccal and lower labial mucosa opposite the lower molars. The distinctive maculo-papular rash appears about 4 days after exposure and starts behind the ears and on the forehead. From here the rash spreads to involve the whole body.


25 Complications and risk groups Measles can cause complications such as otitis media, pneumonia, severe diarrhea, and encephalitis leading to hospitalization and death in severe cases. The rates of hospitalization due to complications can be as high as 40% even in developed countries. Due to its high communicability, even a minor decrease in immunization coverage can result in rapidly spreading outbreaks and re-establishment of endemic transmission, as noted in the United Kingdom in the recent past. Unvaccinated children and young adults are at a higher risk of developing measles and they place vulnerable groups such as infants and persons with contraindications to immunization at risk.

26 Spread Airborne spread through aerosolized droplet nuclei has been documented in closed environments (e.g., clinics or waiting rooms) for up to 2 hours after the infected person has left the area. The R0 (expected number of secondary cases resulting from a primary case in the absence of community immunity) for measles is approximately 15, more than 10 times higher than that of the swine-origin H1N1, and three times higher than smallpox.

27 Treatment No specific antiviral treatment exists. Severe complications due to measles can be avoided through supportive care that ensures good nutrition, adequate fluid intake and treatment of dehydration. This solution replaces fluids and other essential elements that are lost through diarrhea or vomiting. Antibiotics should be prescribed to treat eye and ear infections, and pneumonia. All children in developing countries diagnosed with measles should receive two doses of vitamin A supplements, given 24 hours apart.

28 Control Controlling the spread of such a contagious disease that has an 8-9 day-long period of infectiousness remains a major public health challenge. In addition to the isolation of all laboratory-confirmed cases, post-exposure immunization of susceptible contacts with a single dose of measles-containing vaccine within 72 hours of exposure has been demonstrated to decrease transmission and is a standard recommendation. Both serologic and epidemiologic evidence suggest that the immunity induced by the vaccine remains effective long term and possibly for life, in most individuals.

29 Control (cont.) In spite of the progress achieved over the past few decades in eliminating and controlling the disease from many parts of the world through immunization, regions of high measles transmission still exist. Global migration and international travel to and from such regions pose a constant threat of re- introduction of virus transmission in regions that have eliminated measles.

30 Distribution of Laboratory-Confirmed Measles Cases by WHO Region, 2011.

31 Measles in Turkey 20509 cases in 2001 (9 deaths), 1119 cases in 2005 and 34 cases in 2006 whereas 349 cases in 2012 As of September 2013: 6983 cases Measles case burden: Third country in the world Notification is mandatory Elimination program prevails

32 Prevention Routine measles vaccination for children, combined with mass immunization campaigns in countries with high case and death rates, are key public health strategies to reduce global measles deaths. The measles vaccine has been in use for over 40 years. It is safe, effective and inexpensive. It costs less than one US dollar to immunize a child against measles.

33 Prevention (cont.) The measles vaccine is often incorporated with rubella and/or mumps vaccines in countries where these illnesses are problems. It is equally effective in the single or combined form. In 2011, about 84% of the world's children received one dose of measles vaccine by their first birthday through routine health services – up from 72% in 2000. Two doses of the vaccine are recommended to ensure immunity and prevent outbreaks, as about 15% of vaccinated children fail to develop immunity from the first dose.

34 Measles vaccine CompositionLive virus Efficacy95% (range, 90%-98%) The seroconversion rate is 95% and the immunity lasts lifelong. Duration of ImmunityLifelong Schedule2 doses Should be administered with mumps and rubella as MMR or with mumps, rubella and varicella as MMRV.


36 Control In the majority of patients, measles is an acute self- limiting disease that will run its course without the need for specific treatment. However, it is far more serious in the immuno-compromised, the undernourished, and children with chronic debilitating diseases. Such patients can be protected by the administration of human anti- measles gamma-globulin if given within the first 3 days after exposure. Alternatively, the exposed individual can simply be vaccinated within 72 hours of exposure. Pneumonia - antibiotics may be indicated in cases of secondary bacterial pneumonia or otitis media. Encephalitis - treatment of acute measles encephalitis is only symptomatic and supportive. A wide variety of treatment has been tried for SSPE but no convincing effects have been demonstrated.

37 Global Plan In April 2012, the MR Initiative launched a new Global Measles and Rubella Strategic Plan which covers the period 2012-2020. The Plan includes new global goals for 2015 and 2020: By the end of 2015 - To reduce global measles deaths by at least 95% compared with 2000 levels. - To achieve regional measles and rubella/congenital rubella syndrome (CRS) elimination goals.

38 Global Plan (cont.) By the end of 2020 To achieve measles and rubella elimination in at least five WHO regions. The strategy focuses on the implementation of five core components: achieve and maintain high vaccination coverage with two doses of measles- and rubella-containing vaccines; monitor the disease using effective surveillance, and evaluate programmatic efforts to ensure progress and the positive impact of vaccination activities; develop and maintain outbreak preparedness, rapid response to outbreaks and the effective treatment of cases; communicate and engage to build public confidence and demand for immunization; perform the research and development needed to support cost- effective action and improve vaccination and diagnostic tools.

39 Overview Measles is one of the leading causes of death among young children even though a safe and cost-effective vaccine is available. In 2011, there were 158 000 measles deaths globally More than 95% of measles deaths occur in low-income countries with weak health infrastructures. Measles vaccination resulted in a 71% drop in measles deaths between 2000 and 2011 worldwide. In 2011, about 84% of the world's children received one dose of measles vaccine by their first birthday through routine health services – up from 72% in 2000.



42 Definitions of Terms Seasonal influenza: Influenza that occurs every year with gradual variations in the previous year’s virus surface proteins (antigenic drift) Avian Influenza: a disease of birds that occasionally jumps species and infects humans. Ultimately is the source of new influenza A viruses in humans that can lead to pandemics Pandemic influenza: a worldwide surge in human influenza cases caused by the introduction of a new type A virus surface protein (antigenic shift) 42

43 Influenza Viruses Classified into types A, B, and C Types A and B cause significant disease worldwide Types B and C limited to humans Type A viruses More virulent Wild waterfowl reservoir Affect many species 43

44 Influenza A Viruses Categorized by subtype Classified according to two surface proteins Hemagglutinin (HA) – 17 known subtypes Site of attachment to host cells Antibody to HA is protective Neuraminidase (NA) – 10 known subtypes Helps release virions from cells Antibody to NA can help modify disease severity 44

45 H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 N1 N2 N3 N4 N5 N6 N7 N8 N9 45 Influenza A HA and NA Subtypes Other Animals

46 Importance of Influenza Global burden largely unknown Data from temperate climates 3-5 million severe cases/year 300,000 - 500,000 deaths/year 46

47 Transmission Influenza is an acute respiratory disease (causative agent is influenza virus from Orthomyxoviridae family) Signs and symptoms reflect respiratory route Fever, cough, headache, muscle aches Sometimes lower respiratory Transmission of influenza viruses Person-to-person through droplets from coughing or sneezing Transmission from objects (fomites) possible Infectious 1 day before and up to 5 days after becoming sick 47

48 Communicability Viral shedding can begin 1 day before symptom onset Peak shedding first 3 days of illness Subsides usually by 5-7th day in adults Infants, children and the immunosuppressed may shed virus longer 48

49 Seasonality Incubation period Time from exposure to onset of symptoms Average 2 days (range = 1-4 days) Peak shedding first 3 days of illness Seasonality In temperate zones, increases in winter months Driven by mutations and viral preference for cold, dry weather conditions In tropical zones, circulates year-round Fall-winter and rainy season increase has been observed More international data are needed 49

50 Clinical Disease, Human Influenza Clinical symptoms non-specific Couple with laboratory data to verify diagnosis. Abrupt onset Fever, chills, body aches, sore throat, non- productive cough, runny nose, headache. GI symptoms and muscle inflammation more common in young children 50

51 Human Influenza Complications Sinus and ear infections Viral and bacterial pneumonia Myocarditis and Pericarditis Myositis Encephalopathy and encephalitis Febrile seizures Worsening of underlying chronic conditions Sepsis-like syndrome in infants 51

52 Individuals at Increased Risk for Hospitalizations and Death Adults>65 years Adults and children with chronic medical conditions  Neuromuscular dysfunction  Heart disease  Asthma  Chronic lung disease  Liver disease  Diabetes  Immune compromised Pregnant women Nursing home residents Children on long-term aspirin therapy 52

53 Influenza Vaccination Best way to prevent influenza Developed from 3 circulating strains (2 Type A and 1 Type B strain) Seasonal “flu shot” only works for 3 influenza subtypes and will not work on pandemic strains Inactivated, intramuscular vaccine injection for persons 6 months and older Live, intranasal spray vaccine for healthy non-pregnant persons (2 – 49 years old) 53

54 Influenza Antiviral Medications Can be used for both prevention and for treatment: Adamantanes  Rimantadine and Amantadine  Only for Type A viruses  Currently not recommended for use due to resistance among circulating influenza A viruses Neuraminidase inhibitors  Oseltamivir (Tamiflu®) and Zanamivir (Relenza®)  Type A and B viruses  Emergence of global resistance to Oseltamivir in influenza A (H1N1) viruses in 2007-08 54

55 Infection Control Measures for Seasonal, Avian, and Pandemic Influenza Mostly in healthcare settings and nursing homes Standard precautions For example, gloves, hand washing and cough etiquette Transmission-based precautions For example, contact, droplet and sometimes droplet nuclei precautions Annual influenza vaccination of all healthcare workers 55

56 Non-Pharmaceutical Interventions (NPIs) Social distancing Personal protective measures (e.g. masks) Travel screening and restriction Public health communication campaigns 56

57 Avian Influenza 57

58 H5N1 Epizootic – 2003-2008 Since December 2003  >60 countries have reported H5N1 among domestic poultry or wild birds  Current outbreaks in many countries  Expanded from Asia to the Middle East, Europe, and Africa Largest epizootic of avian influenza ever described  Over 200 million birds died or destroyed 58

59 Cause for Concern Avian influenza can have a large impact on poultry Can cause morbidity/mortality in poultry Significant economic impact Rarely, avian influenza A virus infection can cause illness in humans Highly pathogenic avian influenza A viruses could be a source of the next pandemic influenza virus strain 59

60 Avian Influenza Viruses Type A influenza Endemic in birds May be low pathogenic or high pathogenic H5, H7 subtypes can be highly pathogenic and cause serious disease or death in wild birds; often cause death in poultry Virus in saliva and feces of wild birds and poultry can be directly transmitted to humans and other animals 60

61 Avian Influenza Virus Pathogenicity Low pathogenic AI (LPAI) viruses  Most common influenza virus infection in birds  Causes mild clinical and unapparent infections  May be any subtype (H1 to H16) Highly pathogenic AI (HPAI) viruses  Some H5 or H7 virus strains to date  Causes severe illness in poultry and often death  LPAI H5 or H7 virus subtypes can mutate into HPAI H5 or H7 virus subtypes  Usually no symptoms or mild symptoms in wild birds Determined by molecular and pathogenicity criteria 61

62 Highly Pathogenic Avian Influenza A (H5N1) Virus (HPAIV) Currently spreading through Asia, Africa, Europe, Middle East Can be highly lethal to domestic poultry and other animal species Occasional human cases but no sustained human-to- human transmission Virus of greatest concern for pandemic potential, but other influenza viruses in animals also of concern 62 *As of September 2008

63 Influenza A (H5N1) viruses in Other Animals H5N1 viruses can infect other animals: Pigs (China, Vietnam) Dogs Domestic cats; has infected civet cats Tigers, leopards (Thailand, China) Tiger-to-tiger transmission (Thailand) 63

64 Avian Influenza Virus Infections Usually do not jump species Wild bird strains do not usually infect domestic poultry Usually do not infect people Humans can become infected with avian influenza viruses Usually through close exposure to infected domestic poultry 64

65 65 Wild Water Fowl Domestic Birds Transmission Across Species Influenza A subtypes circulate in wild birds which can then infect domestic birds. Wild birds are reservoir for Influenza A strains and are the source for viruses infecting other species.

66 Human Infection with H5N1 Virus 66

67 H5N1 in Humans: Clinical Features Case fatality proportion: 63% Median age: 18 years Previously healthy children, young adults Incubation period: 2-7 days Fever, cough, shortness of breath, diarrhea Pneumonia, acute respiratory disease syndrome, multi-organ failure 67 World Health Organization. New England J Medicine 2008;358:261-73. *WHO WER;26:249-260

68 H5N1 Clinical Disease Very severe with high mortality Has primarily affected children and young adults Severe pneumonia is common Incubation period may be longer than for seasonal influenza Duration of infectious period likely longer than seasonal influenza, particularly among adults Multi-organ dysfunction is common 68

69 Avian Influenza in Humans YearSubtypeLocationCasesDeaths 1996H7N7United Kingdom10 1997H5N1Hong Kong186 1998H9N2China60 1999H9N2Hong Kong20 2002H7N2United States10 2003H7N2United States10 2003H9N2Hong Kong10 2003H5N1Hong Kong21 2003H7N7The Netherlands891 2006H5N1Turkey124 2007H7N2United Kingdom40 2003-13H5N1Worldwide637378 69

70 Worldwide H5N1 Outbreak in Birds 70 Source: WHO

71 Worldwide H5N1 Outbreak in Humans 71 Source: WHO

72 Direct and close contact with sick or dead poultry Slaughtering or cleaning poultry Visiting a live poultry market No evidence of sustained person-to- person spread Limited probable person-to-person spread 1 72 Human H5N1 Epidemiology 1 World Health Organization. NEJM 2008; 358:261-73.

73 Possible Mechanisms of International Spread Legal poultry business Illegal bird trade Migrating birds Humans (contaminated objects) Untreated fertilizer 73.

74 74 What is Pandemic Influenza? Pandemic: epidemic spreading around the world affecting hundreds of thousands of people, across many countries Influenza pandemic: global epidemic of new influenza A virus subtype that:  Passes easily from person to person  Causes severe disease Essentially no pre-existing immunity; everybody at risk

75 Characterized by ability to change: Continually (antigenic drift) → yearly epidemics Drastically (antigenic shift) → rare pandemics 75 Influenza Viruses

76 Antigenic “Drift” Minor antigenic changes to the hemagglutinin protein Point mutation in viral RNA Continuous process during viral replication Cause of seasonal epidemics Immunity may be limited to a specific strain Vaccine strains must be updated each year 76

77 Antigenic “Shift” Major antigenic changes leading to emergence of a new human influenza A virus subtype through: Genetic reassortment (human and animal viruses) Direct animal (poultry) to human transmission A pandemic can occur if: Efficient and sustained virus transmission occurs among humans (sustained person-to- person spread) 77

78 Drift and Shift, Illustrated 78

79 79 Human virus virus Reassortantvirus Non-humanvirus Re-assortment and Direct Transmission DIRECT

80 Requirements for an Influenza Pandemic Virus A new influenza A subtype virus emerges that can infect humans AND Causes serious illness AND Spreads easily from human-to-human in a sustained manner 80

81 Pandemic Influenza 81 Timing unpredictable High sickness rates across age groups Increased mortality  Higher proportion of deaths in younger persons

82 Estimated Mortality from Previous Influenza Pandemics 82 1918-19 (H1N1)  20 -50 million deaths worldwide 1957-58 (H2N2)  1 million deaths worldwide 1968-69 (H3N2)  1 million deaths worldwide

83 Human Influenza A public health problem each year Usually some immunity built up from previous exposures to the same subtype Infants and elderly most at risk Result of Antigenic Drift Influenza Pandemics Appear in the human population rarely and unpredictably Human population lacks immunity to a new influenza A virus subtype All age groups, including healthy young adults, may be at increased risk for serious complications Result of Antigenic Shift 83 Seasonal Epidemics vs. Pandemics

84 84 Timeline of New Influenza A Subtype Virus Infections in Humans H1 H3 H2 1918 Spanish Influenza H1N1 1957 Asian Influenza H2N2 1968 Hong Kong Influenza H3N2 1915 1925 1935 1945 1955 1965 1975 1985 1995 2005 2009 H7 H5 Avian Influenz a H9 H1 1977 Emergence of H1N1 2003 Emergence of H5N1

85 Concerns about Pandemic Influenza Rapid global spread (morbidity and mortality) Shortages and delays – vaccines and antiviral medications Increased burden on hospitals and outpatient care systems Disruption of national and community infrastructures 85

86 Review Question Seasonal Flu Avian Flu Pandemic Flu Occurred 3 times in the 20 th century Outbreaks result from antigenic drift Usually does not infect people 86 Match each term to the statement that it best fits

87 Potential Strategies to Decrease the Impact of a Pandemic Prevent or delay introduction, slow spread Decrease morbidity and death  Vaccine when available  Antiviral treatment and isolation for people with illness  Non-pharmaceutical interventions 87 Weeks Impact Prepared Unprepared

88 WHO Phases of a Pandemic 88

89 WHO Phases of a Pandemic Inter-pandemic Period Phase 1: No new Influenza virus subtypes in humans Phase 2: No new virus subtypes in humans; animal subtype poses a risk of human disease Pandemic Alert Period Phase 3: Human infection with novel virus; no or very limited human-to- human spread Phase 4: Small, localized clusters of human-to-human spread Phase 5: Larger clusters, still localized; virus adapting to humans Pandemic Period Phase 6: Increased and sustained transmission in the general population. Post Pandemic Period Recovery phase 89


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