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Epidemiology of Airborne Diseases Dr. Yeşim YASİN Fall-2013 Outline • Basics of epidemiology • Basics of airborne infections • Epidemiology of “tuberculosis” • Epidemiology of “measles” • Epidemiology of “influenza” Introduction • “Epidemiology: The study of the distribution and determinants of a healthrelated 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. 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. 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. 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. Modes of transmission Airborne transmission Transmission medium 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. 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. 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) 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 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. Mycobacterium tuberculosis? 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) MEASLES 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. 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. Time and portals • Temporal pattern: Peak in late winterspring • Portals of exit/entry Respiratory system • Exit: exhalation • Entry: inhalation 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. 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. 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. 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. 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. 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. 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 reintroduction of virus transmission in regions that have eliminated measles. Distribution of Laboratory-Confirmed Measles Cases by WHO Region, 2011. 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 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. 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. Measles vaccine • Composition Live virus • Efficacy 95% (range, 90%-98%) The seroconversion rate is 95% and the immunity lasts lifelong. • Duration of Immunity Lifelong • Schedule 2 doses • Should be administered with mumps and rubella as MMR or with mumps, rubella and varicella as MMRV. Control • In the majority of patients, measles is an acute selflimiting 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 antimeasles 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. 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. 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 costeffective action and improve vaccination and diagnostic tools. 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. INFLUENZA 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 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 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 Influenza A HA and NA Subtypes H1 H2 H3 H4 H5 H6 H7 H8 H9 H10 H11 H12 H13 H14 H15 H16 N1 N2 Other Animals Other Animals Other Animals Other Animals N3 N4 N5 N6 N7 N8 N9 Other Animals Other Animals 45 Importance of Influenza • Global burden largely unknown • Data from temperate climates • 3-5 million severe cases/year • 300,000 - 500,000 deaths/year 46 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 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 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 Clinical Disease, Human Influenza • Clinical symptoms non-specific • Couple with laboratory data to verify diagnosis. • Abrupt onset • Fever, chills, body aches, sore throat, nonproductive cough, runny nose, headache. • GI symptoms and muscle inflammation more common in young children 50 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 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 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 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 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 Non-Pharmaceutical Interventions (NPIs) • Social distancing • Personal protective measures (e.g. masks) • Travel screening and restriction • Public health communication campaigns 56 Avian Influenza 57 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 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 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 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 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-tohuman transmission • Virus of greatest concern for pandemic potential, but other influenza viruses in animals also of concern 62 *As of September 2008 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 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 Transmission Across Species Wild Water Fowl Influenza A subtypes circulate in wild birds which can then infect domestic birds. Domestic Birds Wild birds are reservoir for Influenza A strains and are the source for viruses infecting other species. 65 Human Infection with H5N1 Virus 66 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 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 Avian Influenza in Humans Year Subtype Location Cases Deaths 1996 H7N7 United Kingdom 1 0 1997 H5N1 Hong Kong 18 6 1998 H9N2 China 6 0 1999 H9N2 Hong Kong 2 0 2002 H7N2 United States 1 0 2003 H7N2 United States 1 0 2003 H9N2 Hong Kong 1 0 2003 H5N1 Hong Kong 2 1 2003 H7N7 The Netherlands 89 1 2006 H5N1 Turkey 12 4 2007 H7N2 United Kingdom 4 0 2003-13 H5N1 Worldwide 637 378 69 Worldwide H5N1 Outbreak in Birds 70 Source: WHO Worldwide H5N1 Outbreak in Humans 71 Source: WHO Human H5N1 Epidemiology • Direct and close contact with sick or dead poultry • Slaughtering or cleaning poultry • Visiting a live poultry market • No evidence of sustained person-toperson spread • Limited probable person-to-person spread1 1 World Health Organization. NEJM 2008; 358:261-73. 72 Possible Mechanisms of International Spread • Legal poultry business • Illegal bird trade • Migrating birds • Humans (contaminated objects) • Untreated fertilizer . 73 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 74 Influenza Viruses Characterized by ability to change: • Continually (antigenic drift) → yearly epidemics • Drastically (antigenic shift) → rare pandemics 75 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 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-toperson spread) 77 Drift and Shift, Illustrated 78 Re-assortment and Direct Transmission Non-human virus Human virus Reassortant virus 79 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 Pandemic Influenza • Timing unpredictable • High sickness rates across age groups • Increased mortality Higher proportion of deaths in younger persons 81 Estimated Mortality from Previous Influenza Pandemics • 1918-19 (H1N1) 20 -50 million deaths worldwide • 1957-58 (H2N2) 1 million deaths worldwide • 1968-69 (H3N2) 1 million deaths worldwide 82 Seasonal Epidemics vs. Pandemics Human Influenza Influenza Pandemics • A public health problem each year • Appear in the human population rarely and unpredictably • Usually some immunity built up from previous exposures to the same subtype • Human population lacks immunity to a new influenza A virus subtype • Infants and elderly most at risk • All age groups, including healthy young adults, may be at increased risk for serious complications • Result of Antigenic Drift • Result of Antigenic Shift 83 Timeline of New Influenza A Subtype Virus Infections in Humans Avian Influenza H9 H7 H5 H3 H2 H1 H1 1915 1925 1935 1945 1955 1965 1975 1985 1995 2005 2009 1918 1957 1968 1977 2003 Spanish Influenza H1N1 Asian Influenza H2N2 Hong Kong Influenza H3N2 Emergence of H1N1 Emergence of H5N1 84 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 Review Question Match each term to the statement that it best fits • Seasonal Flu • Avian Flu • Pandemic Flu • Occurred 3 times in the 20th century • Outbreaks result from antigenic drift • Usually does not infect people 86 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 Unprepared Impact 87 Prepared Weeks WHO Phases of a Pandemic http://www.who.int/csr/disease/avian_influenza/phase/en/index.html 88 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-tohuman 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. 89 Post Pandemic Period Recovery phase THANK YOU!