Presentation on theme: "Epidemiology of Airborne Diseases"— Presentation transcript:
1Epidemiology of Airborne Diseases Dr. Yeşim YASİNFall-2013
2Outline Basics of epidemiology Basics of airborne infections Epidemiology of “tuberculosis”Epidemiology of “measles”Epidemiology of “influenza”
3Introduction“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.Epidemiology, in general, describes the patterns of disease and determinants in terms of incidence, prevalence, morbidity and mortality.
4Basics 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 RateThe proportion of exposed susceptible personswho become infected.Measles has high infectivity whereas leprosy has low infectivity.
5Basics 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.
6Basics of Epidemiology (cont.) VIRAL SHEDDINGMultiplication of a virus in an infected personwith subsequent release of the virus from thatinfected person, such that others who come intocontact with the person may become infected. Astate of being contagious.VIRULENCEThe 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.
10Airborne transmission Airborne transmission occurs by particles that are suspended in air.There are two types of these particles:- dust- droplet nucleiDust 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.
11Airborne transmission (cont.) Droplet nucleiThey 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.
12Airborne infection requirements Pathogen must be dispersed as fine particles (1-5 μm size)Respiratory tract-cough aerosolTB woundRemain suspended in airReach the alveolar level (TB)Resistant upper respiratory tractMinute infectious dose (droplet nucleus)
13Particle size and suspension in air Particle size & deposition site100 μ20 μ10 μ-upper airway1-5 μ-alveolar depositionTime to fall the height of a room10 sec4 min17 minSuspended indefinitely by room air currents
14Droplet vs. airborne spread Transmission within a meter of the sourceRelatively 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 effectiveTransmission beyond a meter-shared breathing volumeRelatively small numbers of organisms in inoculum-virulence requiredAccess to vulnerable site (alveoli in the case of TB)Hand washing not effective.
15Mycobacterium tuberculosis? More than 1m!Mycobacterium tuberculosis?
17Model 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)
19Agent 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: DropletIndirect: AirborneThe 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.
20Reservoir 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.One of the most contagious diseases, caused by a virus.
21Time and portals Temporal pattern: Peak in late winter-spring Portals of exit/entryRespiratory systemExit: exhalationEntry: inhalation
22Incubation 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.
23Clinical featuresKoplik'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.
25Complications 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.
26SpreadAirborne 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.
27Treatment 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.
28ControlControlling 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.
29Control (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.
30Distribution of Laboratory-Confirmed Measles Cases by WHO Region, 2011.
31Measles in Turkey20509 cases in 2001 (9 deaths), 1119 cases in 2005 and 34 cases in 2006 whereas 349 cases in 2012As of September 2013: 6983 casesMeasles case burden: Third country in the worldNotification is mandatoryElimination program prevails
32PreventionRoutine 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.
33Prevention (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.
34Measles vaccine Composition Live virus Efficacy 95% (range, 90%-98%) The seroconversion rate is 95% and the immunity lasts lifelong.Duration of Immunity LifelongSchedule 2 dosesShould be administered with mumps and rubella as MMR or with mumps, rubella and varicella as MMRV.
36ControlIn 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.
37Global PlanIn April 2012, the MR Initiative launched a new Global Measles and Rubella Strategic Plan which covers the periodThe 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.
38Global 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.
39OverviewMeasles 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 measles deaths globallyMore 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.
42Module 2: ABCs of Influenza and Pandemics Definitions of TermsSeasonal 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 pandemicsPandemic influenza: a worldwide surge in human influenza cases caused by the introduction of a new type A virus surface protein (antigenic shift)
43Module 2: ABCs of Influenza and Pandemics Influenza VirusesClassified into types A, B, and CTypes A and B cause significant disease worldwideTypes B and C limited to humansType A virusesMore virulentWild waterfowl reservoirAffect many species
44Module 2: ABCs of Influenza and Pandemics Influenza A VirusesCategorized by subtypeClassified according to two surface proteinsHemagglutinin (HA) – 17 known subtypesSite of attachment to host cellsAntibody to HA is protectiveNeuraminidase (NA) – 10 known subtypesHelps release virions from cellsAntibody to NA can help modify disease severity
45Module 2: ABCs of Influenza and Pandemics Influenza A HA and NA SubtypesModule 2: ABCs of Influenza and PandemicsH1H2H3H4H5H6H7H8H9H10H11H12H13H14H15H16N1N2N3N4N5N6N7N8N9Other AnimalsOther AnimalsOther AnimalsOther AnimalsOther AnimalsOther Animals
46Importance of Influenza Module 2: ABCs of Influenza and PandemicsImportance of InfluenzaGlobal burden largely unknownData from temperate climates3-5 million severe cases/year300, ,000 deaths/year
47Module 2: ABCs of Influenza and Pandemics TransmissionInfluenza is an acute respiratory disease (causative agent is influenza virus from Orthomyxoviridae family)Signs and symptoms reflect respiratory routeFever, cough, headache, muscle achesSometimes lower respiratoryTransmission of influenza virusesPerson-to-person through droplets from coughing or sneezingTransmission from objects (fomites) possibleInfectious 1 day before and up to 5 days after becoming sick
48Module 2: ABCs of Influenza and Pandemics CommunicabilityViral shedding can begin 1 day before symptom onsetPeak shedding first 3 days of illnessSubsides usually by 5-7th day in adultsInfants, children and the immunosuppressed may shed virus longer
49Module 2: ABCs of Influenza and Pandemics SeasonalityIncubation periodTime from exposure to onset of symptomsAverage 2 days (range = 1-4 days)Peak shedding first 3 days of illnessSeasonalityIn temperate zones, increases in winter monthsDriven by mutations and viral preference for cold, dry weather conditionsIn tropical zones, circulates year-roundFall-winter and rainy season increase has been observedMore international data are needed
50Clinical Disease, Human Influenza Module 2: ABCs of Influenza and PandemicsClinical Disease, Human InfluenzaClinical symptoms non-specificCouple with laboratory data to verify diagnosis.Abrupt onsetFever, chills, body aches, sore throat, non-productive cough, runny nose, headache.GI symptoms and muscle inflammation more common in young children
51Human Influenza Complications Module 2: ABCs of Influenza and PandemicsHuman Influenza ComplicationsSinus and ear infectionsViral and bacterial pneumoniaMyocarditis and PericarditisMyositisEncephalopathy and encephalitisFebrile seizuresWorsening of underlying chronic conditionsSepsis-like syndrome in infants
52Individuals at Increased Risk for Hospitalizations and Death Module 2: ABCs of Influenza and PandemicsIndividuals at Increased Risk for Hospitalizations and DeathAdults>65 yearsAdults and children with chronic medical conditionsNeuromuscular dysfunctionHeart diseaseAsthmaChronic lung diseaseLiver diseaseDiabetesImmune compromisedPregnant womenNursing home residentsChildren on long-term aspirin therapy
53Influenza Vaccination Module 2: ABCs of Influenza and PandemicsInfluenza VaccinationBest way to prevent influenzaDeveloped 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 strainsInactivated, intramuscular vaccine injection for persons 6 months and olderLive, intranasal spray vaccine for healthy non-pregnant persons (2 – 49 years old)
54Influenza Antiviral Medications Module 2: ABCs of Influenza and PandemicsInfluenza Antiviral MedicationsCan be used for both prevention and for treatment:AdamantanesRimantadine and AmantadineOnly for Type A virusesCurrently not recommended for use due to resistance among circulating influenza A virusesNeuraminidase inhibitorsOseltamivir (Tamiflu®) and Zanamivir (Relenza®)Type A and B virusesEmergence of global resistance to Oseltamivir in influenza A (H1N1) viruses in
55Infection Control Measures for Seasonal, Avian, and Pandemic Influenza Module 2: ABCs of Influenza and PandemicsInfection Control Measures for Seasonal, Avian, and Pandemic InfluenzaMostly in healthcare settings and nursing homesStandard precautionsFor example, gloves, hand washing and cough etiquetteTransmission-based precautionsFor example, contact, droplet and sometimes droplet nuclei precautionsAnnual influenza vaccination of all healthcare workers
56Non-Pharmaceutical Interventions (NPIs) Module 2: ABCs of Influenza and PandemicsNon-Pharmaceutical Interventions (NPIs)Social distancingPersonal protective measures (e.g. masks)Travel screening and restrictionPublic health communication campaigns
57Module 2: ABCs of Influenza and Pandemics Avian Influenza
58Module 2: ABCs of Influenza and Pandemics H5N1 Epizootic –Since December 2003>60 countries have reported H5N1 among domestic poultry or wild birdsCurrent outbreaks in many countriesExpanded from Asia to the Middle East, Europe, and AfricaLargest epizootic of avian influenza ever describedOver 200 million birds died or destroyed
59Module 2: ABCs of Influenza and Pandemics Cause for ConcernAvian influenza can have a large impact on poultryCan cause morbidity/mortality in poultrySignificant economic impactRarely, avian influenza A virus infection can cause illness in humansHighly pathogenic avian influenza A viruses could be a source of the next pandemic influenza virus strain
60Avian Influenza Viruses Module 2: ABCs of Influenza and PandemicsAvian Influenza VirusesType A influenzaEndemic in birdsMay be low pathogenic or high pathogenicH5, H7 subtypes can be highly pathogenic and cause serious disease or death in wild birds; often cause death in poultryVirus in saliva and feces of wild birds and poultry can be directly transmitted to humans and other animals
61Avian Influenza Virus Pathogenicity Module 2: ABCs of Influenza and PandemicsAvian Influenza Virus PathogenicityLow pathogenic AI (LPAI) virusesMost common influenza virus infection in birdsCauses mild clinical and unapparent infectionsMay be any subtype (H1 to H16)Highly pathogenic AI (HPAI) virusesSome H5 or H7 virus strains to dateCauses severe illness in poultry and often deathLPAI H5 or H7 virus subtypes can mutate into HPAI H5 or H7 virus subtypesUsually no symptoms or mild symptoms in wild birdsDetermined by molecular and pathogenicity criteria
62Highly Pathogenic Avian Influenza A (H5N1) Virus (HPAIV) Module 2: ABCs of Influenza and PandemicsHighly Pathogenic Avian Influenza A (H5N1) Virus (HPAIV)Currently spreading through Asia, Africa, Europe, Middle EastCan be highly lethal to domestic poultry and other animal speciesOccasional human cases but no sustained human-to-human transmissionVirus of greatest concern for pandemic potential, but other influenza viruses in animals also of concern*As of September 2008
63Influenza A (H5N1) viruses in Other Animals Module 2: ABCs of Influenza and PandemicsInfluenza A (H5N1) viruses in Other AnimalsH5N1 viruses can infect other animals:Pigs (China, Vietnam)DogsDomestic cats; has infected civet catsTigers, leopards (Thailand, China)Tiger-to-tiger transmission (Thailand)
64Avian Influenza Virus Infections Module 2: ABCs of Influenza and PandemicsAvian Influenza Virus InfectionsUsually do not jump speciesWild bird strains do not usually infect domestic poultryUsually do not infect peopleHumans can become infected with avian influenza virusesUsually through close exposure to infected domestic poultry
65Module 2: ABCs of Influenza and Pandemics Transmission Across SpeciesDomesticBirdsWild Water FowlInfluenza A subtypescirculate in wild birds which can then infect domestic birds.Wild birds arereservoir for Influenza A strains and are the source for viruses infecting other species.
67H5N1 in Humans: Clinical Features Module 2: ABCs of Influenza and PandemicsH5N1 in Humans: Clinical FeaturesCase fatality proportion: 63%Median age: 18 yearsPreviously healthy children, young adultsIncubation period: 2-7 daysFever, cough, shortness of breath, diarrheaPneumonia, acute respiratory disease syndrome, multi-organ failureWorld Health Organization. New England J Medicine 2008;358:*WHO WER;26:
68Module 2: ABCs of Influenza and Pandemics H5N1 Clinical DiseaseVery severe with high mortalityHas primarily affected children and young adultsSevere pneumonia is commonIncubation period may be longer than for seasonal influenzaDuration of infectious period likely longer than seasonal influenza, particularly among adultsMulti-organ dysfunction is common
69Avian Influenza in Humans Module 2: ABCs of Influenza and PandemicsAvian Influenza in HumansYearSubtypeLocationCasesDeaths1996H7N7United Kingdom11997H5N1Hong Kong1861998H9N2China199922002H7N2United States2003The Netherlands892006Turkey1242007Worldwide637378Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO,
70Worldwide H5N1 Outbreak in Birds Module 2: ABCs of Influenza and PandemicsWorldwide H5N1 Outbreak in BirdsSource: WHO
71Worldwide H5N1 Outbreak in Humans Module 2: ABCs of Influenza and PandemicsWorldwide H5N1 Outbreak in HumansSource: WHO
72Module 2: ABCs of Influenza and Pandemics Human H5N1 EpidemiologyDirect and close contact with sick or dead poultrySlaughtering or cleaning poultryVisiting a live poultry marketNo evidence of sustained person-to-person spreadLimited probable person-to-person spread11 World Health Organization. NEJM 2008; 358:
73Possible Mechanisms of International Spread Module 2: ABCs of Influenza and PandemicsPossible Mechanisms of International SpreadLegal poultry businessIllegal bird tradeMigrating birdsHumans (contaminated objects)Untreated fertilizer.
74Module 2: ABCs of Influenza and Pandemics What is Pandemic Influenza?Pandemic: epidemic spreading around the world affecting hundreds of thousands of people, across many countriesInfluenza pandemic: global epidemic of new influenza A virus subtype that:Passes easily from person to personCauses severe diseaseEssentially no pre-existing immunity; everybody at risk
75Module 2: ABCs of Influenza and Pandemics Influenza VirusesCharacterized by ability to change:Continually (antigenic drift) → yearly epidemicsDrastically (antigenic shift) → rare pandemics
76Module 2: ABCs of Influenza and Pandemics Antigenic “Drift”Minor antigenic changes to the hemagglutinin proteinPoint mutation in viral RNAContinuous process during viral replicationCause of seasonal epidemicsImmunity may be limited to a specific strainVaccine strains must be updated each year
77Module 2: ABCs of Influenza and Pandemics 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 transmissionA pandemic can occur if:Efficient and sustained virus transmission occurs among humans (sustained person-to-person spread)
78Drift and Shift, Illustrated Module 2: ABCs of Influenza and PandemicsDrift and Shift, Illustrated
79Module 2: ABCs of Influenza and Pandemics Re-assortment andDirect TransmissionDIRECTNon-humanvirusHumanvirusReassortantvirus
80Requirements for an Influenza Pandemic Virus Module 2: ABCs of Influenza and PandemicsRequirements for an Influenza Pandemic VirusA new influenza A subtype virus emerges that can infect humansANDCauses serious illnessSpreads easily from human-to-human in a sustained manner
81Module 2: ABCs of Influenza and Pandemics Pandemic InfluenzaTiming unpredictableHigh sickness rates across age groupsIncreased mortalityHigher proportion of deaths in younger persons
82Module 2: ABCs of Influenza and Pandemics Estimated Mortality from Previous Influenza Pandemics(H1N1)million deaths worldwide(H2N2)1 million deaths worldwide(H3N2)
83Module 2: ABCs of Influenza and Pandemics Seasonal Epidemics vs. PandemicsHuman InfluenzaA public health problem each yearUsually some immunity built up from previous exposures to the same subtypeInfants and elderly most at riskResult of Antigenic DriftInfluenza PandemicsAppear in the human population rarely and unpredictablyHuman population lacks immunity to a new influenza A virus subtypeAll age groups, including healthy young adults, may be at increased risk for serious complicationsResult of Antigenic Shift
84Module 2: ABCs of Influenza and Pandemics Timeline of New Influenza A Subtype Virus Infections in HumansH9AvianInfluenzaH7H5H3H2H1H11957AsianInfluenzaH2N21968Hong KongInfluenzaH3N21977Emergence of H1N12003Emergence of H5N11918SpanishInfluenzaH1N1
85Concerns about Pandemic Influenza Module 2: ABCs of Influenza and PandemicsConcerns about Pandemic InfluenzaRapid global spread (morbidity and mortality)Shortages and delays – vaccines and antiviral medicationsIncreased burden on hospitals and outpatient care systemsDisruption of national and community infrastructures
86Module 2: ABCs of Influenza and Pandemics Review QuestionMatch each term to the statement that it best fitsSeasonal FluAvian FluPandemic FluOccurred 3 times in the 20th centuryOutbreaks result from antigenic driftUsually does not infect people
87Potential Strategies to Decrease the Impact of a Pandemic Module 2: ABCs of Influenza and PandemicsPotential Strategies to Decrease the Impact of a PandemicPrevent or delay introduction, slow spreadDecrease morbidity and deathVaccine when availableAntiviral treatment and isolation for people with illnessNon-pharmaceutical interventionsWeeksImpactPreparedUnprepared
88WHO Phases of a Pandemic Module 2: ABCs of Influenza and PandemicsWHO Phases of a Pandemic
89WHO Phases of a Pandemic Module 2: ABCs of Influenza and PandemicsWHO Phases of a PandemicInter-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