INFLUENZA VIRUS INFLUENZA VIRUS CDC WEBSITE http://www.cdc.gov/ncidod/diseases/flu/fluinfo.htm

Swine Influenza A (H1N1) Infection in Two Children --- Southern California, March--April 2009 On April 17, 2009, CDC determined that two cases of febrile respiratory illness occurring in children who resided in adjacent counties in southern California were caused by infection with a swine influenza A (H1N1) virus. The viruses from the two cases are closely related genetically, resistant to amantadine and rimantadine, and contain a unique combination of gene segments that previously has not been reported among swine or human influenza viruses in the United States or elsewhere. Neither child had contact with pigs; the source of the infection is unknown. Investigations to identify the source of infection and to determine whether additional persons have been ill from infection with similar swine influenza viruses are ongoing. Although this is not a new subtype of influenza A in humans, concern exists that this new strain of swine influenza A (H1N1) is substantially different from human influenza A (H1N1) viruses, that a large proportion of the population might be susceptible to infection, and that the seasonal influenza vaccine H1N1 strain might not provide protection. The lack of known exposure to pigs in the two cases increases the possibility that human-to-human transmission of this new influenza virus has occurred. Clinicians should consider animal as well as seasonal influenza virus infections in their differential diagnosis of patients who have febrile respiratory illness and who 1) live in San Diego and Imperial counties or 2) traveled to these counties or were in contact with ill persons from these counties in the 7 days preceding their illness onset, or 3) had recent exposure to pigs. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm Editorial Note (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm): In the past, CDC has received reports of approximately one human swine influenza virus infection every 1--2 years in the United States (2,3). However, during December 2005--January 2009, 12 cases of human infection with swine influenza were reported; five of these 12 cases occurred in patients who had direct exposure to pigs, six in patients reported being near pigs, and the exposure in one case was unknown (1,4,5). In the United States, novel influenza A virus infections in humans, including swine influenza infections, have been nationally notifiable conditions since 2007. The recent increased reporting might be, in part, a result of increased influenza testing capabilities in public health laboratories, but genetic changes in swine influenza viruses and other factors also might be a factor (1,4,5). Although the vast majority of human infections with animal influenza viruses do not result in human-to-human transmission (2,3), each case should be fully investigated to be certain that such viruses are not spreading among humans and to limit further exposure of humans to infected animals, if infected animals are identified. Such investigations should include close collaboration between state and local public health officials with animal health officials.

‘FLU’ True influenza influenza virus A or influenza virus B (or influenza virus C infections - much milder) Febrile respiratory disease with systemic symptoms caused by a variety of other organisms often inaccurately called ‘flu’

South Carolina 1996-1997 DHEC bulletin malathia influenzae per le stelle no virus CULTURE RESULTS influenza A influenza B SEASONAL INFLUENZA http://www.state.sc.us/dhec/LAB/labbu017.htm

THE IMPACT OF INFLUENZA PANDEMICS Deaths: 1918-19 figures have been revised upwards in recent years, so this is higher than will find in older books. Remember US population in 1918 about 1/3 of what it is now. 1918 ~100,000,000, current ~300,000,000

THE IMPACT OF INFLUENZA In the US, 1990-1999, on average: 36,000 deaths per year 226,000 hospitalizations per year Figures have tended to increase recently - in part due to aging of population? http://www.cdc.gov/flu/professionals/acip/clinical.htm

ORTHOMYXOVIRUSES pleomorphic influenza types A,B,C febrile, respiratory illness with systemic symptoms http://www.uct.ac.za/depts/mmi/stannard/fluvirus.html

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

TRANSMISSION AEROSOL SURFACES 18-72 HR INCUBATION SHEDDING 100,000 TO 1,000,000 VIRIONS PER DROPLET SURFACES - VIRUS CAN SURVIVE APPROX 2 TO 8 HRS 18-72 HR INCUBATION SHEDDING http://www.cdc.gov/h1n1flu/guidance/workplace.htm : One study showed that influenza virus can survive on environmental surfaces and can infect a person for up to 2-8 hours after being deposited on the surface. To reduce the chance of spread of the novel influenza A (H1N1) virus, disinfect commonly-touched hard surfaces in the workplace, such as work stations, counter tops, door knobs, and bathroom surfaces by wiping them down with a household disinfectant according to directions on the product label.

RECOVERY INTERFERON - SIDE EFFECTS INCLUDE: FEVER, MYALGIA, FATIGUE, MALAISE CELL-MEDIATED IMMUNE RESPONSE TISSUE REPAIR CAN TAKE SOME TIME

An immunological diversion INTERFERON

INTERFERON time course of virus production will vary from virus to virus

INTERFERON

INTERFERON antiviral state

INTERFERON antiviral state

INTERFERON antiviral state

TYPES OF INTERFERON TYPE I Interferon-alpha (leukocyte interferon, about 20 related proteins) - leukocytes, etc Interferon-beta (fibroblast interferon) - fibroblasts, epithelial cells, etc TYPE II Interferon-gamma (immune interferon) - certain activated T-cells, NK cells

INDUCTION OF INTERFERON interferon-alpha and interferon-beta induced by viral infection (especially RNA viruses) double stranded RNA certain bacterial components - strong anti-viral properties interferon-gamma - antigens, mitogenic stimulation of lymphocytes

INTERFERON induces variety of proteins in target cells many consequences, not all fully understood

INTERFERON-ALPHA AND INTERFERON-BETA

interferon-alpha, interferon-beta interferon receptor induction of 2’5’oligo A synthase induction of ribonuclease L induction of protein kinase R (PKR) 2’5’oligo A activated 2’5’oligo A synthase activated ribonuclease L activated protein kinase R ATP ATP phosphorylated initiation factor (eIF-2) 2’5’oligo A mRNA degraded inhibition of protein synthesis

interferon-alpha, interferon-beta interferon receptor induction of 2’5’oligo A synthase induction of ribonuclease L induction of protein kinase R (PKR) ds RNA ds RNA 2’5’oligo A activated 2’5’oligo A synthase activated ribonuclease L activated protein kinase R ATP ATP phosphorylated initiation factor (eIF-2) 2’5’oligo A mRNA degraded inhibition of protein synthesis

interferons only made when needed

OTHER EFFECTS OF INTERFERONS ALL TYPES INCREASE MHC I EXPRESSION CYTOTOXIC T-CELLS ACTIVATE NK CELLS CAN KILL VIRALLY INFECTED CELLS

OTHER EFFECTS OF INTERFERONS INTERFERON-GAMMA INCREASES MHC II EXPRESSION ON APC HELPER T-CELLS INCREASES ANTIVIRAL POTENTIAL OF MACROPHAGES INTRINSIC EXTRINSIC

THERAPEUTIC USES OF INTERFERONS ANTI-VIRAL e.g. interferon-alpha is currently approved for certain cases of acute and chronic HCV and chronic HBV MACROPHAGE ACTIVATION interferon-gamma has been tried for e.g. lepromatous leprosy, leishmaniasis, toxoplasmosis ANTI-TUMOR have been used in e.g. melanoma, Kaposi’s sarcoma, CML MULTIPLE SCLEROSIS interferon-beta

Viral response to host immune system Viruses may : block interferon binding inhibit function of interferon-induced proteins interfere with MHC I or MHC II expression inhibit NK function block complement activation inhibit apoptosis etc!

SIDE EFFECTS OF INTERFERONS FEVER MALAISE FATIGUE MUSCLE PAINS

BACK TO INFLUENZA

SYMPTOMS FEVER HEADACHE MYALGIA COUGH RHINITIS OCULAR SYMPTOMS GI tract symptoms not typically seen but common with 2009 H1N1 influenza (‘swine flu’) vomiting, diarrhea

INTERFERON time course of virus production will vary from virus to virus

PROTECTION AGAINST RE-INFECTION IgG and IgA IgG less efficient but lasts longer antibodies to both HA and NA important antibody to HA more important (can neutralize)

CLINICAL FINDINGS SEVERITY VERY YOUNG ELDERLY IMMUNO-COMPROMISED HEART OR LUNG DISEASE

PULMONARY COMPLICATIONS CROUP (YOUNG CHILDREN) PRIMARY INFLUENZA VIRUS PNEUMONIA SECONDARY BACTERIAL INFECTION Streptococcus pneumoniae Staphlyococcus aureus Hemophilus influenzae

NON-PULMONARY COMPLICATIONS myositis (rare, > in children, > with type B) cardiac complications encephalopathy 2002/2003 season studies of patients younger than 21 yrs in Michigan - 8 cases (2 deaths) liver and CNS Reye’s syndrome peripheral nervous system Guillian-Barré syndrome

Reye’s syndrome liver - fatty deposits brain - edema vomiting, lethargy, coma risk factors youth certain viral infections (influenza, chicken pox) aspirin

Guillian-Barré syndrome peripheral nervous system involved autoimmune 3000-6000 cases per year US most recover fully may follow infectious disease Campylobacter jejuni one of most common risk factors may be associated with some viral infections 1976/77 swine flu vaccine 35,000,000 doses 354 cases of GBS (approx 1-2 additional cases per 100,000 vaccinated) 28 GBS-associated deaths recent infuenza vaccines much lower risk risk from vaccination much lower than risk from infection http://www.cdc.gov/h1n1flu/vaccination/gbs_qa.htm: About two-thirds of people who develop GBS symptoms do so several days or weeks after they have been sick with a diarrheal or respiratory illness. Infection with the bacterium Campylobacter jejuni is one of the most common risk factors for GBS. People can also develop GBS after having the flu or other infections (such as cytomegalovirus and Epstein Barr virus). On very rare occasions, they may develop GBS in the days or weeks following receiving a vaccination.

MORTALITY MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH SEASONAL INFLUENZA MORTALITY MAJOR CAUSES OF INFLUENZA VIRUS- ASSOCIATED DEATH BACTERIAL PNEUMONIA CARDIAC FAILURE 90% OF DEATHS IN THOSE OVER 65 YEARS OF AGE

DIAGNOSIS ISOLATION SEROLOGY PCR RAPID TESTS NOSE, THROAT SWAB GROW IN TISSUE CULTURE OR EGGS SEROLOGY PCR RAPID TESTS provisional - clinical picture + outbreak Rapid tests - signifcance in ascertaining whether the infection is influenza and which type it is since now have therapeutic agents (some of which are type specific) - signifcance in differential diagnosis - eg if need to determine if Flu v. SARS - advent of rapid easy tests may increase diagnosis - may realise that flu involved in more illnesses than realised (eg enhanced surveillance of patients <21 at low risk for complications who were admitted to hospital for a variety of symptoms revealed that more severe morbitity and mortality assoc with influenza that was realised -2003).

HA protein - attachment, fusion membrane S host enzymes inside of virion =antibody

NA protein - neuraminidase membrane inside of virion =antibody

ANTIGENIC DRIFT HA and NA accumulate mutations RNA virus immune response no longer protects fully sporadic outbreaks, limited epidemics

ANTIGENIC SHIFT “new” HA or NA proteins pre-existing antibodies do not protect may get pandemics

where do “new” HA and NA come from? ~16 types HA ~9 types NA all circulate in birds pigs can be infected by avian and human influenza viruses

Where do “new” HA and NA come from?

Where do “new” HA and NA come from 2009 PANDEMIC H1N1?

Where do “new” HA and NA come from - can ‘new’ bird flu directly infect humans? Current “Bird flu” H5N1? 1918 influenza

H5N1 – in birds Avian H5N1 has spread to humans So far human cases in Asia and Africa 442 cases (12-1-03 through 09-24-09) 262 (59%) fatal Have been a few instances where may have spread human-to-human So far no sustained spread in humans Surveillance continues

2009 NOVEL H1N1 PANDEMIC first novel H1N1 patient in the United States confirmed by laboratory testing at CDC on April 15, 2009. Quickly determined that the virus was spreading from person-to-person. By June 3, 2009, all 50 states in the United States and the District of Columbia and Puerto Rico were reporting cases of novel H1N1 infection. http://www.cdc.gov/h1n1flu/update.htm

why do we not have influenza B pandemics? so far no shifts have been recorded no animal reservoir known

SURVEILLANCE http://www.csiro.au/science/AIatAAHL.html

% typed cases influenza season

actual percentage of deaths CDC: http://www.cdc.gov/flu/weekly/

VACCINE ‘BEST GUESS’ OF MAIN ANTIGENIC TYPES CURRENTLY SEASONAL VACCINE TRIVALENT type A - H1N1 type A - H3N2 type B each year choose which strain of each subtype is the best to use for optimal protection the 2009-2010 trivalent vaccine for seasonal influenza has: A/Brisbane/59/2007 (H1N1)-like A/Brisbane/10/2007 (H3N2)-like B/Brisbane/60/2008

VACCINE inactivated (trivalent inactivated influenza vaccine, TIV) egg grown some formulations licensed for children reassortant, trivalent live vaccine (live attenuated vaccine, LAIV) for healthy non-pregnant persons (those not at risk for complications from influenza infection) ages 2-49 years (not approved for children under 5yrs with a history of recurrent wheezing)

usual timing – 2009 rather different CDC

http://www. cdc. gov/flu/professionals/acip/flu_vax_adults0910 http://www.cdc.gov/flu/professionals/acip/flu_vax_adults0910.htm#box2

http://www. cdc. gov/flu/professionals/acip/flu_vax_children0910 http://www.cdc.gov/flu/professionals/acip/flu_vax_children0910.htm#box1

PREVENTION - DRUGS ZANAMIVIR (NA) types A and B OSELTAMIVIR (NA) RIMANTADINE (M2) type A only AMANTADINE (M2) 2005 to present: high levels of resistance of influenza A viruses to amantidine and rimantidine, so these drugs not recommended until resistance drops have been reports of some strains being oseltamivir resistant pandemic 2009 H1N1 is sensitive surveillance and rapid diagnosis techniques important in determining optimal drug treatment

TREATMENT - DRUGS ZANAMIVIR (NA) OSELTAMIVIR (NA) RIMANTADINE (M2) types A and B, needs to be given early OSELTAMIVIR (NA) (some resistant strains but resistant strains currently still sensitive to zanamivir) RIMANTADINE (M2) type A only, needs to be given early currently resistance problems so not recommended AMANTADINE (M2) –

NA protein - neuraminidase . . . . . . . . . . . . . . . . . . .

OTHER TREATMENT REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS) BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY

severity of illness animal reservoir human pandemics human epidemics antigenic changes segmented genome amantadine, rimantidine zanamivir, oseltamivir surface glycoproteins TYPE A ++++ yes shift, drift (sensitive) sensitive 2 TYPE B ++ no yes drift no effect sensitive 2 TYPE C + no no (sporadic) drift yes no effect (1)

seasonal pandemic Outbreaks follow predictable seasonal patterns; occurs annually, usually in winter, in temperate climates Usually some immunity built up from previous exposure Healthy adults usually not at risk for serious complications; the very young, the elderly and those with certain underlying health conditions at increased risk for serious complications Health systems can usually meet public and patient needs Vaccine developed based on known flu strains and available for annual flu season Adequate supplies of antivirals are usually available Average U.S. deaths approximately 36,000/yr Symptoms: fever, cough, runny nose, muscle pain. Deaths often caused by complications, such as pneumonia. Generally causes modest impact on society (e.g., some school closing, encouragement of people who are sick to stay home) Manageable impact on domestic and world economy Occurs rarely (a few times a century) No previous exposure; little or no pre-existing immunity Healthy people may be at increased risk for serious complications Health systems may be overwhelmed Vaccine probably would not be available in the early stages of a pandemic Effective antivirals may be in limited supply Number of deaths could be quite high (e.g., U.S. 1918 death toll approximately 675,000) Symptoms may be more severe and complications more frequent May cause major impact on society (e.g. widespread restrictions on travel, closings of schools and businesses, cancellation of large public gatherings) Potential for severe impact on domestic and world economy www.pandemicflu.gov/season_or_pandemic.html

Swine Influenza A (H1N1) Infection in Two Children --- Southern California, March--April 2009 On April 17, 2009, CDC determined that two cases of febrile respiratory illness occurring in children who resided in adjacent counties in southern California were caused by infection with a swine influenza A (H1N1) virus. The viruses from the two cases are closely related genetically, resistant to amantadine and rimantadine, and contain a unique combination of gene segments that previously has not been reported among swine or human influenza viruses in the United States or elsewhere. Neither child had contact with pigs; the source of the infection is unknown. Investigations to identify the source of infection and to determine whether additional persons have been ill from infection with similar swine influenza viruses are ongoing. Although this is not a new subtype of influenza A in humans, concern exists that this new strain of swine influenza A (H1N1) is substantially different from human influenza A (H1N1) viruses, that a large proportion of the population might be susceptible to infection, and that the seasonal influenza vaccine H1N1 strain might not provide protection. The lack of known exposure to pigs in the two cases increases the possibility that human-to-human transmission of this new influenza virus has occurred. Clinicians should consider animal as well as seasonal influenza virus infections in their differential diagnosis of patients who have febrile respiratory illness and who 1) live in San Diego and Imperial counties or 2) traveled to these counties or were in contact with ill persons from these counties in the 7 days preceding their illness onset, or 3) had recent exposure to pigs. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm Editorial Note (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm58d0421a1.htm): In the past, CDC has received reports of approximately one human swine influenza virus infection every 1--2 years in the United States (2,3). However, during December 2005--January 2009, 12 cases of human infection with swine influenza were reported; five of these 12 cases occurred in patients who had direct exposure to pigs, six in patients reported being near pigs, and the exposure in one case was unknown (1,4,5). In the United States, novel influenza A virus infections in humans, including swine influenza infections, have been nationally notifiable conditions since 2007. The recent increased reporting might be, in part, a result of increased influenza testing capabilities in public health laboratories, but genetic changes in swine influenza viruses and other factors also might be a factor (1,4,5). Although the vast majority of human infections with animal influenza viruses do not result in human-to-human transmission (2,3), each case should be fully investigated to be certain that such viruses are not spreading among humans and to limit further exposure of humans to infected animals, if infected animals are identified. Such investigations should include close collaboration between state and local public health officials with animal health officials.

the end...............

SEASONAL INFLUENZA http://www.cdc.gov/flu/professionals/acip/clinical.htm#signs

Novel Influenza A Virus – Jan 24th 2009 (week 3) One case of human infection with a novel influenza A virus was reported by the South Dakota Department of Health during week 3. The person was infected with a swine influenza A (H1N1) virus, and an investigation is currently underway to determine the source of illness. Although human infection with swine influenza is uncommon, sporadic cases have occurred in many years, usually among people in direct contact with ill pigs or who have been in places where pigs may have been present (e.g. agricultural fairs or farms). The sporadic cases of human infections with swine influenza viruses identified in recent years have not resulted in sustained human-to-human transmission or community outbreaks. Nonetheless, when cases are identified, CDC recommends thorough investigations to evaluate the extent of the outbreak and possible human to human transmission, as transmission patterns may change with changes in swine influenza viruses. (This was a regular swine flu virus, not the pandemic strain)

Public health response – 2009 April 15, 2009 The first novel H1N1 patient in the US was confirmed by laboratory testing at CDC. April 17, 2009 The second patient was confirmed. It was quickly determined that the virus was spreading from person-to-person. April 22, 2009 CDC activated its Emergency Operations Center to better coordinate the public health response April 26, 2009 The US Government declared a public health emergency and actively implemented the nation’s pandemic response plan http://www.cdc.gov/h1n1flu/background.htm

06-19-2009 http://www.cdc.gov/h1n1flu/update.htm - downloaded 6/22/09 The first novel H1N1 patient in the United States was confirmed by laboratory testing at CDC on April 15, 2009. The second patient was confirmed on April 17, 2009. It was quickly determined that the virus was spreading from person-to-person. On April 22, CDC activated its Emergency Operations Center to better coordinate the public health response. On April 26, 2009, the United States Government declared a public health emergency and has been actively and aggressively implementing the nation’s pandemic response plan. Since the outbreak was first detected, an increasing number of U.S. states have reported cases of novel H1N1 influenza with associated hospitalizations and deaths. By June 3, 2009, all 50 states in the United States and the District of Columbia and Puerto Rico were reporting cases of novel H1N1 infection. June 19th 2009. While nationwide U.S. influenza surveillance systems indicate that overall influenza activity is decreasing in the country at this time, novel H1N1 outbreaks are ongoing in parts of the U.S., in some cases with intense activity. CDC is continuing to watch the situation carefully, to support the public health response and to gather information about this virus and its characteristics. The Southern Hemisphere is just beginning its influenza season and the experience there may provide valuable clues about what may occur in the Northern Hemisphere this fall and winter. http://www.cdc.gov/h1n1flu/update.htm - downloaded 6/22/09

CDC site – for 2007 Influenza-Associated Pediatric Hospitalizations: Laboratory-confirmed influenza-associated pediatric hospitalizations are monitored in two population-based surveillance networks: the Emerging Infections Program (EIP) and the New Vaccine Surveillance Network (NVSN). EIP estimated rates of hospitalization for influenza will be reported every two weeks beginning October 26, 2007. NVSN estimated rates of hospitalization for influenza will be reported every two weeks, beginning November 30, 2007.

Influenza - USA SEASONAL INFLUENZA Estimated rates of influenza-associated hospitalizations and deaths varied substantially by age group in studies conducted during different influenza epidemics. During 1990--1999, estimated average rates of influenza-associated pulmonary and circulatory deaths per 100,000 persons were: 0.4--0.6 among persons aged 0--49 years 7.5 among persons aged 50--64 years 98.3 among persons aged 65 years and older. http://www.cdc.gov/flu/professionals/acip/clinical.htm#signs

Novel H1N1 U.S. Hospitalization Rate per 100,000 Population, By Age Group (07-31-09)                                                                                                                                                  http://www.cdc.gov/h1n1flu/surveillanceqa.htm

2009 PANDEMIC INFLUENZA Danger signs in all patients Worldwide, the majority of patients infected with the pandemic virus continue to experience mild symptoms and recover fully within a week, even in the absence of any medical treatment. In addition to the enhanced risk documented in pregnant women, groups at increased risk of severe or fatal illness include people with underlying medical conditions, most notably chronic lung disease (including asthma), cardiovascular disease, diabetes, and immunosuppression. Some preliminary studies suggest that obesity, and especially extreme obesity, may be a risk factor for more severe disease. Within this largely reassuring picture, a small number of otherwise healthy people, usually under the age of 50 years, experience very rapid progression to severe and often fatal illness, characterized by severe pneumonia that destroys the lung tissue, and the failure of multiple organs. No factors that can predict this pattern of severe disease have yet been identified, though studies are under way. As progression can be very rapid, medical attention should be sought when any of the following danger signs appear in a person with confirmed or suspected H1N1 infection: shortness of breath, either during physical activity or while resting difficulty in breathing turning blue bloody or colored sputum chest pain altered mental status high fever that persists beyond 3 days low blood pressure In children, danger signs include fast or difficult breathing, lack of alertness, difficulty in waking up, and little or no desire to play. 2009 PANDEMIC INFLUENZA http://www.who.int/csr/disease/swineflu/notes/h1n1_pregnancy_20090731/en/index.html , downloaded 7-31-09