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Emerging pathogens 2009


Antigenic Drift. Minor genetic variations in HA and NA ... Antigenic Shift. Major genetic changes in HA and NA. Reassortment in double infected cell ... – PowerPoint PPT presentation

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Title: Emerging pathogens 2009

Emerging pathogens 2009
  • Peter H. Gilligan PhD
  • Clinical Microbiology-Immunology Labs
  • UNC Hospitals

How I became a clinical microbiologist
  • Obtained doctoral degree in microbiology at the
    University of Kansas
  • Did post-doctoral training (2 years) in medical
    and public health microbiology at UNC Hospitals
  • Director of Microbiology Labs at St Christophers
    Hospital for Children (Philadelphia) for 4 years
  • Past 25 years, Associate Director then Director
    of the Clinical Microbiology-Immunology Labs at
    UNC Hospitals
  • Have served on medical school admission committee
    for approximately 15 years and the MD/PhD
    advisory (admissions) committee for the past 10

What do clinical microbiologists do?
  • We serve
  • our patients
  • our health care-providing colleagues, physicians,
    nurses, physician assistants, pharmacy colleagues
  • hospital administrators
  • We make money for the institution
  • general public by insuring the public health
  • Involved in studying outbreaks of several
    emerging infectious diseases-will tell you about
    one today-novel H1N1 (swine flu)

How do we serve?
  • central role in the diagnosis and management of
    infectious diseases
  • central role in infection control and
    antimicrobial use
  • recognize emerging disease threats and outbreaks
    including bioterrorism events
  • we educate train health care providers
  • we create new knowledge (research) to deal with
    practical problems

Best things about my job
  • Direct impact on patient care and public health
    of the community
  • Intellectually challenging job requiring a broad
    fund of knowledge-need to know a little about a
    lot of things I am never bored!!!!!!!
  • Work with highly motivated and intelligent
  • Get to be at the cutting edge of infectious
    disease diagnosis

Worst things about my job
  • Incredible amounts of governmental oversight
  • Increasing emphasis on financial aspects of the
  • Declining talent pool of technologists
  • Need to be responsible for an organization that
    run 24/7/365-we never close. Personally have
    worked through ice storms, blizzards, and

How you can become a clinical microbiologist
  • CLS programs available here, ECU, WCU, WSSU, Wake
    Forest, UNC-CH
  • Education is also available on line
  • 2 more years of school to get a BS in CLS
  • There is no unemployment in this group
  • Take ASCP certification exam to become certified
    as a MT.
  • Starting salary is 38,000 and up
  • Career options are amazingly diverse many former
    UNC students work in leadership positions in the
    pharmaceutical and biotech industries

Emerging Infectious Diseases in the Past 30 Years
  • novel H1N1 influenza A
  • Clostridium difficile
  • HIV
  • SARS
  • Cryptosporidium
  • E. coli O157H7
  • Nipah virus
  • nv Creutzfeldt-Jakob disease
  • Sin Nombre Virus
  • West Nile Virus
  • Vibrio vulnificus
  • Cyclospora
  • Bacillus anthracis (BT agent)
  • TSST-1 S. aureus
  • XDR- and MDR-TB
  • MDR- pneumococcus
  • MDR-Acinetobacter
  • Rapidly growing mycobacterium
  • Rotavirus
  • Norovirus
  • BK virus
  • Chlamydophila pneumoniae
  • Penicillium marneffei
  • Legionella
  • Burkholderia cepacia complex
  • Burkholderia gladioli
  • Helicobacter pylori
  • HHV-6
  • HPV
  • HCV
  • Avian influenza (H5N1)
  • Ehrlichia chaffenesis
  • Borrelia burgdorferi (Lyme disease)
  • Enterotoxigenic E. coli
  • Enteroadherent E. coli
  • Bordetella avium

How do new pathogens emerge
  • Changing ecosystems
  • Changes in food production techniques
  • Evolution of medical devices and care
  • Long term survival of immunosuppressed
  • Pathogens that are detected because of new
  • Misuse of micro-organisms
  • Biocrime/bioterrorism
  • Organism evolution as a result of human
  • Antibiotic pressure
  • Organisms that jump species barriers

How do microbes change?
  • Bacteria, because they evolve very quickly, can
    readily adapt to hostile environments
  • Assume a generation time for a bacteria of 50
  • 30 generations/day or 220,000 bacterial
    generations for each human generation (assume
    generation is 20 years)
  • Bacteria have a huge evolutionary advantage over

How emerging pathogens develop?
  • Mutation drives evolution
  • constantly occurring
  • usually silent or lethal
  • environmental pressure such as antibiotics may
    select resistance mutation
  • Key feature of success of antibiotic resistant
    strains is their genetic fitness I.e. their
    ability to compete in a complex microbial
  • Recognition that certain bacteria may be
    hypermutators because of mutation in DNA repair
  • These strains may not be as fit as wild-types
    but may predominant in certain chronic infections
    such as P. aeruginosa
    causing chronic pulmonary infections in CF

How do emerging pathogens develop?
  • Recombination
  • Resistance genes from antibiotic producing
  • genetic exchange of resistant genes can occur
    among organisms which are genetically diverse
  • Think Cholera toxin genes to E. coli
  • transfer of resistance/virulence genes can be
    mediated by plasmids/phage/transposons/ integrons

Changing ecosystems
  • Lyme disease
  • A perfect storm
  • Farmland in New England returned to forest
  • Natural predators for deer were eliminated
  • Deer populations and the ticks they carried
    increased because of ecosystem changes
  • People built homes and spent increasing amounts
    of time in the woods
  • This resulted in increased exposure to deer ticks
    that carried Borrelia
  • Ticks were pencil point in size and often
    difficult to see

Changes in food production techniques
  • Increased use of factory farming
  • Feedlots bring together large numbers of animals
    who produce large amounts of waste
  • Waste can lead to run-off of EHEC that can
    contaminant adjacent fields as was seen in recent
    spinach outbreaks
  • Large meat packing operations can result in 50
    ton lots of ground meat containing 100s of
  • Meat can be distributed throughout the US
  • Contaminated lots can then lead to large scale

Changes in medical care
  • Immunosuppression either as a result of HIV or
    medically therapy (ex. transplants) results in
    emerging infections
  • Pneumocystis, MAC, toxoplasma and CMV in HIV
  • CMV, adenovirus and HHV-6 in transplant patients
  • The use of indwelling artificial materials such
    as catheters, shunts, artificial joints present
    new ecosystems and new organisms
  • Examples-coagulase negative staphylococci growing
    as a biofilm on artificial joints/catheters/shunts
  • Rapidly growing mycobacteria causing keratitis
    following LASIK surgery

Pathogens detected with new technology
  • Prime example is HCV
  • Viral genome elucidated using molecular cloning
  • Broad range 16S RNA primers are used to detect
    non-cultivable bacteria
  • Next big thing- application of molecular tools to
    understand how mixed microbial populations cause
  • Likely diseases caused by mixed microbial
    populations are bacterial vaginosis, peridontal
    disease, inflammatory bowel disease, CF lung

How does bacterial resistance develop?
  • Bacterial resistance develops in response to
    antimicrobial pressure
  • It is estimated that 3 million lbs of
    antimicrobials are used each year in the US
  • Much of it is used in children to treat viral
    respiratory illness
  • Estimated that 3/4 of children in US younger than
    two receive antimicrobials
  • Children then may serve as a key role for the
    emergence of antimicrobial resistance
  • 10x that amount are used in animals
  • End result- tremendous selective pressure that
    results in the emergence of bacterial resistance

Antibiotic associated adverse effects
  • Antimicrobial toxicity and allergic reactions
  • Anti-parasiticgtanti-fungalgtanti-viralgtantibacteria
  • 20 of ER visits for drug adverse events are due
    to antimicrobials
  • Alteration in the microbial flora
  • Candida vaginitis and thursh
  • C. difficile infection
  • Salmonellosis
  • Emergence of resistance
  • Few organisms where resistance is not clinically

Organisms that jump species barriers
  • HIV, SARS, Novel H1N1 flu
  • HIV likely jumped from primates to humans
  • SARS from pigs(?)
  • Novel H1N1 is a reassorted strain of H1N1 with
    genes from two swine viruses and avian virus, and
    human virus
  • Technology allows us to quickly develop
    diagnostics for new pathogens
  • Took years to develop HIV diagnostics
  • Took weeks to develop SARS diagnostics
  • Took 3 day to develop novel H1N1 diagnostic
    testing strategy in our lab and a few weeks more
    to develop a specific novel H1N1 assay

Structure of the Influenza Virus
Hemagglutinin (HA) 16 types in influenza A
Neuraminidase (NA) 9 types in influenza A
ssRNAhighly mutable
8 segments allows reassortment during double
Adapted from Hayden FG et al. Clin Virol.
Pathology of Influenza Virus
  • Virus attaches to sialic acid receptors on
    columnar epithelial cells
  • Viral proteins take over cellular machinery
  • Shuts down host cellular protein synthesis
  • Eventually results in cell death
  • Virus is released from cell and initiates
    infection in adjacent cells
  • End result necrosis of respiratory tissue
  • Defect in ciliary function puts patients at risk
    for secondary bacterial infections

Antigenic Drift
  • Minor genetic variations in HA and NA
  • Accumulation of point mutations (2)

Antigenic Shift
  • Major genetic changes in HA and NA
  • Reassortment in double infected cell
  • Human and non-human

Novel H1N1-an overview
  • In April 09, a novel variant of the H1N1 virus
    was reported from CDC from two California cases
  • In late April 09, news reports of young adults
    with severe disease and deaths were being
    reported from Mexico City
  • This resulted in school closures in Mexico City
    for approximately 3 weeks and recommendation for
    social distancing nationwide including soccer
    games played in empty stadiums
  • First report of disease from Mexico City showed
    mortality was highest in children and young
    adults (NEJM 361680, 2009)
  • By May 5, 09, 642 confirmed cases of novel H1N1
    had been reported in US (NEJM 3602605, 2009)
  • Included closure of one school in NYC-epidemic
    began after students returned from a trip to
    Cancun similar outbreak seen in New Zealand
    starting with individuals who recently visited
  • By late May, we were beginning to see cases of
    the novel H1N1 _at_ UNC Health Care
  • By early June we had a validated, PCR specific
    for novel H1N1 the initial PCR test we had for
    influenza A did not detect this variant of the
    virus indicating changes in the matrix protein
    which were subsequently reported

Novel H1N1-an overview
  • By early June the World Health Organization (WHO)
    declared a global pandemic
  • With the arrival of students back to Chapel Hill,
    we have begun to see a resurgence in probable
    cases of novel H1N1 cases

Emergence of Quadruple-Reassortant H1N1/09
Garten et al., Science, 2009 325198
Novel H1N1-what we know as of 10-4-09
  • From briefing note 9 of WHO (published Aug 28 _at_
  • H1N1 is the dominant virus globally
  • Large population are susceptible to infection
  • Specific populations are at risk
  • Important to monitor for drug resistant
  • Disease is not the same as seasonal flu
  • For patients requiring hospitalization,
    requirement for intensive care is greatly
  • Little data from developing world
  • Co-infection with HIV
  • Does not appear to result in more severe illness
    in those receiving antiretrovirals these data
    are limited
  • What will happen in the 16 million HIV infected
    patients not receiving drug is unknown

Novel H1N1-what we know as of 10-4-09
  • Novel H1N1 is sensitive to oseltamivir and
    zanamivir but resistant to amantidine
  • recombinant genes from a H1 Eurasian swine flu
    strain are responsible for amantidine resistance
  • Oseltamivir resistance has been recognized in
    epidemiologically linked patients in NC (letter
    from NC PH epidemiologist Aug 21)
  • Seasonal influenza A H1 is oseltamivir resistant
    while H3 is amantidine resistant

Novel H1N1-what we know as of 10-4-09
  • What do we now about H1N1?
  • Transmission appears to be highly efficient
  • Virus is the result of a reassortment of four
    different viruses
  • Distantly related to 1918 H1N1
  • Matrix proteins and H1 proteins quite different
    from seasonal H1N1
  • Gene segments on novel H1N1 show high identity
    indicating the introduction of a single strain
    into humans
  • Vaccination of seasonal H1N1 does not protect
    against novel H1N1
  • Severe respiratory illness is due directly to
    influenza induced disease and not secondary
    bacterial agents as was seen in 1918 pandemic
  • Most of the illnesses have been mild and the
    mortality has been similar to seasonal influenza

H1N1/09 Age Distribution
Graph A Novel H1N1 Confirmed and Probable Case
Rate in the United States, By Age Group
Graph B Novel H1N1 U.S. Hospitalization Rate per
100,000 Population, By Age Group
H1N1/09 Age Distribution
Graph C Novel H1N1 U.S. Deaths, By Age Group
Chowell et al., NEJM 2009, 3617
Novel H1N1-what we know as of 10-4-09
  • Target groups with increased risk and thus the
    priority population for novel H1N1 vaccination
    due in mid-October
  • Pregnant women
  • Health Care Workers and Emergency Medical Service
  • Persons living with or provide care for infants
    lt6 months of age
  • Persons 6 months to 24 years of age
  • Persons 25-64 with medical conditions that put
    them _at_ increased risk for influenza
  • For the first time this will include morbidly
    obese individuals

International Epidemiology
International Co-circulation of 2009 H1N1 and
Seasonal Influenza (As of September 20, 2009
posted September 25, 2009)
Influenza Testing at UNC May November 2009
as of 11/02/09 UNC
H1N1 hospitalizations 62
H1N1 deaths 5
Diagnosis of novel H1N1-what we know
  • Rapid antigen tests have low sensitivity for this
    virus depending upon the population tested- used
    by 83 of labs (survey of 146 labs clinmicronet
    survey July 2009)
  • DFA reagents will detect this virus-29 of labs
    (clinmicronet survey July 2009)
  • Widely used viral culture system (Rmix cells)
    will detect this virus-51 of labs used
    (clinmicronet survey July 2009)
  • PCR tests have evolved to be the gold standard
    for novel H1N1-30 of labs use plus method of
    choice in public health labs in US (clinmicronet
    survey July 2009)
  • PCR can be used to do subtyping to distinguish
    seasonal H1N1, from novel H1N1 from H3N2

Why do we care WHICH influenza you have?
  • Treatment
  • Amantadine/Rimantadine
  • Interfere with influenza A virus M2 protein
    (membrane ion channel protein) and inhibit viral
  • Zanamivir/Oseltamivir
  • Neuraminidase inhibitors
  • Results in viral aggregation at the host cell
    surface and reduces the number of viruses
    released from the infected cell
  • Must be administered in first 48 h
  • Also work for chemoprophylaxis

2 in NC
What other things do we need to think about with
the novel H1N1?
  • A recent study (J Infect Dis. 2008 198962)
    suggest that bacterial superinfection was the
    major cause of death in the US during the 1918
    flu pandemic
  • Organisms believed to be important were
    Strepococcus pneumoniae, Haemophilus influenzae
    and Group A streptococci
  • In August Group A streptococci activity was low
    with lt10 of tests (culture and rapid antigen)
    being positive
  • Remember there were no antibiotics, no intensive
    care units, and no ECMO (Extracorporeal Membrane
    Oxygenation) machines
  • Studies so far suggest that this has not been the
    case with novel H1N1
  • We are in an era of CA-MRSA, MDR-Acinetobacter,
    and KPC producing Enterobactericeae. Will they
    be a major problem?
  • Several of the organisms seen as important in the
    1918 pandemic are vaccine preventable. It is
    now, more than ever, important to have infant and
    children, the at risk population, vaccinated
    against S. pneumoniae and H. influenzae

As Brian the scientist would say, Any Questions?
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