DANGEROUS MICROBES: FIGHTING BACK!
| AVIAN INFLUENZA —David A. Pegues, MD, Professor of Clinical Medicine, Division of Infectious Diseases, David
Geffen School of Medicine at the University of California, Los Angeles
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| Introduction: concerns include possibility of further adaptation of avian-adapted influenza virus to become more tropic,
infectious, or transmissible in humans
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| Influenza types: type A—causes moderate to severe clinical illness; reservoirs include birds, swine, and other large animals;
ability of virus to adapt and exchange genetic information between reservoirs results in new viral strains that have
new antigenic epitopes or virulence genes; typically occurs in areas where humans live in close proximity to avian hosts;
type B—causes milder disease; adapted to cause infection only in humans; type C—affects only humans; epidemics
rarely reported
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| Influenza virus: hemagglutinin (H)—surface protein; mediates binding to respiratory epithelium; neuraminidase
(N)—cleaves budding virus from surface of productively infective cell, leading to cell-to-cell transmission; RNA
genome—8 segments; primary reason virus can easily rearrange and adapt or acquire ≥1 gene from another species
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| Pandemics of 20th century: Spanish influenza—1918 to 1919; ≈40 million deaths worldwide (≥500,000 in United
States); all 8 RNA gene segments derived from avian species; gene rearrangements adapted virus to be highly infectious
and transmissible in humans; Asian influenza—1957 to 1958; 70,000 US deaths; Hong Kong flu—1968 to 1969;
H3N2 virus (continues to circulate today); associated with 34,000 US deaths; Hong Kong and Asian influenza contained
gene segments of Spanish influenza strain of 1918 to 1919 and human gene segments
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| Global impact of Spanish influenza: affected young (average age 30-40 yr) previously healthy persons; life expectancy
reduced by 13 yr for several decades; average time from illness onset to death ≈1 wk; associated clinical syndrome
of severe necrotizing hemorrhagic viral pneumonitis; infects entire lung; induces high levels of macrophage chemokines
and cytokines; marked inflammation of inflammatory cells in lung tissue; 1 of 5 amino acid changes that appear to be
critical to adapt virus strain to cause infection in humans currently present in avian influenza strain H5N1; all 8 gene segments
from virus strain of 1918 to 1919 appear to be required for pathogenicity and virulence; concerns about new virus
strains—baseline prevalence of antibodies that protect against virus strains in susceptible population 0%; attack rate
high; mortality rate high (depending on virulence); with subsequent seasonal influenza peaks, number of cases declines
as prevalence of protective antibodies (from natural immunity or vaccination) rises
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| Impact of seasonal influenza: ≈200,000 patients yearly require hospitalization; 20,000 to 30,000 deaths in United
States; health care—high demand for clinical services; estimated need for surgical capacity 25% above that of maximal
hospital capacity; staff absenteeism and illness
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| H5N1 virus: from Asia, spread to avian species in Middle East, sub-Saharan Africa, and Eastern and Western Europe;
transmission increases during winter months; role of migratory water fowl in disease transmission clear; all genes of bird
origin; 2 distinct varieties of H5N1 virus currently circulating, but no significant gene mutations detected since reemergence
in 2003; influenza A virus with intrinsic resistance to amantadine and rimantadine; oseltamivir (Tamiflu) and zanamivir
(Relenza) should be effective; oseltamivir resistance reported in Vietnam
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| Containment: culling of sick or potentially infected and exposed birds; travel to at-risk areas—avoid guided tours to
poultry farms; avoid contact with animals in food markets; avoid fecally contaminated surfaces; several circumstances of
person-to-person and familial transmission reported from North Sumatra; no evidence of significant gene changes that increase
infectivity
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| Clinical manifestations: necrotizing viral pneumonitis; reports of direct contact with poultry followed by rapid onset
(3 days) of symptoms; incubation period may be 5 to 7 days; fever; dramatic tachypnea; shortness of breath; hypoxemia;
nonproductive cough; viremia (high titers in stool); diarrhea; none had typical symptoms of viral upper respiratory infection
(eg, runny nose, sore throat); abnormal auscultatory and radiographic findings; low white blood cell count; lymphopenia;
thrombocytopenia; mild to moderate elevations in liver function tests; bilateral interstitial alveolar infiltrates
with consolidation and collapse may be seen on chest radiography; small (not clinically significant) pleural effusions
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| Laboratory testing: case-by-case testing recommended, based on epidemiologic risk and clinical illness (ie, fever,
cough, sore throat, shortness of breath, and recent epidemiologic exposure to human case of avian influenza); based on
incubation estimate of 3 to 7 days, monitor symptoms for up to 10 days following exposure; virus culture; polymerase
chain reaction (PCR) assays; antigen capture assays using direct fluorescent antibodies under development
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| Infection control: cover mouth when coughing or sneezing; clean hands of respiratory secretions; hand hygiene before
and after contact with patient; wear gowns and gloves; eye protection; respiratory protection (eg, N95 or surgical mask
[debatable]); travel recommendations—emphasize need to monitor health for 10 days after returning
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| US pandemic plan: vaccination and immunization—stockpiling 20 to 40 million doses of current prepandemic avian
influenza virus strain; availability of 20 million doses to health care workers by fall of 2006 goal; resources directed to infrastructure
to rapidly produce vaccine against pandemic strain; antiviral therapy—stockpiling 20 million doses of
oseltamivir by end of 2006; availability of ≈81 million doses in 2007 goal; communication and surveillance—system
to identify influenza virus strains; primary care physicians report number of patients who present with influenza illness;
mortality statistics from Centers for Disease Control and Prevention (CDC)
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| Risk factors for complications: immunocompromised; advanced age; residence in long-term care facilities; second
or third trimester of pregnancy; long-term aspirin therapy for rheumatic valvular heart disease rare; chronic disease (eg,
endstage renal disease)
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| Diagnostic testing: serology useful for retrospective epidemiologic studies; virus culture—gold standard; identifies
circulating strains; not useful as diagnostic tool because of long turnaround time (5-10 days); direct fluorescent antibody
testing—adequate respiratory specimens include nasopharyngeal washes, tracheal aspirates, and expectorated or
suctioned respiratory secretions; throat swab inadequate; turnaround time 60 min; 4 commercially available kits (turnaround
time <30 min; sensitivity and specificity 80%-85%)
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| Influenza vaccines: trivalent inactivated virus vaccine—grown in eggs; contains 2 circulating type A strains and 1
type B strain; target groups for special vaccination—children 6 to 23 mo of age and parents and siblings in household;
health care workers (annual vaccinations or documentation of declination by health care institutions may be recommended);
most effective in children and young adults; less effective in older or at-risk individuals, but prevents severe
morbidity and mortality and results in milder disease; cold-adapted live attenuated virus vaccine—approved by Food
and Drug Administration (FDA) for use in nonpregnant individuals 5 to 49 yr of age; causes mild or no clinical illness;
temperature-sensitive (ie, does not replicate efficiently or cause disease in lower respiratory tract); cold-adapted (ie, replicates
in upper airway and potentially can be transmitted from person to person to protect others); associated symptoms
include mild rhinorrhea; not recommended for immunocompromised patients and those in same household; highly effective;
appropriate for use in health care settings; low risk for transmission from health care worker to patient
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| Oseltamivir and zanamivir: oseltamivir drug of choice for treatment of infection; amantadine and rimantadine no
longer appropriate for chemoprophylaxis; effective against influenza A and B; indicated for treatment and prophylaxis in
high-risk individuals; oseltamivir indicated for individuals >1 yr of age; zanamivir (inhaled formulation) indicated for
treatment of patients ≥7 yr of age and for prophylaxis in those ≥5 yr of age; given twice daily for treatment, once daily for
prophylaxis; duration depends on length of epidemic (6 wk for oseltamivir, 10 days for zanamivir); reduce severity and
duration of symptoms; oseltamivir shown to decrease rate of secondary bacterial complications; primary side effects of
oseltamivir include nausea and vomiting, bronchospasm for zanamivir
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| IMMUNIZATIONS UPDATE —James D. Nordin, MD, MPH, Adjunct Professor of Pediatrics, University of Minnesota
Medical School, Minneapolis, and Staff Pediatrician, HealthPartners Medical Group, St. Paul, MN
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| Pertussis: severity highest in infants; prevalent in secondary schools; studies show >70% of infants with pertussis from
same household as adult or older sibling who had pertussis first
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| New vaccines: tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap); 2 available; 1) licensed
for use in individuals 10 to 18 yr of age; 2) licensed for individuals 11 to 65 yr of age; safety profile similar to
diphtheria and tetanus toxoids combined (DT; Td); no pertussis-containing vaccine for children 7 to 10 yr of age;
benefits—reduction in death from pertussis by 50% through adolescent and adult herd immunity; substantial impact on
morbidity in adolescents and adults; cost-effective; one dose produces ≈3 times antibody titer against pertussis as 3 doses
of standard vaccine in infancy; recommendations—should routinely be given at age 12 yr instead of Td; used once in
adults due for Td booster; special emphasis on immunizing adults who are frequently near infants (postpartum or
prepregnancy); no studies about use in pregnancy; workers in public schools and day care centers; interval since previous
Td—for low-risk adults, Tdap licensed to be given as soon as 5 yr after last Td, with no increase in adverse reactions;
for high-risk adults, can be given as soon as 2 yr after last Td; in outbreak situations, may be given in shorter
intervals, but risk for local and systemic reactions may increase; may eventually replace Td to use every 10 yr, but studies
of repeated administration not yet completed
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| Human papillomavirus (HPV): infects ≤50% of young women; 30 anogenital subtypes (50% oncogenic; 2 subtypes
account for 70% of cervical infections); 300,000 HPV infections with high-grade dysplasia in United States annually; essentially
all cervical cancer comes from high-grade dysplasia; HPV vaccine—2 under development; 1) tested only in
adolescent girls; 2 oncogenic strains; 2) tested for use in girls and boys; 2 oncogenic strains and 2 strains that cause ≈60%
of genital warts; 70% decrease in rate of dysplasia and severe dysplasia in vaccinated, compared to unvaccinated, women
seen in trials; potential for dramatic reduction in cervical cancer; cost-benefit analysis complex but favorable; in children
12 yr of age, 3 doses required; controversial
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| Conjugated pneumococcal vaccines: 11- and 13-valent vaccines in trials; less coverage of disease (serotypes that
cause disease in elderly broad)
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| Rotavirus vaccine: oral; RotaTeq (conjugated human rotavirus; currently licensed) should be given at 2, 4, and 6 mo; 2-
dose vaccine (conjugated bovine rotavirus) to be licensed next year; children should receive first dose of RotaTeq by 12
wk of age and should receive last dose by 32 wk of age; trials showed prevention rate in all cases 74%, 98% in severe
cases, and 60% in gastroenteritis hospitalizations; trials showed no increase in intussusception
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| Meningococcal polysaccharide (serogroups A, C, Y, and W-135) diphtheria toxoid conjugate vaccine
(Menactra): licensed for use in individuals 10 to 55 yr of age; 6 times as much diphtheria toxoid as in standard Td; cellular
and humoral response; immunologic memory; longer lasting; in 2005, 5 cases of Guillain-Barré syndrome reported
shortly after receipt of Menactra, but later suggested Guillain-Barré syndrome not caused by Menactra; safety studies continue;
safety issues not reason to not use vaccine; rate of meningococcal disease—rate of disease highest in infants; risk
increases at age 15 to 25 yr; cost-effectiveness—≈$633,000 per case of meningococcal disease prevented; $121,000 per
year of life saved; $138,000 per quality-adjusted life year (QALY) saved, compared to Tdap (≈$1000 per QALY saved);
recommendations—Advisory Committee on Immunization Practices (ACIP) recommends giving routinely at age 11 to
12 yr, 15 yr, and 18 yr; problems include cost and vaccination at 12 yr might not last until risk period (3 yr); vaccination at
age 12 yr unknown to last until end of college; speaker recommends routinely immunizing adolescents age 14 to 16 yr and
for incoming college freshmen when Menactra available (use meningococcal polysaccharide vaccine [Menomune-A/C/Y/
W-135] when not available); to be licensed for use in young children within ≈1 yr
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| Herpes zoster: lifetime risk 15% to 30%; >90% occurs after age 50 yr; postherpetic pain difficult to treat, with significant
impact on quality of life; live zoster vaccine (Zostavax)—prevents ≈75% of severe pain; good safety profile; substantial
local reaction rate
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| Universal hepatitis A vaccination in infancy: both licensed vaccines indicated for use in infants 1 yr of age; rates
highest in Hispanic populations and states that do not have universal recommendations; 2 doses recommended for all infants
(at age 1 yr and 6-18 mo later)
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| Measles, mumps, rubella, and varicella (MMRV) vaccine: ACIP does not recommend second MMRV vaccine
because of cost concerns; contains same level of MMR antigens; varicella titer ≈2.5 times that of single-entity varicella
vaccine (similar efficacy in combined and separate immunizations); second MMRV produced chickenpox titers 12 to 16
times higher than those after 1 dose; fever >102ºF observed in >20% of children with MMRV, ≈15% with separate vaccine
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| Vaccines under development: Streptococcus pneumoniae; human metapneumovirus; avian influenza; herpes simplex
virus; parainfluenza virus; malaria; HIV; meningococcal type B; severe acute respiratory syndrome (SARS); Staphylococcus
aureus; bioterrorism agents; smallpox; hepatitis C and E; therapeutic vaccines—monoclonal antibodies
for cancer (eg, trastuzumab [Herceptin] for breast cancer); B-cell lymphoma; melanoma; prostate cancer
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Educational Objectives
| The goal of this program is to educate the listener about avian influenza and immunization recommendations. After hearing
and assimilating this program, the participant will be better able to:
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 | 1. Describe the impact of influenza pandemics.
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| 2. Recognize clinical manifestations of avian influenza infection.
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| 3. Select agents for prophylaxis and treatment of avian influenza.
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| 4. Review recommendations for the tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap)
vaccine.
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| 5. Counsel patients about new vaccines such as the human papillomavirus (HPV) and herpes zoster vaccines.
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Discussed on This Program
Amantadine [Symmetrel]
Diphtheria and tetanus toxoids, adsorbed
Diphtheria and tetanus toxoids, combined (DT; Td)
Diphtheria CRM197 protein (see pneumococcal 7-valent conjugate vaccine
Diphtheria toxoid conjugate vaccine (meningococcal polysaccharide [serogroups A, C, Y, and W-135]) [Menactra]
Diphtheria and tetanus toxoids and acellular pertussis vaccine, adsorbed (DTaP) [Daptacel, Infanrix, Tripedia]
Hepatitis A vaccine, inactivated [Havrix, Vaqta]
Human papillomavirus vaccine [Gardasil]
Influenza virus vaccine [Fluarix, FluMist, Fluvirin, Fluzone]
Measles, mumps, and rubella virus vaccine, live [M-M-R II]
Measles, mumps, rubella, and varicella virus vaccine, live [ProQuad]
Meningococcal polysaccharide vaccine [Menomune-A/C/Y/W-135, Menactra]
Oseltamivir phosphate [Tamiflu]
Pneumococcal 7-valent conjugate vaccine (diphtheria CRM197 protein) [Prevnar]
Pneumococcal vaccine, polyvalent [Pneumovax 23]
Rimantadine HCl [Flumadine]
Rotavirus vaccine [RotaShield] (withdrawn)
Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis, adsorbed (Tdap) [Adacel, Boostrix]
Trastuzumab [Herceptin]
Varicella virus vaccine [Varivax]
Zanamivir [Relenza]
Zoster vaccine live [Zostavax]
Suggested Reading
Guillain-Barré syndrome among recipients of Menactra meningococcal conjugate vaccine. Ann Pharmacother 40:1007,
2006; Rotateq: a new oral rotavirus vaccine. Med Lett Drugs Ther 48:61, 2006; Bailey J et al: Planning for the HPV
vaccine and its impact on cervical cancer prevention. Compr Ther 32:102, 2006; Bartlett JG: Planning for avian influenza.
Ann Intern Med 145:141, 2006; Bridges CB et al: Effectiveness and cost-benefit of influenza vaccination of
healthy working adults: A randomized controlled trial. JAMA 284:1655, 2000; Bright RA et al: Incidence of adamantane
resistance among influenza A (H3N2) viruses isolated worldwide from 1994 to 2005: a cause for concern. Lancet
366:1175, 2005; Doroshenko A: US study suggests universal vaccination of children with pneumococcal conjugate vaccine
is beneficial for adults. Euro Surveill 10:E051124.4, 2005; Emanuel EJ et al: Public health. Who should get influenza
vaccine when not all can? Science 312:854, 2006; Frampton JE et al: Reduced-antigen, combined diphtheria-
tetanus-acellular pertussis vaccine, adsorbed (Boostrix) US formulation): use as a single-dose booster immunization in adolescents
aged 10-18 years. Paediatr Drugs 8:189, 2006; Glass RI et al: Rotavirus vaccines: current prospects and future
challenges. Lancet 368:323, 2006; Halperin SA: Prevention of pertussis across the age spectrum through the use of the
combination vaccines PENTACEL and ADACEL. Expert Opin Biol Ther 6:807, 2006; Hien TT et al: Avian influenza-
-a challenge to global health care structures. N Engl J Med 351:2363, 2004; Hughes RA et al: No association between
immunization and Guillain-Barre syndrome in the United Kingdom, 1992 to 2000. Arch Intern Med 166:1301, 2006; Influenza
team: Early Containment Strategy: a protocol to contain pandemic influenza when it first emerges globally.
Euro Surveill 11:E060330.1, 2006; Kobasa D et al: Enhanced virulence of influenza A viruses with the haemagglutinin
of the 1918 pandemic virus. Nature 431:703, 2004; Kopterides P et al: Potential consequences of the pneumococcal
conjugate vaccine. N Engl J Med 355:95; author reply 95, 2006; Mink CM: Introduction of tetanus toxoid and reduced
diphtheria toxoid vaccines in the United States. Pediatr Infect Dis J 25:363, 2006; Twombly R: U.S. girls to receive
HPV vaccine but picture unclear on potential worldwide use, acceptance. J Natl Cancer Inst 98:1030, 2006; Ungchusak
K et al: Probable person-to-person transmission of avian influenza A (H5N1). N Engl J Med 352:333, 2005.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant financial
relationship with the manufacturer or provider of any commercial product or service discussed. The following has been disclosed:
Dr. Nordin has received research grant support from Aventis Pasteur, Inc.
Dr. Pegues spoke in Beverly Hills, CA, at the 33rd Annual UCLA Family Practice Refresher Course, presented June
5-9, 2006, by the David Geffen School of Medicine at the University of California, Los Angeles. Dr. Nordin was recorded
in St. Paul, MN, at Family Medicine Today, presented March 9-10, 2006, by HealthPartners Institute for Medical
Education. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the
production of this program.
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