Literature Review

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					Literature Review
Homepage: Sustained efficacy up to 4-5 years of a bivalent L1 virus-like particle
vaccine against human papillomavirus types 16 and 18: follow-up from a randomized
control trial [Harper Diane M Lancet 2006;367:1247]: The goal of the study was to
determine the long term efficacy, immunogenicity and safety of the bivalent HPV-16/18
vaccine (GlaxoSmithKline) against incident and persistent infection with HPV 16 and 18 and
their associated cytopathic complications.

Methods: The initial trial was done in the early 2000’s and published in 2002 showing this
vaccine was almost completely protective against the two majorHPV types associated with
cervical cancer (Koutsky LA N Engl J Med 2002;347:1645). The present study enrolled
women who participated in that trial to determine long term immunogenicity, incident
infections with HPV, yearly cervical cytology and safety.

Results: There were 776 women in the follow-up study who were followed for a mean of 48

      Immunogenicity: Geometric mean titers were maintained at above 500 log10 EU/ml
       throughout the observation period of averaging four years. These levels are at least
       133 fold higher than the mean titers for the placebo group and they are higher than
       natural infection with HPV-16 and HPV-18 by 17 and 14 fold, respectively. The
       number with serologic response exceeded 99% for all participants tested during the
       eight periods of evaluation.
      Incident infection: The frequency of persistent HPV-16/18 infection detected in
       cervical samples with the initial and follow-up study showed one in the vaccine
       recipient group and 16 in the control group.
      Histologic abnormalities: Abnormal cytologic and histologic outcomes (CIN1 and 2)
       were not detected in any vaccine recipients compared to 35 in the placebo group.
      Summary: These data are summarized in the following table:

                             HPV Vaccine: Efficacy at 4 Years
                                 (Lancet 2006;367:1247)

Method: Placebo-controlled trial HPV 16/18 vaccine x 3 doses 2000-1
Results: Mean FU at 4 years; n = 707-1002

                                          Vaccine                        Placebo
Med titer log10 EU/ml                     >400*                            25*
Persistent infection 16/18                   1                              16
CIN 1 or 2                                   0                              35

*Geometric mean titer; placebo group is for natural infection

Conclusion: The authors conclude that this vaccine is highly immunogenic, safe and
effective for up to 4.5 years.
Comment: Cervical cancer is the second most common cause of cancer among women in
the world. This vaccine is a remarkable achievement, but it faces some stiff challenges
which include parent activist groups in the US and access in the developing world where it is
needed most. Of interest in the above study is the apparent protective effect of this vaccine
against infection with HPV45 and 31 as well as HPV types in the vaccine.

Homepage: A randomized trial of diagnostic techniques for ventilator-associated
pneumonia [The Canadian Critical Care Trials Group, N Engl J Med 2006;355:2619]: The
purpose was to determine the best diagnostic method for detecting pathogens in patients with
ventilator-associated pneumonia.

Methods: This is a multicenter study in 28 ICUs in Canada and the US in 740 critically-ill
patients with ventilator-associated pneumonia (VAP). Patients were included if they had
chest x-ray evidence of pneumonia and supportive clinical features. They were excluded if
immunocompromised or infected/colonized with pseudomonas sp or MRSA, or not expected
to survive 72 hours. Participants were randomized to undergo BAL with quantitative culture
or endotracheal aspiration with nonquantitative culture. All patients received empiric
antibiotic treatment until results of cultures were available. The empiric antibiotics were
meropenem (1 gm tid) or this antibiotic combined with ciprofloxacin, 400 mg bid. The
concentrations of potential pathogens considered significant in the BAL cultures was 104/ml.
Semiquantitative data for the ET aspirates was not considered.

Results: The primary endpoint was the 28 day mortality and this showed no significant
difference for the two groups. Secondary outcomes were survival, duration of mechanical
ventilation, length of stay, the use of antibiotics after culture results were received, number of
antibiotic-free days and the organ-dysfunction score. None of these showed a significant
difference in outcome. The results for the 28 day mortality, the number who received
targeted therapy after culture results were received and the antibiotic-free days are shown in
the following table:

                                              ET Tube
                                              Aspirate                     BAL
                                             Non-quant.*                  Quant.*
         Method                                n = 374                    n = 365
         28 mortality                          18.9%                      18.4%
         Targeted therapy                      74.6%                      74.2%
         Antibiotic-free days                    10.6                       10.4

*Non-quant. = non-quantitative culture of ET tube aspirate; Quant. = quantitative culture of
BAL with 104/ml of potential pathogen considered significant.
Conclusions: The authors conclude that quantitative culture of BAL and non-quantitative
culture of endotracheal aspirates are equally effective and the management of VAP in terms
of clinical outcomes and impact on the overall use of antibiotics.

Comment: Prior studies have shown conflicting results on the relative merits of quantitative
cultures of BAL, quantitative cultures of ET tube aspirates and non-quantitative cultures of
ET tube aspirates (Sanchez-Neito JM Am J Respir Crit Care Med 1998;157:371; Ruez M Am
J Respir Crit Care Med 2000;162:119; Sole Violan J Crit Care Med 2000;28:2737; Fagon
JY Ann Intern Med 2000;132:621). The present study was done to definitively answer the
question by investigators who actually went into the study with the preconceived bias that
quantitative BAL was superior. In fact, a meta-analysis of the four randomized trials cited
above showed an increased benefit of quantitative BAL in terms of antibiotic selection with a
OR of 2.9 (Shorr AS Crit Care Med 2005;33:46). The study from France with 413 patients
also showed a significant difference in mortality favoring the quantitative BAL group (26%
vs. 16%; p = 0.02) (Fagon JY Ann Intern Med 2000;132:621). Instead, the study from
Canada and the US reported above showed no significant difference in clinical outcome nor
in antibiotic selection. There were no significant differences with subset analysis according
to the APACHE II score, days spent in the ICU prior to randomization, prior antibiotic use,
or pathogen recovered. One important limitation is that the rates of MRSA and pseudomonas
were only 1.6 and 6.4%, respectively. The authors caution that centers with higher rates of
these organisms might have a different experience.

Homepage: Extensively drug-resistant tuberculosis as a cause of death in patients co-
infected with tuberculosis and HIV in a rural area of South Africa [Gandhi NR Lancet
2006;368:1575]: The purpose was to assess the prevalence and consequences of multidrug-
resistant tuberculosis (MDRTB) and extensively drug-resistant tuberculosis (XDRTB) in
KwaZulu Natal, South Africa.

Methods: The authors increased surveillance for MDRTB with sputum cultures and drug
susceptibility testing in patients with suspected tuberculosis. The analysis included
genotyping of resistant strains and susceptibility testing for first and second line drugs.

Results: Sputum cultures for TB were done on 1,539 patients; this showed 542 (35%) were
positive; of these, 221 (40%) were MDRTB and 53 (24%) of the MDRTB were XMDRTB.
These results are summarized in the following table:

       Total tested                                         1539
       Culture pos                                          542
       MDR M. tuberculosis                                  221
       XMDR M. tuberculosis                                 53
           No prior treatment                              26 (55%)
           HIV pos/no tested                               44/44 (100%)
           Hospitalized < 2 years                          35 (66%)
           Mortality                                       52 (98%)
               Median time to death                           116 days
              Genotype KZN                                   39/46

Analysis of the 53 cases involving XMDRTB showed only about 50% had received prior
therapy for tuberculosis, 2/3 had been hospitalized within the prior two years, and all 44 who
had HIV serology were positive. Of particular note was the observation that 52 of the 53
died and the median time to death among these patients from the time of the positive culture
was a median of 16 days.

Genotyping indicated 39 of 46 strains were in the KZN family.

Conclusion: The authors conclude that this study shows the presence and potential serious
consequences of XDRTB in resource-limited areas with high rates of HIV, and they
emphasize the need for “urgent local and international intervention”.

Comment: This is an extremely disturbing report that was presented by Dr. Gandhi at the
2006 International AIDS Conference in Toronto; in this report he finished by warning that
this strain of TB could undo all of the achievements to date in the international effort to treat
and control the HIV epidemic in the developing world. KwaZulu Natal is a rural province in
South Africa in which about 80% of patients with active TB have HIV co-infection; mortality
rates in those with co-infection are reported as high as 40%/year despite treatment for TB.
The authors of the present study note that the rate of MDRTB was only 1.7% when surveyed
in 2000-02, but had increased to 9% in 2003-06. XDRTB is defined as MDR (resistance to
IMH and rifampin) plus resistance to at least three of the six second-line drugs. In the US,
these account for about 4% of the MDR strains and up to 15-19% in reports from Korea and
Latvia (MMWR 2006;55:301). This susceptibility pattern renders these strains virtually
untreatable (Hopewell PC Lancet Infect Dis 2006;6:710). The authors of the report
summarized above emphasize four needs:

              There needs to be better surveillance to determine the full extent of MDR and
               XDR tuberculosis in the areas with high prevalence rates of HIV.
              Treatment programs need to be strengthened to improve the rates of treatment
               including access to second line drugs.
              Infection control practices, especially those within health care settings, need to
               be enhanced with inclusion of protection of health care workers.
              There needs to be simpler and more aggressive testing to detect TB and drug
               resistance in resource-limited areas.

In a more recent editorial comment by Mario Raviglione and Ian Smith (N Engl J Med
2007;356:656) call attention to the unique features of this epidemic that emphasizes the
important points noted above. This includes the fact that most of the patients in KwaZulu-
Natal province had never been treated, most had been hospitalized suggesting nosocomial
acquisition, and all who were tested had HIV infection. XDRTB has been reported in at least
17 countries. Their conclusion is that the “global threat of XDRTB has great significance for
the public health field” and “its very existence is a reflection of weakness in tuberculosis
Homepage: CJD Update 2007 [ProMED-AHEAD Digest V2007:44:1]: The International
Society for Infectious Disease has provided the following update on vCJD:

Global Experience: The following table summarizes the total cases, number of persons
living with vCJD, the number with residence in the UK for over six months and the number
of cases implicating blood transfusions for the four countries with the most cases:

                         Total              Living             > 6 mo
                         Cases              Cases              In UK              Blood tx
United Kingdom            162                  6                165                  3
France                     21                  2                  1                  0
Ireland                     4                  1                  2                  0
USA                         3                  1                  2                  0
Total                     198                 12                  --                 3

Cases in UK: The total number of deaths from definite vCJD in the UK is 158 and the
number of probable cases in persons still alive is 7; the total is 165 through February, 2007.
The initial cases were reported in 1995, the zenith was 28 cases in 2000 and the number has
subsequently decreased suggesting the cases are on the wane. These data are summarized in
the following table:

                                         Cases in UK

                                  Year                 New cases
                                  2000                    28
                                  2001                    20
                                  2002                    17
                                  2003                    18
                                  2004                     9
                                  2005                     5
                                  2006                     5

Fourth case of transfusion-associated vCJD: The fourth case is a patient who developed
symptoms 8.5 years after receiving a transfusion of RBCs from a donor who developed the
disease 17 months after the blood donation. All four cases have involved non-leukocyte
depleted RBC between 1996 and 1999. Leukocyte depletion has been standard practice in
the UK since October, 1999. All four cases are patients who are methionine homozygote on
codon 129 of the prion protein gene. Persons who have received vCJD-implicated blood
transfusions in the UK have been warned of this exposure and advised to take the precautions
to prevent further transmission by donating blood.

Engineered resistance in cattle: The report indicates that scientists in the US and Japan
had successfully used genetic engineering to produce cattle that are resistant to BSE
(Kuroiwa Y Nat Biotech). The method was “gene targeting” with a knockout of the prion
protein gene. It was shown that this protein is not necessary for the normal development and
survival of cattle.

Homepage: Management and Outcomes of a First Recurrence of Clostridium difficile-
Associated Disease in Quebec, Canada [Pepin J Clin Infect Dis 2006;42:758]: The goal
was to determine the relative merits of metronidazole and oral vancomycin in the treatment
of patients with a relapse following Clostridium difficile-associated diarrhea.

Methods: The authors review data for patients with C. difficile diagnosed in Quebec using
their database for the period 1991 through 2005 for Sherbrooke Hospital. Treatment
consisted of metronidazole, 250 mg four times daily or 500 mg three times daily for 10-14
days, or oral vancomycin 125 mg four times daily for 10-14 days. The diagnosis was based
on positive toxin assay of stool or evidence or PMC by endoscopy or histopathology of a

Results: There were 463 patients with a relapse according to the protocol definition, and
154 (33%) had a second recurrence. Of these, 286 were treated with either oral vancomycin
or metronidazole and the rate of relapse was approximately the same in both groups as shown
in the following table:

                     Table 1: Frequency of Second Relapse
                Vancomycin                      68/171 (40%)
                Metronidazole                   42/115 (37%)

Risk factors for the second occurrence were limited to age and duration of hospitalization.
There was no relationship with the analysis according to hospital vs. community-acquired
infection, the period of the diagnosis (1991-02 vs. 2003-05), immunosuppression or the peak
leukocyte count. Data for significant associations are summarized in the following table:

Table 2: Risk for Second Relapse

Significant association
    Age
       0-64 years: 33/138 (24%)
       > 65 years: 121/325 (37%)
    Duration Hospitalization
       0              : 49/173 (28%)
       1-15 days      : 52/155 (34%)
       > 16 days      : 52/126 (41%)

Conclusions: The authors conclude that oral vancomycin and oral metronidazole are equally
effective for the treatment of first recurrences after C. difficile-associated diarrhea.
Comment: The authors show essentially no difference in the rate of relapses following oral
vancomycin or metronidazole after the initial relapse. However, this is actually not the most
important question to ask. The major controversy is the relative merits of these drugs for
response in patients with serious disease. In the present study, the rate of serious
complications was 51/463 (11%) including shock (10 patients), colectomy (3), toxic
megacolon (2) and death within 30 days (43). The authors note that these complications
were less with vancomycin compared to metronidazole, but no specific results were given
and the difference was not statistically significant (p = 0.09).

Homepage: Methicillin-Resistant S. aureus Infections among Patients in the
Emergency Department [Moran GJ N Engl J Med 2006;355:666]: The purpose was to
determine the frequency of community-acquired MRSA in patients with purulent skin and
soft-tissue infections encountered in emergency rooms in 11 locations in the US.

Methods: The study is a product of the EMERGEncy ID Net which is a network of
university-affiliated emergency departments in 11 cities in the US. The study was done in
August, 2004 for adults who presented with purulent skin and soft tissue infections less than
one week in duration. Cultures were obtained, S. aureus isolates were characterized by
sensitivity testing, pulsed-field gel electrophoresis (PFGE) and strains were examined for
detection of toxin genes. Outcome was evaluated with telephone inquiries at 15-21 days
after the emergency room visit.

Results: The total number of infections associated with purulent drainage that could be
cultured was 422; of these, S. aureus was detected in 320 (76%). Sensitivity tests in these
320 strains showed 249 were methicillin-resistant indicating MRSA accounted for 59% of
the entire population surveyed. PFGE was done on 216 and 214 of these (99%) were in the
USA300 family. Analysis of these 214 strains indicated that 156 (74%) were the USA300-
0114 strain, 213 (98%) contained the PVL gene and the SCCmec type IV element for
methicillin resistance. In vitro sensitivity test for the MRSA strains showed all were
sensitive to rifampin and TMP-SMX, 95% were sensitive to clindamycin and 92% were
sensitive to tetracycline. These results are provided in the following table:

Table 1: Bacteriology results with 422 cases

Total                                        422
Staph aureus                                 320 (76%)
      MRSA                                   249 (59%)
      PFGE results                           216
      1. USA300                              214 (99%)
               USA300-0114                  156 (74%)
               PVL gene                     213 (98%)
               SCCmec                       213 (98%)
               Enterotoxins                 < 5 ea
      2. In vitro sensitivity tests
               Rifampin        100%          Fluroquinolones        60%
               TMP-SMX 100%                  Erythromycin           6%
              Clindamycin 95%
              Tetracycline 92%

Treatment of these infections included incision and drainage and/or antibiotics in 95%.
Among the 175 with MRSA, 100 (57%) were treated with a betalactam. The telephone
follow-up at 15-21 days in 248 patients showed 238 (96%) indicated that the lesion had
improved or was cured. This response was not different for those who received a betalactam
for MRSA-involved infections. These results are summarized in the following table:

Table 2: Treatment of S. aureus skin and soft tissue infections

Incision and drainage
        (1 & D only)                 79 (19%)
1 & D plus antibiotics               267 (66%)
Antibiotics only                     39 (10%)
Neither 1 & D or Abx                 21 (5%)
Antibiotic selection
  Betalactam                         311 (64%)
        MRSA                         100/175 (57%)

Outcome at 15-21 days                248
 No. improved or cured               238 (96%)

Risk factors for MRSA were identified by multivariate logistic-regression analysis and
showed the following significant associations:

                   Table 3: Risk factors for MRSA infection

                         Characteristic               OR
                  Race-African American               1.9
                  Antibiotic-use, past month          2.3
                  Reported spider bite                3.0
                  Contact with person with
                  similar infection                   3.8

Conclusions: The authors conclude that MRSA is now the most common identifiable cause
of skin and soft tissue infections among patients who present to emergency departments in 11
cities in the US. They urge clinicians to obtain cultures and to use appropriate antibiotics
when antibiotics are deemed necessary.

Comment: This is an important study that has some obvious important relevant clinical
   1.      MRSA and especially the USA300-0114 strain is now highly prevalent in the US.
           This is the strain that has been identified in multiple MRSA outbreaks (Kazakova
           SV N Engl J Med 2005;352:468; McDougal LK J Clin Microbiol 2003;41:5113).
   2.      The susceptibility test results of this strain seem relatively predictable with over
           90% of strains sensitive to clindamycin, TMP-SMX and doxycycline;these would
           be the preferred drugs when antibiotics are deemed necessary. Nevertheless, the
           authors also warn that nonpurulent cellulitis cases were was not included in the
           study, these infections are usually caused by group A streptococcus and strep are
           often resistant to TMP-SMX; clindamycin would be a preferred option.
   3.      Although most of the patients with MRSA infections were treated erroneously
           with cephalexin, it did not seem to make a difference in outcome. These results
           emphasize the primary role of I and D.
   4.      It is important to emphasize infection control including the need to cover wounds,
           use of hand hygiene and avoidance of sharing of contaminated items.

Homepage: Impact of Emergency Colectomy on Survival of Patients With Fulminant
Clostridium difficile Colitis During an Epidemic Caused by a Hypervirulent Strain
[Lamontagne F Ann Surg 2007;245:267]: The authors examined the potential value of
emergency colectomy in patients with fulminant C. difficile-associated colitis.

Methods: The authors reviewed retrospectively an observational cohort of 165 patients with
C. difficile-associated colitis who required admission to ICU between 2003 and 2005 in two
hospitals in Sherbrooke, Canada.

Results: Among those who were seriously ill the mortality was 87/165 (53%). Among those
who underwent emergency colectomy, the mortality was five fold less (odds ratio 0.2) and
this procedure seemed most beneficial in those of age 65 or greater. Other risk factors
associated with increased mortality are summarized in the following table:

                             Seriously ill patients with C. difficile
        (defined as requiring ICU admission or retention in the ICU due to C. difficile)

        Cases                                        165
        Deaths (≤ 30 days)                           87 (53%)
         Predictors                                  OR
           WBC > 50,000/mm3                          18.6
           Lactate > 5 mmol/L                        12.4
           Age > 75 years                            6.5
          Immunosuppression                          7.9
          Shock                                      3.4
          Emergency colectomy                        0.2

Conclusions: The authors conclude that emergency colectomy decreases mortality in
patients with fulminant C. difficile-associated colitis.
Comment: The obvious concern with this type of retrospective analysis is the potential for
bias in those selected for surgery. Nevertheless, this is the first such analysis with a
comparison group in patients who were seriously ill with C. difficile-associated colitis.

Homepage: A Two-Amino Acid Change in the Hemagglutinin of the 1918 Influenza
Virus Abolishes Transmission [Tumpey TM Science 2007;315:655]: The authors address
the issue of person-person transmission of avian strains of influenza A.

Methods: Receptor binding preference differs for avian influenza strains: for humans, the
binding to target cells is mediated by the viral hemagglutinin surface glycoconjugate
containing terminal sialiac acid residues which preferentially binds to an alpha 2, 3 linkage
which is most prevalent in the epithelial cells of intestines of birds; by contrast, human
influenza viruses bind preferentially to receptors with alpha 2, 6 linkages that are
predominant in the human respiratory tract epithelium. The authors used the reconstructed
1918 pandemic strain to determine the effect of transmissibility in mammals with this strain
when it was “avianized” by two amino acid mutations that switch receptor binding
preference. Transmissibility was examined by infections in ferrets placed in cages next to
healthy ferrets. The preferential binding in birds compared to humans and humans vs. the
H5N1 strain of avian influenza are summarized in the following table which provides the
background rationale for this study:

Table 1: Binding of HA glycoconjugates to siliac residues on epitheal cells

                 Receptors                   Flu virus
Receptor Binding Birds Humans                H1 H3 H5
a-2, 3             +       -                  -     -  +
a-2, 6              -      +                  +    +   -

Results: The results of the experiment show that the mutations affecting preferential
attachment to the receptor sites with or without the mutations noted showed the reconstructed
initial strain both infected ferrets and was efficient efficiently transmitted. However, the
mutated strains showed poor transmission of this strain, and showed that the human alpha 2,
6 siliac acid binding preference was essential for transmission. These results are summarized
in the following table:

Table 2: Receptor binding specificity at codons 190 & 225 HA

Influenza Strain        HA amino acid                  Ferrets              Transmission
                        substitution                   Infected
SC18                    1918 parent strain               3/3                   Efficient
AV18                    HA                                 0/3                   None
NY18                    HA                                 1/3                Inefficient
Conclusion: The authors conclude that the hemagglutinin receptor specificity plays an
essential role in the transmission of influenza viruses among mammals.

Comment: This is an association which has been previously the subject of speculation. For
pandemic influenza, there needs to be three factors: 1) humans need to be susceptible due to
immunologic naivete; 2) the virus needs to cause disease in humans and 3) there needs to be
efficient person-to-person transmission. Avian influenza (H5N1) clearly has the first two
required properties, but there has been no sustained human-to-human transmission which
now appears to be the Achilles heel for pandemic influenza. The study noted above clearly
supports this thesis. The implication is that H5N1 could become “humanized” with efficient
human-to-human transmission with a few HA mutations. In an editorial comment, influenza
expert Yoshihiro Kawaoka from the University of Wisconsin suggested that mutations and
other genes are probably necessary as well (Enserink M Science 2007;315:582).

Homepage: Pandemic and Seasonal Influenza: Principles for U.S. Action
[Recommendations of the Pandemic Influenza Task Force of the Infectious Diseases Society
of America, January 2007]: As background information, it is noteworthy that between 2005
and 2007, federal and state governments, private industry and international stakeholders
made substantial advances to prepare for pandemic influenza. In the US, over six billion
dollars was committed for pandemic flu preparedness to date. In December, 2006, Congress
passed the Pandemic and All Hazards Preparedness Act that authorized substantial funding to
support the public health system and its ability to respond to emergencies. Included in the
Act is the Biomedical Advanced Research and Development Authority (BARDA) designed
to foster research, development and purchase of countermeasures including therapeutics,
diagnostics and vaccines. The IDSA Influenza Task Force applauded these developments,
but also felt there needed to be a much greater effort. The following are recommendations
including some that will require additional support from Congress. These are addressed by a
tabulation of priorities which address both seasonal influenza and preparedness for pandemic

   1.      Strengthen pandemic influenza vaccine efforts by establishing a
           multinational pandemic influenza master program: DHHS has invested over
           $1 billion to develop cell-based vaccines, and HHS has stockpiled about 8 million
           doses of vaccine against clade one H5N1 (a possibly antiquated clade recovered
           in Vietnam in early 2004). The IDSA expressed concern about the “lack of
           coordination, rapid sharing of results and transparency”. Their proposal is for a
           global Master Program funded at the “scale of the Apollo Space Project” (funded
           at $73 billion from 1960-73). This would be a global plan to increase vaccine
           research and development, and increase vaccine production capacity (which is
           now limited to 400 million doses of influenza vaccine/year for the world). The
           recommended investment is $2.8 billion for FY07 from the US based on the
           WHO projection of a need for $3-10 billion of over 5-10 years for a global plan.
2.   Strengthen anti-infected pharmaceutical research and development, and
     stockpiling efforts: HHS plans sufficient antiviral courses to treat 25% of the
     US population and has allocated $782 million in 2006 to purchase neuraminidase
     inhibitors. The HHS plan also includes $200 million in contracts for the
     development of new antiviral agents. The recommendation is to accelerate the
     development of an adequate stockpile, additional research on new agents and
     establishment of methods to ensure equity in antiviral supplies.
3.   Improve quality and availability of diagnostic tools for influenza: This is
     needed to quickly and accurately detect pandemic influenza strains in the
     laboratory that also needs to be made available at the point-of-care. Recent
     developments include the Flu Chip and the Influenza A/H5 virus real-time RP-
     PCR; these need to be developed and critically analyzed along with other novel
     detection methods.
4.   Accelerate development of countermeasures to prevent, treat and diagnose
     pandemic influenza: The goal is to increase incentives for Pharma and
     streamline the regulatory processes to facilitate production of products relevant to
     this effort including vaccines and antivirals.
5.   Update US plans for countermeasure distribution and priorization of use:
     The request is for national guidelines on the use of antivirals and vaccines. It is
     noted that the HHS Plan does contain plans for distribution, but there is no
     tracking system for distribution and use of influenza vaccine currently available.
6.   Expand vaccine uptake, stabilize vaccine manufacture and test and evaluate
     vaccine distribution plans during the annual influenza seasons: The case is
     made for promotion of more public uptake of vaccinations for seasonal influenza
     and strong case is made for mandatory annual influenza vaccine for health care
7.   Protect the health care work force during a pandemic: Health care workers
     are obviously critical to the response with pandemic influenza, but this work
     obviously puts them at substantial risk. The recommendation is to make this
     group a high priority for immunization, antiviral drug treatment and establish an
     injury compensation fund plus provide liability protection where relevant.
8.   Build national, regional and local health care systems capable of responding
     to mass casualty events: The request is to establish a national strategy to ensure
     a coordinated continuum of care during pandemic influenza. There are three
     components: A) Establish protocols for a sustained medical surge capacity; B)
     Provide training and credentialing of public health personnel for this task and C)
     Develop evidence-based guidance that will include guidelines for medical triage,
     allocation of scarce resources including prioritization of equipment-like masks,
     ventilators, etc.
9.   Develop and test community mitigation measures: This refers to community
     interventions for “social distancing” including school closures, business closures,
     border closing, quarantines, prophylactic antivirals, mathematical modeling for
     disease containment, etc. The concern is that the science supporting the efficacy
     of these maneuvers is pretty thin and the request is additional research and
     collaborative input from stakeholders and technical experts.
10.   Improve and coordinate influenza surveillance: The issue here is the
      importance of surveillance as a critical component to detect emergence of a novel
      influenza A virus. The request is to establish an effective surveillance system that
      will include the US health care system, public health, animal health and global
11.   Continue to strengthen leadership, international collaboration and
      communication: There are three components: A) Strengthen leadership by the
      federal government; B) Foster international coordination and C) Improve
      communication to better educate public health and health care sectors.
12.   Allocate significant and sustainable funding for long term planning and
      action: The presidential request in 2005 was for $7.1 billion and Congress has
      now allocated approximately $6 billion toward that effort. The concern is
      sustainability. Specifically, sustained funding is needed for the influenza vaccine
      development plan (the highest priority) for stockpiling and distribution, surge
      capacity and planning, personnel, surveillance (US and international) and
      community mitigation.

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