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					Literature Review
Homepage: Community-Acquired Bacterial Meningitis in Adults
Community-Acquired Bacterial Meningitis in Adults [van de Beek D, de Gans J,
Tunkel AR, et al. N Engl J Med 2006;354:44
act&list_uids=16394301&query_hl=27&itool=pubmed_docsum]: The authors provide a
“Review Article” on current concepts of the management of pyogenic meningitis in

Presentation: Only 44% of patients present with the classic triad of fever, stiff neck and
altered mental status; nearly all have at least two of the four classic symptoms: headache,
fever, stiff neck and altered mental status defined as a score of less than 14 on the
Glasgow Coma Scale.

Diagnostic Evaluation: “Lumbar puncture is mandatory …” although the procedure can
be hazardous. Indications for cranial imaging (CT or MRI) should be done before LP
with the following conditions: new-onset seizures, immunocompromised patient, signs
of a space-occupying lesion or moderate-severe impairment of consciousness [Hasbun R,
Abrahams J, Jekel J, et al. N Eng J Med 2001;345:1727
act&list_uids=11742046&query_hl=29&itool=pubmed_docsum]. These indications
apply to about 45% of patients [van de Beek D, de Gans J, Spanjaard L, et al. N Engl J
Med 2004;351:1849
act&list_uids=15509818&query_hl=27&itool=pubmed_docsum]. In addition to
herniation, the LP may be harmful with a coagulopathy that may lead to a spinal subdural
or epidural hematoma. Delays in treating pyogenic meningitis of over 4-6 hours are
associated with increase in complications or death [Proulx N, Frechette D, Toye B, et al.
QJM 2005;98:1091
act&list_uids=15760921&query_hl=32&itool=pubmed_docsum]. Thus, if imaging is
performed prior to LP, antibiotic therapy should be initiated first. The expected findings
on CSF analysis are summarized in the following table:

                                      CSF Findings

              Analysis                        Expected Result
              WBC                             100-10,000/mm3
              PMNs                            80-95%
              Glucose                         <40% serum levels
              Protein                         > 50 mg/dL
              Gram stain positive             60-90%
                specificity                   97%
              PCR for bacteria                “Promising”
Bacteriology: The following table summarizes the anticipated pathogens and suggested
antibiotic treatment:

                          Treatment of Pyogenic Meningitis

Risk Factor          Common Pathogen                         Antibiotic Treatment
Age 16-50 years      N. meningitis                           Vancomycin + ceftriaxone
                     S. pneumoniae                           or cefotaxime
     > 50 years      Above plus L. monocytogenes             Vancomycin + (ceftriaxone
                     Gram + neg bacilli                      or cefotaxime) + ampicillin
Alcoholism or immune S. pneumoniae                           As above
suppression          L. monocytogenes
                     H. influenza

Adjunctive Dexamethasone: The indications are a CSF that is cloudy, has a WBC over
1,000/mm3 or has bacteria on Gram stain. Support for this is from studies showing a
reduction in mortality from 15% to 7% [de Gans J, van de Beek D N Engl J Med
act&list_uids=12432041&query_hl=34&itool=pubmed_docsum]. The authors also
recommend the administration of adjunctive dexamethasone in patients with suspected
meningitis. The dose is 10 mg, it should be initiated before or with the first dose of
antibiotics and it should be continued for four days at a dose of 10 mg every six hours.
This treatment should be stopped if the diagnosis of pyogenic meningitis is not
established. The authors recommend continuation of dexamethasone for four days
regardless of the microbial pathogen or clinical severity, although efficacy is best
established for pneumococcal meningitis [Tunkel AR, Hartman BJ, Kaplan SL,et al. Clin
Infect Dis 2004;39:1267
act&list_uids=15494903&query_hl=36&itool=pubmed_docsum]. Clinical efficacy has
been analyzed and meta-analysis by clinical trials which showed a mortality relative risk
of 0.9 and a risk of neurologic sequelae of 0.5 [van de Beek D, de Gans J, McIntyre P,et
al. Lancet Infect Dis 2004;4:139
act&list_uids=14998499&query_hl=27&itool=pubmed_docsum ].

Intensive Care Management: The following table summarizes recommendations for
management in the intensive care unit:

                                   ICU Management

High risk of brain herniation: Monitor intracranial pressure and:
    Osmotic diuretics (mannitol 25%) or hypertonic saline (3%) to keep intracranial
       pressure <15 mm3 + perfusion > 60 mm Hg
    Initiate repeated LP’s, lumbar drain or ventriculoscopy
    EEG monitoring with history of seizures
Airway: Intubate or non-invasive ventilatory support

Circulatory support
     Septic shock: Low dose steroids if corticotrophin test is positive
     Inotropic agents (dopamine or milrinone) to keep BP > 70-100
     Crystalloids or 5% albumin to maintain fluid balance
     Consider Swan-Ganz catheter

GI care: N-G tube + prophylaxis with PPI

Other: SC heparin, maintain normoglycemic, antipyretic agents for temperature > 40° C

Repeat LP: If no improvement within 48 hours

Outcome: Patients who have a decline in consciousness or fail to improve within 48
hours of appropriate antibiotic therapy should have imaging and a repeat LP. The most
common cause of a decline in consciousness is development of meningoencephalitis
leading to cerebral edema and increased intracranial pressure. For patients whose course
is complicated by focal cerebral abnormalities, the most common causes are stroke,
seizures or a combination of both. The frequency of these and other complications are
summarized in the following table:


Complications                                                       Frequency
 Cardiorespiratory failure                                             29%
 Hyponatremia (inappropriate ADH)                                      26%
 DIC                                                                    8%
Decreased consciousness increases
 Meningoencephalitis                                                  15-20%
 Seizures                                                             10-15%
Neurologic sequelae
 Cerebrovascular complications                                        15-20%
 Arterial infarction/vasculitis                                       10-15%
 Hearing loss                                                         14-20%

With regard to microbial pathogen, the following table summarizes mortality rates and
frequency of neurologic sequelae for pneumococcal and meningococcal meningitis:

         Outcome                         Fatality                   Neuro sequelae
Microbial pathogen
 S. pneumoniae                           19-37%                            30%*
 N. meningitis                            3-13%                            3-7%
* Primarily cognitive impairment [van de Beek D, Schmand B, de Gans J, et al. J Infect
Dis 2002;186:1047

Homepage: Worldwide distribution of HPV types of cytologically normal women in
the IARC HPV prevalence surveys.
Worldwide distribution of human papillomavirus types of cytologically normal
women in the International Agency for Research on Cancer HPV prevalence
surveys: a pooled analysis [Clifford GM, Gallus S, Herrero R, et al. Lancet
act&list_uids=16168781&query_hl=40&itool=pubmed_docsum ]: The report is from the
International Agency for Research on Cancer (IARC) HPV prevalence surveys with a
goal to compare HPV-type distribution in representative samples of women from 13 areas
and 11 countries including sub-Saharan Africa, Asia, South America and Europe. The
results are based on observations in 15,613 women age 15-74 who did not have cytologic
abnormalities. The most common HPV type was 16 followed in rank order by 42, 58, 31,
18, 56, 81, 35, 33 and 45. There were a total of 1,429 positive specimens including 1250
with high risk types and 675 with low risk types. There were substantial regional
differences between HPV prevalence and prevalence of specific types, such as HPV 16.
These data are shown on the following table:

Country/Area                         Age standardized prevalence
                              Any HPV        HPV 16 in HPV positive cases
Nigeria                        25.6%                    12.3%
Asia                            8.7%                    18.4%
S. America                     14.3%                    21.4%
Europe                          5.2%                    25.5%
All areas                      10.5%                    19.7%

The authors conclude that the distribution of HPV types in different populations need to
be taken into account when developing tests for screening for HPV and for predicting the
effect of vaccines on the incidence of infection.

Comment: These data are obviously important in the context of the newly licensed
HPV vaccine.

Homepage: Routine Hospital Use of a Whole Blood Interferon-γ Assay for the
Diagnosis of TB Infection
Routine Hospital Use of a New Commercial Whole Blood Interferon-γ Assay for the
Diagnosis of Tuberculosis Infection [Ferrara G, Losi M, Meacci M, et al. Am J Respir
Crit Care Med 2005;172:631
act&list_uids=15961696&query_hl=42&itool=pubmed_DocSum]: The report is from
Italy with the analysis of results using the Quanti-FERON-TB-Gold (QFT-Gold) a IFN-
gamma assay for detection of M. tuberculosis which appears to show higher specificity
than the tuberculin skin test (TST). The test was performed according to physician
request. Results were correlated with clinical observations and results of TST. Of the
318 patients, 65 (20%) were receiving immunosuppressive treatment. Of the 318, 68
(21%) had an indeterminate QFT-Gold result. This group had a significantly higher rate
of indeterminate results with an odds ratio of 3.35. The authors conclude that
immunosuppressive therapy and possibly other immunosuppressive conditions limit the
performance of this test, particularly in the most vulnerable population.

Comment: IFN gamma assays for detection of M. tuberculosis including the QFT-Gold
assay which has been approved by the FDA. The definition of an indeterminate test is
the lack of a response to the positive mitogen control. As noted in the accompanying
editorial by Pai and Lewinsohn [Am J Respir Crit Care Med 2004;172:519
act&list_uids=16120714&query_hl=45&itool=pubmed_DocSum] this low mitogen
response may reflect anergy or inability to mount a T-cell response. This is viewed as
potentially useful information in the sense that it indicates the possibility of anergy and a
false-negative result, thus avoiding the confusion between anergy and a true negative test.

Homepage: Reinfection and Mixed Infection Cause Changing TB Drug-Resistance
Reinfection and Mixed Infection Cause Changing Mycobacterium tuberculosis Drug-
Resistance Patterns [van Rie A, Victor TC, Richardson M, et al. Am J Respir Crit Care
Med 2005;172:636
act&list_uids=15947286&query_hl=47&itool=pubmed_docsum ]: The study was done
in Cape Town, South Africa where the incidence of new culture-positive tuberculosis is
313/100,000 per year. The study included serial mycobacterial cultures of sputum from
patients with MDR TB and genotypic analysis was done by IS6110 DNA fingerprinting
on serial sputum cultures. Using a strain-specific PCR, it was noted that up to 20% of
patients simultaneously secreted two different mycobacterial strains in their sputum
[Warren RM, Victor TC, Streicher EM, et al. Am J Respir Crit Care Med 2004;169:610
act&list_uids=14701710&query_hl=49&itool=pubmed_DocSum]. This was previously
reported by the authors and represented a surprise in the sense that tuberculosis has
always been considered a disease caused by a single strain. Further, the incidence of
reinfection disease after successful treatment was about 2%/year [Verver S, Warren RM,
Beyers N, et al. Am J Respir Crit Care Med 2005;171:1430
act&list_uids=15831840&query_hl=51&itool=pubmed_docsum]. This observation
suggested that these cases which had been attributed to re-infection, could represent
relapse by a concurrently present strain. In the present report, DNA fingerprinting of
serial sputum cultures from 48 patients with MDR TB showed 10 were due to reinfection
and one was a mixed infection, but analysis of strain-specific PCR in nine of the eleven
showed mixed infection in five and re-infection in three. Analysis of the clinical data
suggested that the first line therapy possibly selected for a resistant subpopulation; by
contrast, poor adherence resulted in relapse with drug-susceptible MTB.

Conclusion: The authors conclude that some cases of recurrent TB now called
reinfection may actually represent relapse. Treatment combined with adherence dictate
which strain from a mixed population will dominate.

Homepage: Advancement of global health: key messages from the Disease Control
Priorities Project
Advancement of global health: key messages from the Disease Control Priorities
Project [Laxminarayan R, Mills AJ, Breman JG, et al. Lancet 2006;367:1193
act&list_uids=16616562&query_hl=53&itool=pubmed_docsum ]: The Disease Control
Priorities Project is a joint effort of the Fogarty International Center, NIH, WHO, World
Bank and Gates Foundation which was launched in 2001 to identify policy changes and
interventions to deal with health problems in developing countries. The following is a
selected summary of their conclusions for interventions in a multitude of different health
problems expressed as cost effective according to disability-adjusted life years averted.

Disease/Intervention                                       DALY*
 DOTS                                                       $5-35
 BCG vaccinations-peds                                     $40-170
 INH prophylaxis without HIV infection                 $4,000-$25,000
 MDRTB management                                          $70-450
 Prevention-counseling high risk groups                     $1-74
 Voluntary testing & counseling                            $14-261
 Condom promotion & distribution                           $19-205
 Blood & needle safety                                      $4-51
 Treatment of STDs                                         $16-105
 Treatment of HIV                                         $350-500
Vaccine preventable diseases
 DPT, polio & measles                                      $13-24
 Rotavirus immunization                                  $1402-8357
 Cholera immunization                                    $1658-8274
Diarrheal disease
 Oral rehydration                                          $132
 Breast-feeding promotion                                $527-2001
 Water sanitation                                       $1118-14901
 Insecticide treated bednets                                $5-17
 Insecticide spraying                                      $13-24
*DALY= Disability-adjusted life-years

The authors conclude with a tabulation of what they consider to be four important
challenges that face the world in the 21st century.

1. High levels of non-communicable conditions in developing countries (such as heart
   disease, cancer, traffic accidents and smoking);

2. The HIV pandemic;

3. The possibility of an influenza pandemic similar to that of 1918; and

4. The persistence of population subgroups with high levels of preventable disease (such
   as malaria, tuberculosis, diarrhea and pneumonia).

They urge wider use of interventions that have already proven cost-effective and more
attention to some of the non-communicable diseases noted above. They also urge more
research to identify those prevention and treatment programs that are likely to be most

Homepage: Prophylactic human papillomavirus vaccines
Prophylactic human papillomavirus vaccines Lowy DR, Schiller JT J Clin Invest
act&list_uids=16670757&query_hl=59&itool=pubmed_docsum ]: This is a report from
the National Cancer Institute of the NIH dealing with the exciting development of
vaccines for human papillomavirus (HPV). These vaccines are being developed by
Merck and Glaxo. Both target HPV16 and HPV18 which account for about 70% of cases
of cervical cancer; the Merck vaccine also targets HPV6 and HPV11 which account for
about 90% of external genital warts. The following summarizes background information
relevant to this issue:

   Cervical cancer: 10% of cancers in women
   Developing countries account for 80% of cases due to lack of cancer screening
    programs – e.g. Pap smear
   Oncogenic HPV types: total is 15, HPV16 accounts for 50%; HPV18 accounts for
   Prevalence of HPV infection: 20-40% of sexually active 20 year old; lifetime risk
   Most important risk for high grade dysplasia: infection with HPV16 or HPV18 that
    persists > 6 months
   The interval between infection and malignant progression take > 10 years

The following table summarizes four clinical trials with these new vaccines:
                        Koutsky           Harper                Villa            Mao
Source**                    1                2                     3                4
HPV type                   16             16, 18            6, 11, 16, 18          16
Sponsor                  MSD               GSK                  MSD              MSD
Trial site                US         US, Canada, Brazil   US, Europe, Brazil      US
Age (years)              16-23             15-25                16-23            16-23
Number                   1533               721                  468             1,505
Schedule (mo)            0,2,6             0,1,6                0,2,6            0,2,6
Follow-up (year)           1.5              1.5                   2.5              3.5
Persistent infection*     42/0              7/0                  36/4            111/7
CINI*                      9/0              6/0                   3/0             24/0

*Values for controls/vaccine recipients
** 1) Koutsky LA, et al N Engl J Med 2002;347:1645
act&list_uids=12444178&query_hl=61&itool=pubmed_DocSum ; 2) Harper DM, et al.
Lancet 2004;364:1757
act&list_uids=15541448&query_hl=63&itool=pubmed_docsum ; 3) Villa LL, et al.
Lancet Oncol 2005;6:271
act&list_uids=15863374&query_hl=65&itool=pubmed_docsum ; 4) Mao C, et al. Obstet
Gynec 2006;107:18

In terms of impact, the short term outcome in industrialized countries such as the US
would be an anticipated reduction in the number of CIN2 cases by about 1/3 to 1/2 for
vaccinated women compared to those without the vaccine. This would reduce medical
and psychological morbidity in the short run and reduce the incidence of cervical cancer
in the long run. For the developing countries which account for 80% of cervical cancers,
the potential is to save several hundred thousand cancers annually, but there would be a
substantial lag before this benefit would be realized and the authors consider that
vaccination in low-resource settings would be considered cost-effective only if the
expense of the vaccine was modest.

Homepage: Strategies for mitigating an influenza pandemic
Strategies for mitigating an influenza pandemic [Ferguson NM, Cummings DA,
Fraser C, et al. Nature. 2006 Apr 26; Epub ahead of print]: This is a follow-up report by
experts in epidemic modeling to deal with global public health priorities in the event of
pandemic influenza. Here the authors examine four issues as follows:

Internal or border travel restrictions: This and other analyses are based on data for
the US and Great Britain. The results show that border control to restrict passage by
90%, 99% or 99.9% might delay the peak of a US pandemic by 1.5, 3 or 6 weeks,
respectively. Their analysis also showed the eliminating travel in and out of the affected
areas would delay the spread by up to two weeks. Closing airports for domestic airports
had minimal impact.

Treatment of Cases: The analysis showed that this would be effective only if there
was very rapid treatment, meaning “same day treatment” of 90% of cases. This would
reduce the attack rate from 34% to 29% and peak attack rate from 1.9% to 1.6%
assuming an antiviral stockpile sufficient for 25% of the population. The urge for early
therapy was based on the fact that transmission is at a peak soon after symptoms develop.
They also note that effectiveness of antiviral treatment is based on the assumption that
there would not be resistant strains with efficient transmissibility similar to that of wild-
type virus. They point out that such strains have not been reported to date.

Social Distancing: Isolation such as school closings during the peak of the epidemic
could reduce the peak attack rate by up to 40%, but this has little impact on the overall
attack rate. However, case isolation or household quarantine could have substantial
impact. Antiviral prophylaxis to household contacts would reduce the cumulative attack
rates, but this would require a stockpile of antivirals sufficient to treat 46-57% of the
population which was considered unlikely.

Vaccine: Evaluations were based on the assumption that single dose would give 70%
protection. Vaccination at a rate of 1% of the population/day would need to begin two
months before the pandemic outbreak to have a substantial impact. A delay of four
months from the start of the pandemic would mean that the vaccine was available when
the pandemic was over.

The authors conclude by noting the limitation of their data which would be quite different
if the modeling was based on the 1968 or 1957 pandemic rather than the 1918 pandemic.

Comment: It should be noted that this is the team that provided one of the initial
strategies that received substantial attention including adoption of many of the
recommendations by WHO [Ferguson NM, Cummings DA, Cauchemez S, et al. Nature
act&list_uids=16079797&query_hl=69&itool=pubmed_docsum ]. This report seems
rather depressing in terms of strategies that are likely to be effective, it is the quick fix
that we have all wanted. Nevertheless, it is somewhat reassuring that the avian influenza
spread has slowed in both people and poultry.