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IMMUNIZATIONS

Influenza Immunization for the 2011-2012 Season
Influenza season is here! This season the influenza vaccine will contain the same three viruses as the prior influenza season (A/California/7/2009 (H1N1)-like virus, A/Perth/16/2009 (H3N2)-like virus and B/Brisbane/60/2008-like virus). Vaccine distribution has already started among the major manufacturers. This will provide an earlier opportunity to immunize children at high risk of developing influenza complications.

Novartis plans to distribute 30 million doses of Fluvirin« influenza vaccine.

Sanofi-Pasteur plans to distribute 70 million vaccine doses. Fluzone« is available in pediatric and adult doses. There is a 0.25 mL pediatric dose (children 6 months through 35 months) and 0.5 mL dose (children 36 months and older).

GlaxoSmithKline (GSK) plans to distribute 35-37 million doses of FluLaval« and Fluarix« combined. FluLaval« is approved only for adults 18 years and older.

For additional information regarding influenza and immunization:
www.cdc.gov/flu/professionals/vaccination
www.cdc.gov/flu/pdf/dosagechart.pdf

Personal Belief Exemptions for Immunizations
The Vaccine Advocacy Committee of the Pediatric Infectious Diseases Society (which includes our own, Dr. Berman!) recently issued its first position paper on the issue on personal belief exemptions from immunizations. PIDS "opposes any legislation or regulation that would allow children to be exempted from mandatory immunizations based simply on their parent's or, in the case of adolescents, their own secular personal beliefs." They base their stance on: 1) the proven efficacy of vaccinations —four diseases have been eliminated (no longer occur endemically) from the USA: smallpox (1949), polio (1979), measles (2000) and rubella (2004), and 2) the consequences of mass vaccine refusal—deadly pertussis outbreaks in 1970's United Kingdom, and the more recent outbreaks of measles and in the United States (150 cases and counting this year alone). They correctly point out that there lies a fine line between individual autonomy and the government's duty to protect its citizens. For example, a parent cannot claim exemption from putting an infant in a car seat simply because they do not "believe in car seats." Not to mention that not vaccinating one child puts many other children at risk.

Something to think about: refusal to vaccinate a child puts a child at 35X's the risk of measles, 23X the risk of pertussis and 9X the risk of varicella. More than that—ANY child who lives in a state where personal belief exemptions are in place has 1.5X the risk of pertussis than a child who lives in a state where such exemptions do not exist.

Source: A Statement Regarding Personal Belief Exemption From Immunization Mandates. Pediatric Infectious Disease Journal. Volume 30, Number 7, July 2011. 606.

Additional reference: Personal belief exemptions for vaccination put people at risk. Examine the evidence for yourself. (www.immunize.org/catg.d/p2069.pdf).


Immunization Action Coalition
The Immunization Action Coalition (http://www.immunize.org) is an excellent and reliable source of information on immunizations for physicians, nurses and parents. The July issues of two of their publications are available through the links shown below. These publications contain ready-to-print educational materials for healthcare professionals and their patients, updated immunization recommendation tables, vaccine news highlights, and IAC's popular "Ask the Experts" question-and-answer column with answers by CDC experts Andrew Kroger, MD, MPH, Donna Weaver, RN, MN, and William Atkinson, MD, MPH.

Needle Tips (www.immunize.org/nt)
Vaccinate Adults (www.immunize.org/va)
December 2011

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In This Issue

David M. Berman, D.O.
Juan Dumois III, M.D.
Shirley Jankelevich, M.D.
Allison Messina, M.D.
Katie Namtu, Pharm.D.

Inpatient Consultation:
All Children's Hospital
Sarasota Memorial Hospital
Bayfront Baby Place

Outpatient Care Locations:
All Children's Hospital
Outpatient Care, Brandon
Outpatient Care, Sarasota
Outpatient Care, Ft. Myers

Phone: 727-767-4160
Fax: 727-767-8270
Email: pidhl@allkids.org

Grand Rounds:
Archived Infectious Disease Webcasts
The following Infectious Disease Topics are archived on our website for viewing. Click the link on each title to view the archived webcast.

Infectious Disease Newsletter Feedback
Please email your comments and suggestions so we may continue to improve our newsletter!


TREATMENT ISSUES

Should Acyclovir Be A Routine Part of Empiric Therapy in "The Rule-Out Sepsis" Workup?
Sarah Long et al. recently published a study detailing their 20-year experience with the use of acyclovir (along with standard antibacterials) as routine empiric therapy in neonates undergoing a "rule out sepsis" work up. Theirs is a case study of 32 infants with perinatally acquired herpes simplex virus (HSV) infection over a 22-year period. They sought to find distinctive features which might permit a more targeted approach to the used of IV acyclovir.

What they found was interesting! At presentation, fully half of the babies with perinatal HSV infection displayed only non-specific symptoms (75% of which was fever alone). After testing, 75% of infants who had HSV disease had CNS infection--including 40% who presented with mucocutaneous lesions, 83% with seizures and 94% with non- specific complaints. Laboratory indices including liver enzymes and CSF indices were not distinctive in patients with HSV. Age of presentation </= 21 days, who would otherwise receive a "rule out sepsis" workup captured 90% of all infants with HSV. An estimated 1.3% of patients empirically treated with acyclovir had HSV. The anticipated rate of HSV CNS infection was similar to that of bacterial infection.

Long, SS, et al. Pediatric Infectious Disease Journal. Volume 30, Number 7, July 2011 p.556-561.

Infections Due to Extended-Spectrum ▀-lactamase (ESBL)-Producing Organisms

What are ESBLs?
Extended-spectrum ▀-lactamases (ESBLs) are ▀-lactamases that are capable of hydrolyzing expanded-spectrum cephalosporins (ceftriaxone, cefotaxime, and ceftazidime) as well as cefepime and aztreonam. They confer resistance to most ▀-lactam antibiotics except for carbapenems (e.g. meropenem) and cephamycins (e.g. cefoxitin). Any isolate that is positive for an ESBL will be clinically resistant to all β-lactams, EXCEPT the cephamycins, piperacillin/tazobactam and the carbapenems. ESBLs can be isolated from many different Enterobacteriaceae species, but are most commonly isolated from Klebsiella pneumoniae, K. oxytoca, E. coli, or Proteus mirabilis.

What are the clinical consequences of infection with ESBL-producing organisms?
The spectrum of infections caused by ESBL producers that we have witnessed in our patients includes bacteremia, sepsis, pneumonia, urinary-tract infections (UTIs), wound and intra-abdominal infections. Most recently, we have recognized an increasing number of ESBLs in community acquired UTIs. The clinical significance of ESBL infections is that they are associated with an increased risk of clinical treatment failure, mainly due to the limited number of agents available to combat these organisms. ESBL infections are associated with longer hospital stays and higher cost of treatment.

What is the treatment of infections due to ESBL-producing organisms?
Given the ability of ESBLs to hydrolyze many β-lactam antibiotics, it is not surprising that antibiotic choices for these infections are critically reduced. To complicate things further, many of the bacteria that are ESBL-producers also contain plasmids bearing genes encoding resistance to aminoglycosides and trimethoprim/ sulfamethoxazole (TMP/SMX). There is also a strong association between quinolone resistance and ESBL production.

β-lactam/ β-lactamase inhibitor combinations such as ampicillin/clavulanate and piperacillin/tazobactam are usually active against organisms possessing a single ESBL, however many organisms now produce multiple ESBLs, which may reduce the effectiveness of β-lactam/ β-lactamase inhibitor combinations. Also, β-lactam/β-lactamase inhibitor combinations are subject to rising MICs (minumun inhibitory concentrations) as inoculum rises. In addition, there is limited successful clinical experience in the literature in using these agents in the treatment of serious infections due to ESBL-producing organisms. Overall, these agents are not suitable as first-line agents for serious infections caused by ESBL-producing organisms.

With respect to cephamycins, although there is good in-vitro activity, selection of mutants has occurred during therapy, resulting in resistance and relapse of infection.

For serious infections caused by ESBLs, the carbapenems should be regarded as the drugs of choice. Invitro, this class has the most consistent activity against ESBLs since they are not hydrolyzed by ESBLs. Carbapenems have been associated with the best outcomes in terms of survival and bacteriologic clearance. Ertapenem should be considered if pseudomonal coverage is not needed. It is also an attractive outpatient IV therapy agent as it is dosed q12-24h in pediatric patients. Alternative therapy, based on susceptibility, can be a quinolone containing regimen (i.e. ciprofloxacin plus metronidazole for intra-abdominal infection), providing that the organism is not resistant to quinolones.

For the treatment of community-acquired UTIs caused by ESBL-producing organisms, oral therapy choices are often limited. Oral options include TMP/SMX and ciprofloxacin, if susceptible. Nitrofurantoin and fosfomycin have also been shown in the published literature to have in-vitro susceptibility and should be considered as alternative oral treatment options for uncomplicated UTIs.

LABORATORY DIAGNOSIS OF INFECTIOUS DISEASES

Laboratory Diagnosis of RSV Infection

Should laboratory testing be used to make the diagnosis of RSV infection?

AAP makes the following recommendations on the use of RSV diagnostic tests:

"Clinicians should diagnose bronchiolitis and assess disease severity on the basis of history and physical examination. Clinicians should not routinely order laboratory and radiologic studies for diagnosis. The clinical utility of diagnostic testing in infants with suspected bronchiolitis is not well supported by evidence. However, the knowledge gained from such testing rarely alters management decisions or outcomes for the vast majority of children with clinically diagnosed bronchiolitis. Virologic testing may be useful when cohorting of patients is feasible"¹.

Importance of RSV laboratory testing:
Two issues arise with regards to the AAP recommendations. The first is that, while RSV is the most frequent cause of bronchiolitis, influenza (which is treatable) may also cause bronchiolitis, although much less frequently²,³. The second is that RSV diagnostic test results help determine the regional epidemiology of RSV, that is, the onset and completion of RSV season. The knowledge of the duration of RSV season helps determine when neonates and infants at risk of RSV should receive RSV prophylaxis. This is particularly important in Florida, where the RSV season varies from the rest of the U.S.

Specific RSV laboratory tests:

Viral culture:

The gold standard for the laboratory diagnosis of RSV infection has been the inoculation of cell cultures with detection of characteristic cytopathic effects after several days incubation (range, 3-14 days). The efficiency of this method of laboratory diagnosis is limited by the relative lability of the virus while in transit to the laboratory.

Samples for RSV culture should be secretions obtained by either nasopharyngeal wash or aspirate so that sufficient infectious virus necessary for identification by culture can be collected.

The use of nasal swabs for specimen collection results in a significant decrease in sensitivity. This is because RSV is a relatively labile virus, and the amount of live virus in a small-volume nasal swab specimen may be critically less than that in a sample obtained by aspiration4. In children with respiratory syncytial virus (RSV) infection, the rate of detection of RSV by culture in nasopharyngeal aspirates (97%) was significantly higher than that in nasal swabs (76%; P </= 0.001)5.

Caveats regarding RSV culture:

  • Detectable amounts of virus are usually only shed for the first few days of an infection but immunosuppressed patients may have prolonged shedding.
  • Secretions obtained by either wash or aspirate contain the infectious virus necessary for identification by culture
  • NP swabs may be yield false negative results.
  • Throat swabs are not acceptable.

Rapid Antigen Tests
Several rapid direct antigen tests for the detection of RSV are available commercially for use in the clinician's office. Results may be available within 15 minutes to several hours, depending on the specific test used.

All rapid antigen tests detect one or two RSV-specific antigens on the surface of exfoliated epithelial cell that line the nasopharynx via immunofluorescence or enzyme-linked immunosorbent detection techniques.

Validated sensitivity and specificity varies with the specific rapid antigen test and ranges from 57 to 94% for sensitivity and from 69 to 95% for specificity as compared to culture. The sensitivity is increased if the sample is collected by NP aspirate or wash, if the quality of the sample is good (no blood, little mucoid material), if the sample is obtained early in the course of illness (shedding of RSV is greatest in the first few days of illness), if the sample is taken during RSV season (increased pretest probability), and the age of the patient is less than 5 years.

Caveats regarding RSV rapid antigen tests:

  • Detectable amounts of virus are usually only shed for the first few days of an infection but immunosuppressed patients may have prolonged shedding.
  • Suitable specimens are nasal aspirate or wash because they contain the infected exfoliated NP cells required for identification.
  • Throat swabs are not acceptable.
  • NP swabs may be yield false negative results.
  • Excessively mucoid specimens may fail to be absorbed into the test membrane or may yield uninterpretable results.
  • Specimens containing blood have been found to yield uninterpretable or false positive results.
  • Assay performance characteristics are not established for use on specimens from patients greater than or equal to 5 years old.

Direct fluorescent antibody (DFA) staining assay
DFA testing is performed by fixing RSV infected cells on a slide, incubating the slides with RSV-specific antibodies and then using an immunofluorescent detection system. Therefore, as with the rapid antigen tests, the sensitivity of the DFA tests depends on the quality of the material collected. In addition, the sensitivity and specificity are dependent upon the skill of the microscopist. When performed properly, the sensitivity and specificity of RSV rapid antigen detection by DFA were 90% and 99%, respectively, compared with viral culture6.

Caveats regarding RSV DFA tests:

  • Detectable amounts of virus are usually only shed for the first few days of an infection but immunosuppressed patients may have prolonged shedding.
  • Secretions obtained by either wash or aspirate contain the exfoliated NP cells if viral antigen detection methods are used.
  • Throat swabs are not acceptable. NP swabs may be yield false negative results.
  • The sensitivity and specificity are dependent upon the skill of the microscopist.

RT-PCR (Nucleic acid assays)
Molecular assays are highly sensitive and highly specific (both approach 100%) when compared with cell culture or antigen assays (4). Specimens are collected via nasopharygeal swab. Several FDA- approved RT-PCR kits provide results within several hours. There is no limitation with regards to the age of the patient and, in fact, is useful in the detection of RSV in patients with low RSV viral loads such as neonates and adults.

The exquisite sensitivity of the test is problematic in certain situations because it extends the time the virus may be detected in specimens compared to other methods. For example, if a child is RSV-positive by RT-PCR, it may mean that the child is acutely infected with RSV or has been ill recently with RSV. While almost all children are negative by RT-PCR after 14–21 days, a few children will remain positive for up to 4 weeks.

Some RT-PCR RSV testing kits simultaneously detect other respiratory viruses such as influenza A and B.

Caveats regarding RSV PCR tests:

  • Prolonged positive PCR test results in some patients

References

  1. American Academy of Pediatrics. Diagnosis and Management of Bronchiolitis Subcommittee on Diagnosis and Management of Bronchiolitis PEDIATRICS Vol. 118 No. 4 October 2006, pp. 1774-1793.
  2. Antunes H, Rodrigues H, Silva N, Ferreira C, Carvalho F, Ramalho H, Gonšalves A, Branca F. Etiology of bronchiolitis in a hospitalized pediatric population: prospective multicenter study. Clin Virol. 2010 Jun;48(2):134-6.
  3. Miron D, Srugo I, Kra-Oz Z, Keness Y, Wolf D, Amirav I, Kassis I. Sole pathogen in acute bronchiolitis: is there a role for other organisms apart from respiratory syncytial virus?. Pediatr Infect Dis J. 2010 Jan;29(1):e7-e10.
  4. Kelly J. Henrickson, MD,* and Caroline Breese Hall, MD. Diagnostic Assays for Respiratory Syncytial Virus Disease. The Pediatric Infectious Disease Journal. 2007 Nov 26(11 Suppl):S36-40.
  5. Heikkinen T, Marttila J, Salmi AA, Ruuskanen O. Nasal swab versus nasopharyngeal aspirate for isolation of respiratory viruses. J Clin Microbiol. 2002 Nov;40(11):4337-9.
  6. Shetty,AK, Treynor, E,Hill,DW, et al: Comparison of conventional viral cultures with direct fluorescent antibody stains for diagnosis of community-acquired respiratory virus infections in hospitalized children. Pediatr Infect Dis J. 2003;22:789-794.